Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH2:22][C:21]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=2)=[CH:10][CH:9]=1)=[O:7].[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:29]1[CH:28]=[C:27]([C:21]2([C:23]([F:25])([F:24])[F:26])[O:20][N:19]=[C:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:35])=[O:2])=[O:7])=[CH:9][CH:10]=3)[CH2:22]2)[CH:32]=[C:31]([Cl:33])[CH:30]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of N-[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine methyl ester (i.e. the title product of Step A) (620 mg) in tetrahydrofuran (5 mL) was added an aqueous solution of lithium hydroxide (300 mg in 5 mL of water). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with hexane. The aqueous layer was acidified with 6.0 N HCl to pH=2, causing a white precipitate to form. The aqueous mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and concentrated to afford the title compound as a white solid (600 mg, 99% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][S:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH:16]=1)(=[O:13])=[O:12]>C(OCC)C.[OH-].[Na+]>[CH3:10][S:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:17]([C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=1)(=[O:13])=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(COC(=O)c1ccccc1)c1cc(OS(C)(=O)=O)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl chloride (5.6 g) in diethyl ether (50 ml) was added dropwise with vigorous stirring to a solution of 3-(2-hydroxy-1,1-dimethylethyl)-4-hydroxyphenyl methanesulphonate in aqueous sodium hydroxide solution (1.6 g in 100 ml water). The mixture was stirred for three hours at room temperature, then separated, and the ether solution washed with dilute sodium hydroxide solution followed by water. Drying over magnesium sulphate and running down gave 4.5 g of an oil. Crystallisation from ethanol gave 0.7 g of 3-(2-benzoyloxy-1,1-dimethyl-ethyl)-4-benzoyloxyphenyl methanesulphonate, m.p. 100°-101° C. Removal of the solvent from the mother liquors gave 2.5 g of 3-(2-benzoyloxy-1,1-dimethyl-ethyl)-4-hydroxyphenyl methanesulphonate as a viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[C:13]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=3)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:21]([NH:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:19])[CH:18]=[C:9]([C:8]3[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[O:10]2)=[CH:15][CH:14]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2cc(=O)c3ccc(NC(C)=O)cc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(=O)cc(-c3ccc(C(=O)O)cc3)oc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6 g of 7-acetamido-4'-flavonecarboxylic acid methyl ester are dissolved in 600 cc of dioxane. 12 g of sodium carbonate, dissolved in 250 cc of water, are added and the mixture is heated at 100° C. with stirring until the reaction is complete, for about 8 hours. The reaction is checked by plate chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Cl[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:18]=[N:17][N:16]=3)[CH:3]=2)[C:7](=[O:11])[NH:6]1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC1(C)NC(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)c2ccc(Oc3nnnn3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of lactam 62 (1.77 g, 10.0 mmol) and 5-chloro-1phenyl-1H-tetrazole (2.17 g, 12.0 mmol) in dry DMF (50 mL) is treated with solid K2CO3 (2.07 g, 15.0 mmol). The mixture is stirred overnight at rt, then poured into water and extracted with EtOAc (2×). The organic phase is washed with water (3×) and brine (2×), then dried (MgSO4), filtered, and evaporated. The residue is crystallized from CH2Cl2 to give a white solid, mp 202-204° C. The material weighs 3.10 g (97% yield) . 1H NMR (CDCl3) 7.90 (d, 1, J=8.3), 7.80 (m, 2), 7.60-7.55 (m, 4), 7.50-7.45 (m, 1), 6.78 (s, 1), 1.59 (s, 6); 13C NMR (CDCl3) 168.45, 158.80, 156.15, 155.27, 132.83, 129.81, 128.77, 125.78, 122.33, 119.44, 112.11, 59.14, 53.39, 27.59; MS (MW=321.3, EI, eE=70 eV) m/z 321 (M+), 306, 293, 278, 261, 250, 236, 222, 208, 187, 176, 161 (base peak), 145, 133, 117, 103, 91, 77, 65, 42.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH3:20].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 3.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 1.8 g of 1-bromopropane, 2.5 g of sodium bicarbonate and 30 ml of dimethylformamide was stirred and heated at 60° for 2 hr. After stirring at ambient temperature for 14 hr, the reaction was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate yielded 2.3 g (63%) of product. This material was combined with a sample from another experiment and recrystallized from ethyl acetate to yield the analytical sample, mp 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[OH-].[Na+]>[Ni].C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2ccc(O)cc12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1CC(O)CC2
Temperature: 85 °C

Procedure:
A hydrogenation reaction vessel was charged with 8-aminonaphthalen-2-ol (Aldrich, 5.0 g, 31.4 mmol), 50% w/w sodium hydroxide (0.2 g, 2.5 mmol) and Raney nickel (slurry in water, 40% weight load, 2.0 g) in ethanol (100 mL). The vessel was purged with hydrogen gas several times before sealing under a hydrogen atmosphere at a pressure of 1300 psi followed by heating to 85° C. After 6 hours the mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.44-1.68 (m, 1H), 1.79-1.94 (m, 1H), 2.20 (dd, J=16.48, 7.63 Hz, 1H), 2.56-2.85 (m, 3H), 3.85-3.99 (m, 1H), 4.63 (s, 2H), 4.75 (d, J=4.12 Hz, 1H), 6.30 (d, J=7.48 Hz, 1H), 6.44 (d, J=7.78 Hz, 1H), 6.78 (t, J=7.63 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm 27.35, 31.41, 33.36, 65.81, 111.35, 116.48, 119.13, 125.53, 136.00, 146.12. MS (DCI) m/z 164.06 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:19](Cl)[CH:20]=[CH:21][CH3:22]>C(O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:20]=[CH:21][CH3:22]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC=CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC=CCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
8.6 g of 4′-hydroxy-4-biphenylcarboxylic acid was added to hydrous ethanol containing 5.3 g of potassium hydroxide dissolved therein, followed by stirring at room temperature for 30 minutes. While heating at reflux, 5.5 g of crotyl chloride was added dropwise, followed by heating at reflux for 2 hours. After the completion of the reaction, ethanol was distilled off under reduced pressure and 50 ml of 18% HCl was added to deposit a crystal. The deposited crystal was collected by filtration, washed with water and then dried under reduced pressure to obtain 5.3 g of 4′-(2-butenyloxy)-4-biphenylcarboxylic acid (XI-k). Excess thionyl chloride was added, followed by heating at reflux for 2 hours. After the completion of the reaction, excess thionyl chloride was distilled off under reduced pressure. Then, 30 ml of pyrimidine and 2.6 g of (R)-1-(3-methoxyphenyl)ethanol (XI-l) were added to the resulting crude product and the reaction was conducted at 50° C. for one hour. After the completion of the reaction, the reaction product was extracted with toluene in the presence of hydrochloric acid, washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain 5.1 g of 1-(3-methoxyphenyl)ethyl (R)-4′-(2-butenyloxy)-4-biphenylcarboxylate (R-isomer of the compound represented by the formula (XI-m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (15.4 g, 45.1 mmol) in dichloromethane (150 mL) at 0° C. was added mCPBA (approximately 77% purity, 19.7 g, 87.9 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours, then concentrated ammonium hydroxide (50 mL) was added. p-Toluenesulfonyl chloride was added in portions to the mixture, which was stirred for 1 hour then filtered. The filtrate was transferred to a separatory funnel, saturated aqueous sodium bicarbonate (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with 5% aqueous sodium hydroxide (2×75 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to yield a brown solid that was slurried in ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the solid was recrystallized from ethanol/water four times, then was dissolved in dichloromethane (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), then was concentrated under reduced pressure to yield a solid that was recrystallized from ethanol/water three times. The crystals were dried in a vacuum oven at 70° C. to provide ethyl 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as pale yellow crystals, mp 129-131° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(N(C(C)C)CC)(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:8][C:6]1[CH:7]=[C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=[C:4]([F:11])[C:5]=1[O:9][CH3:10]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(F)cc(C#C[Si](C)(C)C)cc1F
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 2 g 5-bromo-1,3-difluoro-2-methoxy-benzene, 1.76 g ethynyl-trimethyl-silane, 629 mg bis(triphenylphosphine)palladium(II) dichloride, 3.1 ml diisopropylethylamine, and 85 mg copper iodide in 20 ml acetonitrile was degassed then heated at 80° C. for 2 hours. The mixture was diluted with dichloromethane and filtered through a plug of silica, washed with dilute ammonia and brine then dried over sodium sulphate, filtered and concentrated in vacuo. Purification over silica afforded 1.71 g (3,5-difluoro-4-methoxy-phenylethynyl)-trimethyl-silane.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][N:11]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([C:15]([F:14])([F:32])[F:33])=[CH:17][CH:18]=4)=[CH:23][CH:24]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-trifluoromethylbenzoyl)benzyl bromide (755 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 3 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as light-brown powder (436 mg, yield 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 78.2 %

Procedure:
A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 34) tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5–66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M++1; Calc'd 576.2, Found, 576.3.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17](Cl)[N:16]=[N:15][C:14]=3[C:20]([NH2:22])=[O:21])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.O>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]4[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:16]=[N:15][C:14]=3[C:20](=[O:21])[NH2:22])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(-n3cccn3)n2)c(C(N)=O)nn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a solution of 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (131 mg, 415 μmol) in NMP (5 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture stirred at 140° C. for 24 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (162 mg, 756 μmol) was added and the mixture heated at 140° C. for a further 24 h. The reaction mixture was cooled, and then diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) then the combined organic phases were washed with brine (50 mL), then concentrated in vacuo, and finally purified by chromatography (silica, 12 g RediSep Gold, 2 to 6% of a 99.5:0.5 methanol:ammonium hydroxide solution in dichloromethane, 20 min) to give tert-butyl (1S,2R)-2-(5-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-carbamoylpyridazin-3-ylamino)cyclohexylcarbamate (70 mg, 142 μmol, 34%) as a beige solid. MS (EI/CI) m/z: 494.3 [M+H].
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (8.1 g, 50 mmol) in THF (20 mL) at 10° C. was added a 1 M solution of 4-fluorophenyl magnesium bromide in THF (65 mL, 65 mmol). The resulting mixture was stirred at room temperature for 2 hours before quenching with saturated NH4Cl solution. The solution was extracted with EtOAc 3 times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was taken up in toluene (80 mL). To it was added p-toluenesulfonic acid monohydrate (80 mg). The mixture was stirred at reflux with removal of water using a Dean-Stark trap for 2 hours. The resulting solution was washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5%, 10% and then 15% EtOAc in hexanes provided the title compound (8.8 g, 75%) as a solid. MS calculated (M+H)+235. Found 235.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: [I-]
Reactant: O=C(O)CCCCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCI
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a mechanically stirred solution of 10-bromodecanoic acid (50 g, 0.2 mol) in 1 L of acetone under nitrogen was added sodium iodide (238.7 g, 1.59 mol) and the resulting heterogeneous reaction mixture was allowed to stir at room temperature for 18 h. The thick reaction mixture was filtered through a pad of Celite 521, concentrated in vacuo to one-fifth volume and diluted with 1 L of brine. This was extracted with 4×250 mL of hexanes. The combined organic extracts were washed with 2×250 mL of freshly prepared 10% aqueous sodium thiosulfate, dried over sodium sulfate, concentrated in vacuo and vacuum dried to give iodo acid 2 (57.5 g, 98%) as a white solid:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=O)=[N:5]1)([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:18][NH2:19])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1nn(C(C)C)c2ccccc12
Solvent: O
Solvent: CCO
Product: CC(C)n1nc(C(=O)NN)c2ccccc21
Yield: 6715.2 %

Procedure:
To a stirred solution of methyl 1-isopropyl-1H-indazol-3-yl carboxylate (40.0 grams, 183.5 mmol, obtained in above step) in ethanol at room temperature hydrazine hydrate (130 mL, 2.56 mmol) was added. The reaction mixture was refluxed for 2 hours. The volatiles were removed under reduced pressure and the crude mass was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain the title compound (37.52 grams).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1
Reactant: NS(=O)(=O)Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CS(N)(=O)=O
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.028 g, 0.094 mmol) in dimethylformamide (1 mL) was added (5-chloro-2-hydroxy-phenyl)-methanesulfonamide (0.023 g, 0.10 mmol), potassium carbonate (0.026 g, 0.19 mmol) and potassium iodide (0.016 g, 0.094 mmol). The reaction was heated at 60° C. for 17 hours, cooled, diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.014 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CCNCC
Solvent: CO
Product: C[C@H](N[C@@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1R)-6-Bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 19.8 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 10.08 (s, 1H), 9.64 (s, 1H), 7.86 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.55-7.45 (m, 3H), 7.42 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.75 (m, J=6.4 Hz, 1H), 4.57 (t, J=4.4 Hz, 1H), 3.47-3.37 (m, 2H), 2.70-2.64 (m, 2H), 2.13-2.07 (m, 2H) 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.32; H, 5.58; N, 6.97.