Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1)#[N:2].[ClH:23]>O1CCOCC1>[ClH:23].[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.24 g (3.4 mmol) of tert-butyl 3-[(5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate (Example 35A) were dissolved in 4.3 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 3 h. After the reaction had gone to completion, the solvent was removed completely. This gave 1.74 g (90% of theory) of the product as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:11])[CH:6]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2ccccc12
Solvent: CC#N
Product: Oc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of naphthol (12, 5.0 g, 35 mmol) in CH3CN (125 mL) at 0° C. was added N-bromosuccinimide (7.9 g, 45 mmole) in several portions. The reaction mixture was warmed to room temperature, stirred for 1 h, and concentrated. The residue was dissolved in EtOAc (500 mL) and the solution was washed with water (300 mL) and brine (300 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 4:1 hexanes/EtOAc) to afford 4-bromonaphthol (13, 5.0 g, 64%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.22-8.16 (m, 2H), 7.62-7.26 (m, 3H), 6.71 (d, J=8.0 Hz, 1H), 5.46 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].B.CO.Cl>O1CCCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
A mixture of 4-methoxycarbonyl-3-nitrobenzoic acid (2.25 g), 1M borane in tetrahydrofuran solution (50 ml) and dry tetrahydrofuran (45 ml) was stirred at room temperature for 48 hours. To this mixture, methanol (2 ml) and 1N hydrochloric acid (10 ml) were added and then the solvents were evaporated off. The crude residue was taken up with ethyl acetate, washed in turn with water and sat. sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give an oil which was chromatographed on silica gel. Elution with toluene-chloroform (1:1) gave methyl 4-hydroxymethyl-2-nitrobenzoate (1.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].CCN(CC)CC.[Br:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)[CH:9]=1)=[O:4]
Reactant: Sc1cccc(Br)c1
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Sc2cccc(Br)c2)c([N+](=O)[O-])s1
Yield: 99.8 %

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.75 mmol) and Et3N (523 μL, 3.75 mmol) were dissolved with THF (10 mL) into a round bottom flask with stir bar. To this 3-bromothiophenol (467 μL, 4.51 mmol) was added with stirring. The reaction became turbid therefore additional THF (12 mL) was added. The reaction was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3 and brine. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (1.40 g, quantitative yield), which was used without further purification. 1H-NMR (CDCl3): δ 7.79 (t, 1H, J=1.8 Hz), 7.67–7.70 (m, 1H), 7.54–7.85 (m, 1H), 7.37–7.41 (t, 1H, J=7.9 Hz), 6.87 (s, 1H), 3.88 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](=[O:7])[N:6]=1.[CH2:8](O)[CH:9]([CH3:11])[CH3:10]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CO
Reactant: O=C1C=CC(O)=N1
Product: CC(C)COC1C=CC(=O)N1
Temperature: 50 °C

Procedure:
A mixture of 3 g of 5-hydroxy-2H-pyrrol-2-one and 1.5 g of Amberlite IR 120 H in 60 cm3 of isobutanol, is heated to 50° C. for 3 hours, then cooled and filtered, and the solvent is evaporated. After chromatographing the residue on silica (eluent: ethyl acetate), 4 g of the expected product is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C.[Pd]>[Cl:32][C:27]1[CH:26]=[C:25]([CH:12]2[C:11]3[C:16](=[CH:17][C:8]([C:5]4[N:6]=[N:7][CH:2]=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH2:15][NH:14][CH2:13]2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(-c3ccc(Cl)nn3)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc(C2CNCc3cc(-c4cccnn4)ccc32)cc1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of tert-butyl 7-(6-chloropyridazin-3-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (259 mg, 0.52 mmol) in ethanol (15 mL) was added 10% palladium on carbon (80 mg) and hydrazine hydrate (128 mL, 2.60 mmol). The reaction mixture was heated at 75° C. for 1 hour under a nitrogen atmosphere. An additional quantity of hydrazine hydrate (128 mL, 2.60 mmol) was added and the reaction mixture heated at 75° C. for 3 hours 10% palladium on carbon (80 mg) was additionally added and the heating continued for another 2 hours. The reaction mixture was filtered through a celite pad and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (10 mL) at ambient temperature for 1 hour. After concentration in vacuo the residue was partitioned between dichloromethane (50 mL) and 2N sodium hydroxide solution. The organic layer was washed with brine then dried over sodium sulfate. Concentration in vacuo gave the crude material which was purified by flash column chromatography ((95:5 to 50:50 ethyl acetate/ethyl acetate:methanol:ammonium hydroxide, 80:18:2 v/v) to give 4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (144 mg, 77%): [α]D=+19.2° (0.06, methanol): 1H NMR (CDCl3, 300 MHz) δ 9.15 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.85 (dd, J=8.5 Hz, 1.5 Hz, 1H), 7.77 (dd, J=8.3 Hz, 2.0 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.99 (dd, J=8.3 Hz, 2.0 Hz, 1H), 4.15-4.11 (m, 3H), 3.44 (dd, J=12.8 Hz, 5.5 Hz, 1H), 3.10 (dd, J=13.0 Hz, 6.0 Hz, 1H), 1.95 (br s, 1H); ESI MS m/z 356 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:9]1([O:14][CH2:13][CH2:12][O:11]1)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)C1(C)OCCO1
Yield: 55.8 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 10 g), ethylene glycol (19.75 g) and p-toluenesulfonic acid (0.3 g) and dried benzene (150 ml) was heated for 2 hours under reflux while removing water azeotropically. The reaction mixture was washed with water (50 ml), a saturated aqueous solution of sodium bicarbonate (50 ml), water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) in turn, dried over magnesium sulfate and then filtered. The filtrate was evaporated to give an oil of ethyl 2-hydroxyimino-3,3-ethylenedioxybutyrate (syn isomer, 7.12 g). (Yield: 55.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[CH:6]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:20]1([S:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH2:14][C:15]3[NH:19][CH:18]=[CH:17][N:16]=3)=[CH:6]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(NCCCn1cc(Cc2ncc[nH]2)c2ccccc21)c1ccccc1
Yield: 29.5 %

Procedure:
A mixture of 1-(3-aminopropyl)-3-(1-imidazolylmethyl)indole (1.27 g) and benzenesulphonyl chloride (0.88 g) in pyridine (15 ml) was heated on a steam bath for 2 hours and then evaporated to dryness. The residue was treated with an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. The column was first eluted with chloroform to remove a small amount of impurity and then the product was eluted with a mixture of chloroform and methanol (20:1). Evaporation of the product containing fractions gave an oil which crystallised on standing. The product was recrystallised from ethyl acetate containing a trace of methanol to give 1-(3-benzenesulphonylaminopropyl)-3-(1-imidazolylmethyl)indole (0.58 g), m.p. 130°-131° C. Found: C, 63.71; H, 5.58; N, 14.03. C21H22N4O2S requires: C, 63.93; H, 5.62; N, 14.20.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCN(CC)CC.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>[CH3:17][C:14]1[N:13]=[C:12]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C#C[Si](C)(C)C)cc2)c(C)c1

Procedure:
[3-(4-Bromobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine, prepared as described in Example 46, (100 mg, 0.225 mmol), Pd(PPh3)2Cl2 (7.9 mg, 0.011 mmol), CuI (2.1 mg, 0.011 mmol) and trimethylsilylacetylene (0.038 mL, 0.270 mmol) were heated at 50° C. in Et3N (0.5 mL) for 16 h. The reaction mixture was stripped in vacuo and the residue was chromatographed on silica gel using 10% EtOAc/hexanes as eluent to give 53 mg [6-methyl-3-(4-trimethylsilanylethynyl-benzenesulfonyl)-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[S:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[CH3:17][NH:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[S:16])[N:18]([CH3:17])[NH2:19])[CH:5]=[C:6]([Cl:13])[C:7]=1[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CNN
Reactant: CCN(CC)c1c(Cl)cc(N=C=S)cc1Cl
Solvent: CCO
Product: CCN(CC)c1c(Cl)cc(NC(=S)N(C)N)cc1Cl

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.2 g (0.0080 mole) of 3,5-dichloro-4-diethylaminophenyl isothiocyanate with 0.37 g (0.0080 mole) of methylhydrazine in 75 ml of ethanol produced a quantitative yield of 4-(3,5-dichloro-4-diethylaminophenyl)-2-methyl-3-thiosemicarbazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13](Cl)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:32][CH:31]=2)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: Brc1cn[nH]c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(Br)cn2)cc1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a suspension of 4-bromopyrazole (1.5 g, 10.2 mmol) and 4,4′,4″-trimethoxytrityl chloride (4.5 g, 12.2 mmol) in anhydrous DMF (20 mL) under argon was added triethylamine (3 mL, 21.5 mmol) and the mixture was cooled over an ice bath. After stirring for 10 min, the ice bath was removed and the reaction stirred for 2.5 hrs. The mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with H2O three times then saturated aqueous NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo. The crude oil was recrystallized from isopropanol to give 4-bromo-1-(tris(4-methoxyphenyl)methyl)-1H-pyrazole as off-white crystals (two batches; 2.55 g, 52% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][O-:28].[Na+]>CO>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([O:28][CH3:27])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Br)c2s1
Yield: 79 %

Procedure:
The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I) (90 mg, 0.195 mmol), NaOMe in MeOH (25% wt, 66 ul) in MeOH (3 ml) was heated at 50° C. for 20 min in sealed microwave vial. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65J (70 mg, 79%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH2:27].CCN(C(C)C)C(C)C>>[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1R,2R)-2-hydroxy-cyclohexylamine and DIEA to give 2-((1R,2R)-2-hydroxy-cyclohexylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 354 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[S:23][C:24]=1[C:25](Cl)=[O:26]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:25]([C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:21][C:20]=3[CH3:19])=[O:26])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: Cc1nc(-c2ccccn2)sc1C(=O)Cl
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Agent: Cl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4ccccn4)nc3C)CCC2)ccc1OC
Yield: 78.8 %

Procedure:
Analogously to Example 2, reaction of 1.1 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 1.2 g of 4-methyl-2-pyridin-2-ylthiazole-5-carbonyl chloride, hydrochloride (“BB”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone (1.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:44]([F:54])=[CH:45][C:46]([F:53])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[F:53][C:46]1[CH:45]=[C:44]([F:54])[C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)c(F)cc3F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0283 g, 0.0613 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.0482 g, 0.195 mmol) to obtain 4-(2,4-difluoro-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0117 g, yield 28%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:17])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.C([Li])(CC)C.CON(C)[C:26]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:26](=[O:27])[C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Reactant: CON(C)C(=O)c1ccsc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccsc2)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (38 mL) was added dropwise sec-butyllithium (1.00 mol/L hexane-cyclohexane solution, 18.5 mL) at −45° C., and this mixture was stirred for 30 minutes. Then, a solution of N-methoxy-N-methylthiophene-3-carboxamide (1.59 g) in tetrahydrofuran (4.1 mL) was added dropwise thereto, and this mixture was stirred at −45° C. for 30 minutes and at room temperature for additional 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.87 g). 1H-NMR (CDCl3) δ ppm: 1.53 (9H, s), 3.79 (3H, s), 4.08 (2H, s), 6.59 (1H, dd, J=2.8, 8.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.35 (1H, dd, J=2.8, 5.1 Hz), 7.43-7.56 (1H, br), 7.60 (1H, dd, J=1.3, 5.1 Hz), 7.80-8.10 (1H, br), 8.23 (1H, dd, J=1.3, 2.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](N)=[O:22])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:25].C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:25])=[O:22])=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nnc2ccc(Oc3ccc(CC(N)=O)cc3)cn12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)c1nnc2ccc(Oc3ccc(CC(=O)O)cc3)cn12

Procedure:
A solution of Example 23 step b (44 mg, 0.12 mmol), TFA (1 mL) and anisole (1 mL) in DCM (1 mL) was stirred at RT for 1 H, then evaporated in vacuo. The resulting residue was suspended in diethyl ether (3 mL), filtered and dried in vacuo to give the title compound (38 mg, quant.). LCMS (Method 5): Rt 3.65 min, m/z 312 [MH+].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][CH:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (27.7 g) in tetrahydrofuran (200 mL) was added 3M hydrochloric acid (200 mL), and the mixture was stirred at 60° C. for 15 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate, and neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized using ethyl acetate, and the resulting solid was collected by filtration, and dissolved in tetrahydrofuran (100 mL). This solution was added dropwise to a solution of lithium borohydride (2M tetrahydrofuran solution, 37 mL) in tetrahydrofuran (150 mL) at −5° C. over 30 min. After stirring for 1.5 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (21.1 g, 83%).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:45](C1SC(CNC2C=CC=C(C3C=C(NC4NN=C(C5CC5)C=4)C(=O)N(C)C=3)C=2CO[Si](C(C)(C)C)(C)C)=C(C(OC)=O)N=1)(C)(C)C>>[C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:8]([C:10]([O:12][CH3:45])=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Reactant: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3cc(C4CC4)n[nH]3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C
Product: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3ccncn3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C

Procedure:
Following the procedures as described for compound 125e and starting with methyl 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(5-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylate, 125d was obtained as a yellow solid (crude). LCMS: (M+H)+ 663.