Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].Cl.[OH-].[Na+]>O.C1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([N:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)N1CCC(Nc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)N1CCC(N(C(=O)Cc2ccc(Cl)c(Cl)c2)c2ccc(Cl)cc2)CC1
Temperature: 40 °C

Procedure:
A suspension of 1.25 parts of sodium amide in 56 parts of benzene is stirred under nitrogen atmosphere and warmed to a temperature of 40° C. Then there is added dropwise a solution of 6 parts of N-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine in 56 parts of benzene. Upon completion, the whole is stirred and refluxed for 16h.45. The mixture is cooled to 25° C. and there is added a mixture of 7.8 parts of 3,4-dichlorobenzeneacetyl chloride in 88 parts of benzene. After stirring and refluxing for 2 additional hours, the reaction mixture is cooled and 80 parts of water are added. The whole is acidified with a diluted hydrochloric acid solution. The aqueous acid phase is alkalized with sodium hydroxide solution and the free base is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of 1,1'-oxybisethane and 120 parts of hexane. The solution is cooled overnight at -10° C., filtered from some impurities and the filtrate is evaporated again. The residue is dissolved in 120 parts of 1,1'-oxybisethane, treated with activated charcoal, filtered and evaporated. The latter residue is crystallized from hexane at -10° C., yielding 2.2 parts of 3,4-dichloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide; mp. 101.7° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].ClS([N:34]=[C:35]=[O:36])(=O)=O.O.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:34][C:35]([O:1][CH2:2][C@@H:3]1[CH2:8][C:7]([C:9]2[N:10]=[C:11]([S:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[S:12][CH:13]=2)=[CH:6][CH2:5][N:4]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:36]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1CO
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC=C(c2csc(SCc3ccc(OC)cc3)n2)C[C@H]1COC(N)=O
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of allyl (2S)-2-(hydroxymethyl)-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (75 mg, 0.17 mmol) in chloroform (1 ml) was added at 0–5° C. chlorosulfonylisocyanate (17 ml, 0.20 mmol). Three hours later, chlorosulfonylisocyanate (10 ml, 0.11 mmol) was further added thereto. Three hours later, to the mixture was added water and the mixture was stirred for 10 minutes. To the solution was added ethyl acetate and the solution was separated with a separating funnel. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic layer was removed in vacuo. The residue was purified with preparative TLC to give allyl (2S)-2-{[(aminocarbonyl)oxy]methyl}-4-{2-[(4-methoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-3,6-dihydro-1(2 H)-pyridinecarboxylate (74.5 mg, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>C(#N)C.C(OCC)(=O)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[NH:11]1[C:12]2[C:8](=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([C:17]4[CH:18]=[CH:19][C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:16]=4)[CH2:27][CH2:28]3)[CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: ClCCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCCCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-4-(4-indolyloxy)butane (prepared from 4-hydroxy-1H-indole and 1-bromo-4-chlorobutane), 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled and diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 48% overall yield as a tan solid. mp . 113°-115° C. FDMS m/e=398 (M+ of free base).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:13](OCC)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Al+3].[Li+].[Cl-].[Na+]>C(COC)OC>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([NH:10][CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13][OH:14])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccc(C)cc1)c1cccnc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)NC(CCO)c2cccnc2)cc1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
89.7 g (0.26 mole) of the sulfonamide was added to a suspension of 12.7 g (0.34 mole) of lithium aluminum tetrahydride in 1250 ml of dry glyme. The mixture was stirred and heated under reflux for 1.5 hours. A saturated sodium chloride solution was added at a temperature of from 0° to 5° C. and the mixture stirred and heated under reflux for 30 additional minutes. The insolubles were removed by filtration after standing overnight and the cake was washed with 200 ml of boiling glyme followed by two 250 ml aliquots of ethyl alcohol. The pH was adjusted to 7.8 with sodium bicarbonate and hydrogen chloride. Most of the glyme and alcohol were removed under reduced pressure and the resulting solid collected, washed with water and dried in a desiccator to yield 75.6 g (95.5% yield) of 3-(p-toluenesulfonamido)-3-(3-pyridyl)propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH2:11]([NH:12][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:23])[C:14]1[CH:22]=[CH:21][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reaction time: 0.17 h
Yield: 154.1 %

Procedure:
In a solution of 0.15 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-fluoro benzoic acid in 10 ml of dichloromethane, 0.3 ml of oxalyl chloride and 2 drops of N,N-dimethylformamide were added at room temperature, and stirred at the same temperature for 10 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, the remaining white solid was dissolved in 10 ml of chloroform, and 0.3 ml of benzylamine and then 0.3 ml of triethylamine were added under cooling with ice, after the completion of the addition, continued to stir at room temperature for further 20 minutes. After the completion of the reaction, 40 ml of water was poured in the reaction mixture, and extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][NH:17][CH2:16][CH2:15][N:14]([CH3:19])[C:13]=3[CH:20]=2)=[N:6][CH:7]=1.[C:33]([O:36][CH2:37][CH2:38]Br)(=[O:35])[CH3:34].C(N(CC)CC)C.CN(C=O)C>CO.ClCCl>[Cl:1][C:2]1[C:3]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:38][CH2:37][O:36][C:33](=[O:35])[CH3:34])[CH2:16][CH2:15][N:14]([CH3:19])[C:13]=3[CH:20]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: CN1CCNCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc2C1
Yield: 59.5 %

Procedure:
To 40 ml sure-seal reaction vial, N-{(1R,2R)-2-[5-chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (90 mg, 0.19 mmole), 2-bromoethyl acetate (36 mg, 0.21 mmole), triethylamine (0.3 ml, 2.1 mmoles), KI (10 mg, catalytic), and DMF (5 ml) were added. The reaction was heated to 70 C for 18 hours. The solvent was removed under vacuum to afford a brown solid. The desired product (64 mg, 54% yield) was isolated via column chromatography with dichloromethane and methanol as eluant. NMR 1H-(CDCl3)-δ-7.94 (s, 1H), 7.16 (d, 1H, J=7.58 Hz), 7.06 (d, 1H, J=8.08 Hz), 6.93 (s, 1H), 6.83 (s, 1H), 5.37 (d, 1H, J=7.58 Hz), 5.31 (d, 1H, J=7.58 Hz), 4.20 (t, 2H, J=5.81 Hz), 3.85-4.00 (m, 3H), 3.15-3.30 (m, 1H), 2.95-3.10 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.70 (t, 2H, J=6.13 Hz), 2.12-2.25 (m, 2H), 2.07 (s, 3H), 1.78-1.90 (m, 2H), 1.30-1.50 (m, 4H) LCMS (ESI+) 566.41 (M+H); MP=110-142° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:7][C:8]12[CH2:9][CH2:10][CH:11]3[CH:20]([CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=43)[CH:21]1[CH2:22][CH2:23][C:24]2=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC2C3CCc4cc(O)ccc4C3CCC12C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
Potassium tert-butoxide (220 mg, 1.96 mmol) was added to dry THF (5 ml) and stirred for 10 minutes to complete dissolution of the salt. Methyl triphenylphosphonium bromide (700 mg, 1.96 mmol) was added portionwise to the salt solution. Estrone (500 mg, 1.85 mmol) was dissolved in THF (5 ml) and added dropwise via a syringe to the bright yellow solution. After stirring at room temperature for 2 h, the reaction was heated at reflux overnight. The reaction was cooled, water added (10 ml) and the mixture extracted using ethyl acetate (3×10 ml). The combined organic fractions were combined, washed with water (2×10 ml) and brine (10 ml), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (SiO2 hexane:ethyl acetate 9:1) and recrystallisation from toluene/hexane afforded alkene 11 as a white crystalline solid (53 mg, 0.198 mmol, 11%). m.p. 130-132° C. (lit. m.p. 134-137° C.). δH (CDCl3) 0.82 (3H, s CH3), 1.20-1.62 (6H, m, alkyl H), 1.78-1.85 (1H, m, alkyl H), 1.90-1.99 (2H, m, alkyl H), 2.16-2.38 (3H, m, alkyl H), 2.50-2.59 (1H, m, alkyl H), 2.78-2.92 (2H, m, alkyl H), 4.50 (1H, s, OH), 4.67 (2H, t, J=2.0, olefinic H), 6.57 (1H, d, J=2.7, ArH-4), 6.63 (1H, dd, J=8.6, 2.7, ArH-2), 7.17 (1H, d, J=8.6, ArH-1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C@@H:28]([NH2:39])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:40])[C@@H:28]([NH:39][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 171 mg of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 300 mg of 4-((S)-2-Amino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 128 mg of HOBT and 160 mg of EDC was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The solid product was triturated with DCM and the precipitate was dried under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:15]=2[C:16]#[N:17])[C:7]([Cl:22])=[CH:6][C:5]=1[O:23][CH3:24].[OH-].C[Sn+](C)C>ClCCCl>[Cl:22][C:7]1[C:8]([C:10]2[CH:11]=[N:12][C:13]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:15]=2[C:16]#[N:17])=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:23][CH3:24])[CH:6]=1
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)O
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (1.2 g, 3.2 mmol) and trimethyltin hydroxide (1.75 g, 9.7 mmol) in 1,2-dichloroethane (50 mL) was heated to 80° C. in a sealed tube for 4 hrs. Additional 5.0 eq. of trimethyltin hydroxide was added and the mixture was heated for total of 48 hrs. The mixture was then cooled to rt, quenched with HCl (2N, 40 mL) and diluted with 1,2-dichloroethane. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with dichloromethane:methanol (9:1) to afford 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid (723 mg). NMR (CDCl3), 5, 8.82 (1H, s), 7.94 (1H, s), 7.81 (1H, s), 7.20 (1H, s), 3.90 (3H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>CN(C=O)C.ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:40][CH2:39][CH2:38][C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCCc1ccncc1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)NCCc4ccncc4)cc3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.1 %

Procedure:
A mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 0.1 mmol), 2-(pyridin-4-yl)ethanamine (15 mg, 0.12 mmol), EDCI (77 mg, 0.4 mmol), N-methyl-imidazole (33 mg, 0.4 mmol), dichloromethane (3 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, triturated with water (10 mL×3), and the residue purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1) to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(pyridin-4-yl)ethyl)benzamide (12 mg, 24%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.68 (s, 1H), 8.81 (s, 1H), 8.74-8.70 (m, 1H), 8.49-8.47 (m, 2H), 8.23 (s, 1H), 8.03-7.95 (m, 4 h), 7.68 (s, 1H), 7.46 (t, 1H, J=8.4 Hz), 7.30 (s, 1H), 7.29 (s, 1H), 6.75 (d, 1H, J=7.5 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.61-3.56 (m, 2H), 3.47-3.40 (m, 2H), 2.92 (t, 2H, J=6.6 Hz), 2.11-1.99 (m, 3H), 1.71 (s, 1H), 0.85 (d, 3H, J=6.6 Hz). LC-MS: [M+H]+, 519, tR=1.333 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.008 min.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1.[N+:10]([O-])([O-:12])=[O:11].[NH4+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.CCOCC.O>[N+:10]([C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12)([O-:12])=[O:11]
Reactant: c1ccn2nccc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cnn2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of pyrazolo[1,5-a]pyridine (2.36 g, 20.0 mmol) (Lober, S. et al J. Med. Chem. 2001, 44, 2691) in concentrated sulfuric acid (20.0 mL) was added the freshly prepared solution of ammonium nitrate (1.84 g, 23.0 mmol) in concentrated sulfuric acid (25.0 mL) dropwise at −5° C. The resulting mixture was stirred at 0° C. for 2 h and added dropwise to a solution of 4 N sodium hydroxide (200 mL) at 0° C. followed by the addition of sodium bicarbonate (60.0 g). Water and ether were added and separated. The aqueous solution was extracted with dichloromethane (2×). The combined organic solution was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 2.49 g (76%) of beige solid as the title compound: mp 179–182° C. (CH2Cl2/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.63 (dd, J=2.0, 6.9 Hz, 1H), 8.41 (dd, J=2.3, 8.9 Hz, 1H), 7.74 (dd, J=7.0, 8.9 Hz, 1H), 7.21 (dd, J=7.0, 7.0 Hz, 1H); IR (diffuse reflectance) 2480, 2465, 2417, 2392, 2350, 1636, 1512, 1479, 1464, 1408, 1288, 1252, 1194, 882, 773 cm−1; MS (EI) m/z 163 (M+); HRMS (FAB) calcd for C7H5N3O2+H 164.0460. found 164.0459; Anal. Calcd for C7H5N3O2: C, 51.54; H, 3.09; N, 25.76. Found: C, 51.42; H, 2.95; N, 25.71.
Reaction SMILES: C(N(CC)CC)C.CC1(C)C(C)(C)OBO1.I[C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:20](C(OC(C)(C)C)=O)[CH:19]=1.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[C:37]([NH2:45])[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[NH:20]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=[C:37]([NH2:45])[CH:36]=2)=[CH:19]1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cccnc21
Reactant: Nc1cc(Br)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OBOC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(-c2c[nH]c3ncccc23)c2ccccc2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.42 ml (3.00 mmol) of triethylamine and 0.22 ml (1.5 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane are added successively to a solution, kept under argon, of 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 344 mg (1.00 mmol) of tert-butyl 3-iodopyrrolo[2,3-b]pyridine-1-carboxylate in 5 ml of dioxane, and the mixture is stirred at 80° C. for 3 hours under argon. The reaction mixture is cooled to room temperature; 5 ml of methanol, 223 mg (1.0 mmol) of 4-bromoquinolin-2-amine and 823 mg (2.50 mmol) of caesium carbonate are added successively. The reaction mixture is stirred at 100° C. for 18 hours. The reaction mixture is cooled to room temperature, absorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/dilute aqueous ammonia as eluent: 4-(1H-pyrrolo-[2,3-b]pyridin-3-yl)quinolin-2-ylamine (“A1”) as pale-pink crystals; m.p. 244° C.; 1H-NMR (d6-DMSO, 500 MHz): δ [ppm]=6.45 (s, 2H), 6.88 (s, 1H), 7.10-7.15 (m, 1H), 7.16 (dd, J=7.9 Hz, J=4.7 Hz, 1H), 7.47-7.51 (m, 1H), 7.53-7.56 (m, 1H), 7.78-7.81 (m, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.89 (dd, J=7.9 Hz, J=1.6 Hz, 1H), 8.34 (dd, J=4.7 Hz, J=1.6 Hz, 1H), 12.2 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([O:15][C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:10][C:6]=3[CH:5]=2)[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2nc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C(F)(F)F)nc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
57 mg (0.26 mmol) 7-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ol and 46 mg (0.30 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 0.11 g (0.78 mmol) potassium carbonate were added and the mixture was stirred overnight at 70° C. The reaction mixture was combined with ice water. The substance was extracted with ethyl acetate and evaporated down i.vac. The crude product was purified by chromatography. The fractions containing product were combined and i evaporated down.vac. to leave the aqueous residue. This was neutralised with an aqueous 4M NaOH solution and extracted with ethyl acetate. The organic phase was evaporated down i.vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:23][Si](C(C)(C)C)(C)C)[C:9]2[N:13]([CH3:14])[C:12]([S:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].FC1C=C(C(O[Si](C(C)(C)C)(C)C)C2N(C)C(Cl)=NC=2)C=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[N:13]([CH3:14])[C:12]([S:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[N:11][CH:10]=2)[OH:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(Sc2ncc(C(O[Si](C)(C)C(C)(C)C)c3cccc(F)c3)n2C)CC1
Agent: Cn1c(C(O[Si](C)(C)C(C)(C)C)c2cccc(F)c2)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Sc2ncc(C(O)c3cccc(F)c3)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{5-[(3-Fluoro-phenyl)-(tert-butyl-dimethyl-silanyloxy)-methyl]-1-methyl-1H-imidazol-2-ylsulfanyl}-1-methyl-piperidine. To a 0° C. solution of 1-methyl-piperidine-thiol (1.5 equivalents) in THF (0.2 M) is added NaH (60% dispersion in oil, 1.5 equivalents). After 30 min, 5-[(3-fluoro-phenyl)-(tert-butyl-dimethyl-silanyloxy)-methyl]-2-chloro-1-methyl-1H-imidazole (1 equivalent) in THF (1 M) is added dropwise. The mixture is heated at reflux until HPLC analysis shows consumption of the starting material. The reaction mixture is cooled to rt, quenched with satd. aq. NH4Cl, and extracted with EtOAc (2×). The combined organic extracts are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by HPLC or flash column chromatography to provide the desired product.