Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-methoxyphenyl)acetate dihydrochloride (I106) (325 mg, 0.89 mmol) in DCM (10 ml), were added triethylamine (374 μl, 2.68 mmol) and benzoyl chloride (125 μl, 1.07 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-methoxyphenyl)acetate (145 mg; 41% yield). The product was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2]C(C)=O.[OH-].[Ca+2].[OH-].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].N>C(Cl)Cl.C(C(C)=O)C>[C:12]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)C(=O)Cl
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COC(=O)CC(=O)C(C)C
Yield: 94.3 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 122.6 g (1.15 mol) of isobutyryl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.2. This gave 136 g (GC purity 79.8%) of methyl isobutyrylacetate (yield 75.4%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.O=S(Cl)Cl.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].O>C(Cl)(Cl)Cl>[CH2:13]([N:15]([CH2:16][CH3:17])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:14]
Reactant: O=C(O)c1ccsc1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccsc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A solution of 5.0 g (39 mmol) of 3-thiophenecarboxylic acid (Aldrich Chemical Co.), to which was added 10 mL (134 mmol) of SOCl2 in 20 mL of CHCl3 was stirred at reflux for 3 hours. After cooling to room temperature, the solution was concentrated in vacuo. The residue was dissolved in 15 mL of methylene chloride, and the solution was cooled in an ice bath. To this was added dropwise 13 mL (126 mmol) of diethyl amine, and the reaction was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with methylene chloride, which was washed with aqueous NaHCO3 solution, water, and bdne, and concentrated to give 9.3 g of crude product. This material was purified by flash chromatography on silica gel, eluting with 6:1 hexane:ethyl acetate, to afford 6.34 g of the title product after removal of the solvents. NMR (CDCl3) δ:7.48 (dd, 1H, J=1, J=3 Hz), 7.32 (dd, 1H, J=3, J=6 Hz), 7.20 (dd, 1H, J=1, J=6 Hz), 3.60-3.30 (bs, 4H), 1.20 (bm, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1>CO.[Pt]>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Yield: 79.7 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl)-pyridine (2.4 g, 9.07 mmol) is suspended in MeOH (30 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 0.8 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture is stirred under hydrogen atmosphere until reaction is complete by TLC (ca 2 hours). The reaction mixture is filtered through a Celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO4) and concentrated to yield 1.7 g (7.23 mmol, 80%) of the desired product.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]#[C:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:20][C:21]#[C:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:6])=[CH:15][CH:14]=1
Reactant: Clc1ccc(SCC#CCOc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CC#CCOc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of m-chloroperoxybenzoic acid (55% purity; 81 g) in dichloromethane (1400 ml) was added dropwise over 2.5 hours to a stirred, ice-cold solution of the crude 1-(4-chlorophenylthio)-4-phenoxybut-2-yne (74.5 g) in dichloromethane (600 ml), then the mixture was stirred at ambient temperature for 18 hours and filtered. The filtrate was washed with 5% aqueous sodium carbonate solution (3×750 ml) and water (3×500 ml) then dried (Na2SO4), and the solvent removed in vacuo. The residue was dissolved in hot dichloromethane (40 ml), then petroleum ether (b.p. 60°-80° C.) (75 ml) was added, and the mixture was triturated to give a sticky solid which was collected by filtration, triturated with hot ether (500 ml), collected by filtration, and dried in vacuo to give 1-(4-chlorophenylsulphinyl)-4-phenoxybut-2-yne as a solid (21.73 g), m.p. 102°-103° C.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH3:13][CH:12]([CH3:14])[CH2:11][CH:5]([C:3]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:22][CH:2]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(CC(C)C)C(=O)CBr
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1csc(-c2ccccc2)n1

Procedure:
A solution comprised of ethyl 2-bromoacetyl-4-methylpentanoate (0.264 gm, 1 mmol) in ethanol (5 mL) was treated with thiobenzamide (0.15 gm, 1.1 mmol). The mixture was heated at refluxed for 1 hour and concentrated to provide ethyl 4-methyl-2-(2-phenylthiazol-4-yl)pentanoate as a crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[C:13](C1NC=CN=1)([C:15]1N[CH:17]=[CH:18][N:19]=1)=[O:14].N1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:19]3[CH2:15][CH2:13][O:14][CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCN1
Solvent: ClCCl
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Indole-6-carboxylic acid (0.60 g, 3.7 mmol) was dissolved in DCM (15 mL) and carbonyl diimidazole (0.63 g, 3.9 mmol) was added and the reaction mixture was refluxed under N2 for 30 min. The mixture was allowed to cool to room temperature before morpholine (0.39 g, 4.5 mmol) was added and the reaction mixture was refluxed for 16 hours. The mixture was allowed to cool to room temperature before it was washed in sequence with HCl (50 mL, 1 N in water), NaOH (50 mL, 1 N in water) and brine (50 mL). The organic phase was dried with MgSO4, and the solvent was removed in vacuo to give 0.74 g of (1H-indol-6-yl)-morpholin-4-yl-methanone.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([F:22])[C:19]([Br:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH2:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:25][CH3:26]>>[Br:23][C:19]1[C:20]([F:22])=[CH:21][C:7]2[N:6]3[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Fc1cc2c(cc1Br)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CCCN1CCNCC1
Product: CCCN1CCN(c2nnc3n2-c2cc(F)c(Br)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-9-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-propylpiperazine to give 8-bromo-9-fluoro-1-(4-propylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=C(C5C=CC=CC=5)C5C=CC=CC=5)[CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-]>O1CCCC1.CCOCC>[NH2:34][C:30]1[CH:29]=[C:28]([C:14]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]3[N:13]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(C(=Nc2cccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)c2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine (2.61 g, 4.22 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 4N hydrochloric acid (20 mL) dropwise. Subsequently, the reaction mixture was stirred for 5 minutes. The reaction mixture was diluted with ether, then saturated aqueous bicarbonate was added slowly till the ether layer turned clear. The resulting mixture was stirred for 30 minutes. The phases were separated, the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration of the filtrate to a solid, followed by recrystallization from ethyl acetate-hexanes, gave 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (1.78 g, 93%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.92 (d, 1H), 7.82 (d, 1H), 7.32 (t, 1H), 7.22 (m, 2H), 7.00–6.94 (m, 2H), 6.78 (m, 1H), 6.34 (d, 1H), 6.04 (m, 2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.75 (broad, 2H), 2.14–2.05 (m, 4H), 1.83–1.54 (m, 12H); MS m/z 454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1CCc2cc(N)c(OC)cc2CC1=O
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1=O
Yield: 36.2 %

Procedure:
Following a procedure similar to 247b, 7-amino-3-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (46 mg, 0.18 mmol) was reacted with N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (60.60 mg, 0.18 mmol), except that the product precipitated from the reaction mixture in the hydrochloride salt form, was collected by filtration, and then free-based by treatment of a solution of the salt in dichloromethane with aqueous saturated NaHCO3. The organic solution was dried (MgSO4), and concentrated to afford N-{(1R,2R)-2-[5-chloro-2-(3-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (35 mg, 36%) as a white solid. MP: 139-150° C.; 1H-NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (s, 1H), 7.33 (s, 1H), 6.65 (s, 1H), 5.25-5.40 (m, 2H), 3.95 (m, 1H), 3.88 (s, 3H), 3.84 (s, 2H), 3.73 (t, J=5.8 Hz, 2H), 3.48 (q, J=7.1 Hz, 2H), 3.25 (m, 1H), 3.12 (t, J=5.6 Hz, 2H), 2.80 (s, 3H), 2.20 (m, 2H), 1.80 (br s, 2H), 1.40 (s, 4H), 1.17 (t, J=7.1 Hz, 3H); LC/MS (ESI+): 537.31 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][O:32][CH3:33].O.CO>CN(C)C=O>[F:27][C:25]1[CH:26]=[C:21]([CH:22]=[C:23]([F:28])[CH:24]=1)[CH2:20][NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:30][CH2:31][O:32][CH3:33])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17]
Reactant: COCCBr
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1cc(F)cc(F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COCCNc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Yield: 30.5 %

Procedure:
37 mg of 6-[(4-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 67) and 14 mg of 2-bromoethyl methylether were dissolved in 0.3 mL of N,N-dimethylformamide, and stirred using a microwave reaction apparatus under an argon atmosphere at 120° C. for 20 minutes. After cooling, water was added to the reaction mixture, extracted with ethyl acetate, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=20:1, developed twice) to obtain 13 mg (yield: 29%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][C:3]=1[Cl:29].[Cl-].[C:31]([O:35][C:36](=[O:39])[CH2:37][Zn+])([CH3:34])([CH3:33])[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:27]=[CH:28][C:2]=1[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(Br)c(Cl)c3)CC2)nc1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC(C)(C)C)c(Cl)c3)CC2)nc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-{(1R,2S)-2-[2-(4-bromo-3-chlorophenoxy)ethyl]cyclopropyl}piperidin-1-yl)-5-(methoxymethyl)pyrimidine (0.91 g, 1.89 mmol) in THF (10 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (9.46 ml, 4.73 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.087 g, 0.189 mmol) and X-PHOS (0.090 g, 0.189 mmol) were added and the resulting mixture heated at 60° C. for 30 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 516 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:11][O:10][CH:9]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:8][CH2:7]1)(=O)C>N.CO>[OH:4][CH2:5][CH:6]1[CH2:11][O:10][CH:9]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:8][CH2:7]1
Reactant: CC(=O)OCC1CCC(n2cc(C)c(=O)[nH]c2=O)OC1
Agent: N
Solvent: CO
Product: Cc1cn(C2CCC(CO)CO2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 53.7 %

Procedure:
1-(5-Acetoxymethyltetrahydropyran-2-yl)thymine (0.07 g) was dissolved in a saturated ammonia solution in methanol, and the mixture stirred overnight. After removing the solvent by evaporation under reduced pressure from the mixture, the residue was purified on a silica gel column (eluent: chloroform/methanol=15/1) to obtain the desired product (0.032 g, 52%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5].[OH-].[Na+].[CH:11](Cl)(Cl)Cl>>[CH3:11][C:2]1[CH:1]=[CH:8][CH2:7][S:4](=[O:5])(=[O:6])[CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC1=CCS(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1=CS(=O)(=O)CC=C1

Procedure:
5-Methyl-2H-thiopyran-1,1-dioxide is prepared in three steps from 3-methyl-3-sulfolene using the method of Gaoni, J. Org. Chem., 46 (1981) 4502. Thus, 3-methyl-3-sulfolene is first reacted with chloroform and aqueous sodium hydroxide in the presence of a quaternary ammonium salt to give the dichlorocarbene adduct. Partial dehalogenation with lithium aluminum hydride in tetrahydrofuran gives the chlorocyclopropane. Finally, base-catalyzed ring expansion with lithium diisopropylamide gives the desired thiopyran dioxide compound (see Scheme 1, above).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][CH2:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[C:14]([C:13](=[O:19])[CH2:12][CH3:11])[C:15](=[O:18])[CH2:16][CH3:17])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: CCC(=O)CC(=O)CC
Reactant: N#Cc1cccc(C=O)c1
Product: CCC(=O)C(=Cc1cccc(C#N)c1)C(=O)CC

Procedure:
The procedure described in Example 19 was repeated by using 1.82 g 3-cyanobenzaldehyde and 3.5 g 3,5-heptanedione. Yield 0.4 g, mp 51°-52° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[OH2:10]>ClCCl>[CH3:1][Si:2]([O:10][Si:2]([CH3:9])([CH3:8])[CH3:1])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: O
Solvent: ClCCl
Product: C[Si](C)(C)O[Si](C)(C)C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of the alcohol 18 (200 mg) and N-(trimethylsilyl)imidazole (0.714 ml) in dichloromethane (13 ml) is stirred at room temperature for 16 hours. After water (4.9 ml) has been added, the mixture is left stirring for 20 minutes. The mixture is then extracted with ethyl acetate. The organic phases are washed with brine and dried. After concentration under vacuum, the residue is purified by chromatography on silica gel (230-400 mesh) (12% diethyl ether in hexane), to give 200 mg of derivative 15b (80% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:8])=[O:7].CO.Cl>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[CH2:12][OH:13])(=[O:8])=[O:7]
Reactant: COCCNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COCCNS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4.0 g of 3-[(2-methoxyethyl)aminosulfonyl]benzoic acid in 200 ml of tetrahydrofuran was added dropwise a solution of 1.07 M borane-tetrahydrofuran complex in 43.5 ml of tetrahydrofuran under ice-cooling, and this was stirred for 30 minutes, and stirred at room temperature overnight. After 40 ml of methanol was added dropwise under ice-cooling, 100 ml of 2 N hydrochloric acid was added dropwise. After warmed to room temperature, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.0 g of oily 3-[(2-methoxyethyl)aminosulfonyl]benzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1>C([O-])([O-])=O.[Na+].[Na+].CCO.C1(C)C=CC=CC=1.CCOC(C)=O.O.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>[Cl:13][C:14]1[N:15]=[N:16][C:17]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Clc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccc(Cl)nn2)cc1F
Temperature: 80 °C

Procedure:
A mixture of 3-fluoro-4-methoxyphenylboronic acid (10 g, 0.059 mol) and 3,6-dichloro-pyridazine (8.79 g, 0.059 mol) in 2 M Na2CO3/EtOH/toluene (80 mL/40 mL/200 mL) was bubbled through N2 for 5 min. Cat. Pd(PPh3)4 (3.47 g, 0.003 mol) was added under N2 and the reaction was heated to 80° C. for 16 h. The mixture was diluted with 200 mL of EtOAc and 40 mL of water. The organic phase was separated, washed with 80 mL of brine, dried over Na2SO4 and concentrated in vacuo. The solid obtained was washed with 50% EtOAc/hexane to provide off-white solid. MS (ESI pos. ion) m/z: 239.0 (M+H). Calc'd Exact Mass for C11H8ClFN2O: 238.65.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([Cl:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:15])[CH:13]=2)=[CH:6][C:5]([F:34])=[CH:4][N:3]=1.C[C:36]#[N:37]>O.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.[C-]#N.[Zn+2].[C-]#N>[Cl:27][C:24]([F:26])([F:25])[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:12]2[CH:13]=[C:8]([C:7]3[C:2]([C:36]#[N:37])=[N:3][CH:4]=[C:5]([F:34])[CH:6]=3)[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=2)=[O:15])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cnc2Cl)c1
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ncc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
(R)-2′-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-2-(3-hydroxypyrrolidin-1-yl)-[3,3′-bipyridine]-5-carboxamide (Example 288, 100 mg, 0.195 mmol), Pd(Ph3P)4 (22.51 mg, 0.019 mmol), zinc cyanide (114 mg, 0.974 mmol) were added to a vial, flushed with argon, treated with DMF (2 mL) and stirred for 18 h at 130° C. The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column NH2, from 16% to 21% in 6 min). The fractions containing product were combined and the solvent was evaporated off under reduced pressure to give a residue which was lyophilized in water/min. vol. MeCN to afford the title product as an off-white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=504.1/506.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.70-1.97 (m, 2H) 2.80-2.94 (m, 1H) 3.09-3.23 (m, 1H) 3.23-3.38 (m, 2H) 4.16-4.29 (m, 1H) 4.85-5.02 (m, 1H) 7.35 (d, J=8.47 Hz, 2H) 7.86 (d, J=8.28 Hz, 2H) 8.08-8.37 (m, 2H) 8.86 (d, J=6.96 Hz, 2H) 10.24 (br. s, 1H).
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]([CH3:25])[C:5](=[O:24])[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]([CH2:18][C:19]([O:21]C)=[O:20])[C:8]1=[O:23]>C1COCC1.O>[CH3:25][N:4]([CH3:3])[C:5](=[O:24])[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]1=[O:23]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)N(C)C)c2cc(C)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(c1)n(CC(=O)N(C)C)c(=O)n2CC(=O)O
Reaction time: 72 h

Procedure:
Lithium hydroxide (131 mg, 3.12 mmol) was added to a solution of methyl {3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step A (333 mg, 1.04 mmol) in THF (3 mL) and H2O (1 mL). After 72 h, H2O was added and the precipitate was collected by filtration to give the title compound. MS: nil/z=306 (M+1).