Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:32])=[C:25]([C:28]([NH:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)C1C=CC=CC=1.[CH3:35]O>[Pd]>[CH3:33][C:13]1[CH:12]=[C:11]([CH3:34])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:32])=[C:25]([C:28]([N:30]([CH3:31])[CH3:35])=[O:29])[CH:26]=[CH:27][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CNC(=O)c1ccc2c(c1C)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CCO2
Reactant: CO
Agent: [Pd]
Product: Cc1cc(C)c(CN2CCOc3ccc(C(=O)N(C)C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-N,6-dimethyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide (130 g, 0.17 g, 0.36 mmol) and Pd/C (93 mg) in MeOH (15 mL) was stirred at room temperature under an H2 balloon for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (Example 130, 130 mg, 94%) as a white solid. 1H NMR (400 MHz, chloroform-d): δ 11.34 (s, 1H), 7.18-7.16 (d, 1H), 6.88-6.86 (d, 1H), 5.97 (s, 1H), 4.90-4.86 (d, 2H), 4.12 (s, 1H), 3.93 (s, 1H), 3.53 (s, 2H), 3.13 (s, 3H), 2.85 (s, 3H), 2.36-2.35 (d, 6H), 2.27 (s, 3H); MS 256.8 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH:15]=[C:14]([Cl:13])[CH:18]=[N:17]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2cc(Cl)cn2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, 4-chloropyrazole and cesium carbonate in NMP. EI-MS m/e (%): 269 (M{37Cl}+H+, 30). 267 (M{35Cl}+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:3]=1.O.[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH:18]([S:15]([CH2:14][C:4]1[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=[C:2]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:35][CH:34]=2)[N:3]=1)(=[O:17])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C

Procedure:
4-{2-Chloro-6-[(isopropylsulfonyl)methyl]pyrimidin-4-yl}morpholine (1.5 g, 4.69 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (36 mL). {4-[(Tert-butoxycarbonyl)amino]phenyl}boronic acid (1.67 g, 7.04 mmol), 2M sodium carbonate solution (12 mL) and dichlorobis(triphenylphosphine) palladium catalyst (165 mg, 0.23 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude oil was dissolved in DCM and filtered to remove insoluble material. A brown solid precipitated from the filtrates and the filtrates were filtered again. The solid was analysed and found to be the desired material (1.9 g).
Reaction SMILES: [CH3:1][C:2]1C=C[C:5]2[N:6]([C@@H:9]3[C@@H:16]4[C@@H:12]([CH2:13][N:14]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=5)[CH2:15]4)[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:29][C:30]1C=CC2N=CN([C@@H]3[C@@H]4[C@@H](CN(C5C=CC=C(C(F)(F)F)N=5)C4)CC3)C=2[CH:56]=1>>[C:3]1([C:4]2[N:8]=[CH:7][N:6]([C@@H:9]3[C@@H:16]4[C@@H:12]([CH2:13][N:14]([C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]=5)[CH2:15]4)[CH2:11][CH2:10]3)[CH:5]=2)[CH:2]=[CH:1][CH:56]=[CH:30][CH:29]=1
Reactant: Cc1ccc2c(c1)ncn2[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: Cc1ccc2ncn([C@H]3CC[C@@H]4CN(c5cccc(C(F)(F)F)n5)C[C@@H]43)c2c1
Product: FC(F)(F)c1cccc(N2C[C@H]3CC[C@H](n4cnc(-c5ccccc5)c4)[C@H]3C2)n1

Procedure:
5-methyl-1-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-1H-benzimidazole and 6-methyl-1-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-1H-benzimidazole;
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[CH2:18][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)nc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 53B. MS m/z 474 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([O:23]C)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCC2CCCO2)cc(-c2ccc(C)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-((tetrahydrofuran-2-yl)methoxy)biphenyl-3-carboxylate (130 mg, 0.40 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added lithium hydroxide (50 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then acidified with 2N aq. H2SO4 to pH 4-5 and concentrated in vacuo. The residue was treated with water and extracted with CH2Cl2 (10 mL×3). The combined organic layers were dried (MgSO4) and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.84 (t, J=1.6 Hz, 1H), 7.54-7.50 (m, 3H), 7.38 (dd, 1H, J=2.8, 1.6 Hz), 7.27 (d, 2H, J=8.0 Hz), 4.34-4.27 (m, 1H), 4.12 (dd, 1H, J=10.0, 3.6 Hz), 4.04 (dd, 1H, J=10.0, 6.4 Hz), 3.97-3.80 (m, 2H), 2.38 (s, 3H), 2.20-1.80 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][CH2:23]O>>[CH2:22]([O:19][C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20])[CH3:23]
Reactant: CCO
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: Cl
Product: CCOC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 92 %

Procedure:
A solution of carboxylic acid 24 (3.5 g, 13 mmol) in HCl/EtOH(100 ml) was refluxed for 2 hr. The reaction was then cooled, concentrated and the product was dissolved in EtOAc, washed with sat NaHCO3, dried over MgSO4, and concentrated to give a solid. The solid was triturated with CH2Cl2, filtered to give the desired product (3.5 g, 92%); Mp=221-223° C.; 1NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.55(s, 1 H), 7.73 (d, 2 H, J=8.5 Hz), 7.23 (d, 1 H, J=2.1 Hz), 7.17 (d. 1 H, J=2.5 Hz), 7.12 (s,1 H), 6.88 (d, 2 H, J=8.5 Hz), 4.43-4.35 (m, 2 H), 1.41 (t, 3 H, J=7.0 Hz); MS 297 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:15])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:6](O)=[O:7])#[N:2].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.CCOCC>[CH2:13]([O:12][C:11]1[C:3]([C:1]#[N:2])=[C:4]([F:15])[C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1)[CH3:14]
Reactant: CCOc1ccc(C(=O)O)c(F)c1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc(CO)c(F)c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 3-cyano-4-ethoxy-2-fluorobenzoic acid (3.0 g, 14.34 mmol) in THF (16 mL) and ether (8 mL) at −78° C. was added diisobutylaluminum hydride (DIBAL-H) solution (1 M in THF, 43.0 mL, 43.0 mmol). The reaction was allowed to warm to 0° C. over 3 h, and then it was stored at −10° C. overnight. 1M Sodium potassium tartrate (100 mL, 100 mmol) and diatomaceous earth were added and stirred at room temperature for 4 h. The mixture was filtered through a diatomaceous earth pad, extracted with dichloromethane, rinsed with saturated sodium bicarbonate solution, and rinsed with brine. It was dried over sodium sulfate, concentrated and dried in vacuo to give 6-ethoxy-3-hydroxymethyl-2-fluorobenzonitrile (2.352 g, 12.05 mmol, 63.0%) which was used as is in the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH2:16])=[N:8]1.F[C:18]1[C:23]([C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]3[N:31]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[N:32]=[CH:33][C:25]=23)=[CH:22][CH:21]=[CH:20][N:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:30][C:28]1[N:27]=[C:26]2[N:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:32]=[CH:33][C:25]2=[C:24]([C:23]2[C:18]([NH:16][C:13]3[C:14]4[C:9]([CH:10]=[CH:11][CH:12]=3)=[N:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:15]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:29]=1
Reactant: Nc1cccc2nn(C3CCCCO3)cc12
Reactant: Cc1nc(-c2cccnc2F)c2cnn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2Nc2cccc3nn(C4CCCCO4)cc23)c2cnn(C3CCCCO3)c2n1
Reaction time: 0.75 h
Yield: 31.2 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (80.2 mg, 369 μmol) and 4-(2-fluoropyridin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (112.0 mg, 357 μmol) in THF (1.0 mL) was stirred in an ice bath and treated dropwise with LHMDS (1.0 M in THF, 1.1 mL, 3 equiv.). The mixture was stirred for 45 min and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a dark residue. The residue was purified by flash chromatography on silica (25-30% EtOAc/hexane) to give N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 31.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.97 (br. s, 1H); 8.43-8.53 (m, 1H); 8.30-8.42 (m, 3H); 7.96 (br. s., 1H); 7.38-7.48 (m, 1H); 7.34 (d, J=7.43 Hz, 1H); 6.94-7.03 (m, 1H); 6.16 (d, J=10.17 Hz, 1H); 5.71 (d, J=9.00 Hz, 1H); 4.14 (d, J=9.98 Hz, 2H); 3.73-3.95 (m, 2H); 3.04 (s, 3H); 2.58-2.76 (m, 1H); 2.26-2.39 (m, 1H); 1.94-2.25 (m, 4H); 1.59-1.93 (m, 6H). m/z (ESI, +ve) 511.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NCCCCC1c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCCCC1c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A solution of 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (2.05 g) in dry DMF was added dropwise to a suspension of sodium hydride (0.3 g). After 30 minutes at ambient temperature, benzyl chloride (1.3 g) was added. The mixture was stirred for a further 2 hours and then cooled, and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers washed thoroughly with water. The solvent was evaporated to give an oil that crystallised from ethyl acetate to give the title compound as a white solid (1.4 g) m.p. 119°-122° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=O)[C@@H:22]([NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:52][CH2:53][C:54]([OH:56])=[O:55].C(N(CC)CC)C>O1CCCC1.O>[C:54]([CH2:53][NH:52][C:25](=[O:27])[C@H:23]1[O:24][C@@H:19]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][CH:17]=[N:18][C:10]=3[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:20]([OH:21])[C@@H:22]1[NH:28][C:29](=[O:51])[C@H:30]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([OH:56])=[O:55]
Reactant: NCC(=O)O
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2C(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
A solution of N-hydroxysuccinimide ester of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid (295 mg) prepared in Example 53 (1) in tetrahydrofuran was added to a solution of glycine (30 mg) and triethylamine (0.085 ml) in water (5 ml). The mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure to remove tetrahydrofuran. The aqueous solution was acidified with 1N hydrochloric acid and extracted with a mixed solvent (chloroform/ethanol=1/1). The extract was dried and evaporated to dryness. The residue was triturated in diethyl ether to give N-carboxymethyl-1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronamide (244 mg), mp. 122°-130° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:20]C(=O)C)([CH2:14][CH2:15][C:16]([F:19])([F:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:15][C:16]([F:19])([F:18])[CH3:17])([OH:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC1(CCC(C)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(F)(F)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-4-acetoxy-4-(3,3-difluorobutyl)piperidine-1-carboxylate (100 mg, 0.426 mmol) in MeOH (10 mL) and H2O (2 mL) was added NaOH (145 mg, 8.45 mmol). The resulting mixture was stirred at 40° C. for 4 h. After cooling to room temperature, the mixture was acidified with 2N HCl solution. After removal of MeOH, the resulting solution was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:17]=[C:16]([CH2:18][C:19]#[N:20])[CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>CC1C=CC(C)=CC=1>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:17]=[C:16]([CH2:18][C:19]#[N:20])[CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:32])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccc(C)cc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(CC#N)n3)cc21
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To [6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile (80 mg, 0.27 mmol, 1 eq) in p-xylene (10 mL) was added Lawesson's reagent (55 mg, 0.14 mmol, 0.5 eq) and the reaction was heated to reflux for 2 hours. The reaction was cooled to room temperature and adsorbed onto silica gel. Purification by flash column chromatography (50% ethyl acetate/hexane) on silica gel gave the title compound (40 mg, 48%) as an off-white solid: mp 215-217° C.; 1H NMR (d6-DMSO, 300 MHz) δ 1.71 (s, 6H), 4.28 (s, 2H), 7.15 (d, 1H, J=8.3 Hz), 7.36 (d, 1H, J=7.3 Hz), 7.89-7.99 (m, 2H), 8.04-8.11 (m, 2H), 12.32 (s, 1H); MS (ESI) [M−H]−=308; Anal. Calcd. for C17H15N3OS: C, 66.00; H, 4.89; N, 13.58. Found: C, 64.43; H, 4.65; N, 12.95.
Reaction SMILES: C(OC([N:8]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:20]=[N:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][C:26]4[NH:29][C:30]([C:32]5[C:40]6[C:35](=[CH:36][C:37]([C:41]7[CH:46]=[C:45]([F:47])[C:44]([OH:48])=[CH:43][C:42]=7[CH2:49][CH3:50])=[CH:38][CH:39]=6)[NH:34][N:33]=5)=[N:31][C:25]=4[CH2:24]3)=[O:22])=[CH:17][N:16]=2)[CH2:10][C@H:9]1[CH3:51])=O)(C)(C)C>O1CCOCC1.Cl.O1CCOCC1>[CH3:14][C@H:13]1[NH:8][C@@H:9]([CH3:51])[CH2:10][N:11]([C:15]2[CH:20]=[N:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][C:26]4[NH:29][C:30]([C:32]5[C:40]6[C:35](=[CH:36][C:37]([C:41]7[CH:46]=[C:45]([F:47])[C:44]([OH:48])=[CH:43][C:42]=7[CH2:49][CH3:50])=[CH:38][CH:39]=6)[NH:34][N:33]=5)=[N:31][C:25]=4[CH2:24]3)=[O:22])=[CH:17][N:16]=2)[CH2:12]1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C5)cn3)C4)n[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5C[C@@H](C)N[C@@H](C)C5)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (3R,5S)-5′-{2-[6-(2-Ethyl-5-fluoro-4-hydroxy-phenyl)-1H-indazol-3-yl]-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl}-3,5-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (80 mg, 0.114 mmol) in dioxane (3 mL), 10% dioxane-HCl (2 mL) was added and the mixture stirred at RT for 18 hours. The reaction mass was evaporated in vacuo and the resulting solid triturated with ether to afford the title compound (HCl salt) as an off white solid (62 mg 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][OH:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[5-Bromo-2-(hydroxymethyl)phenyl]propan-2-ol (1.1 g, 4.4 mmol) and imidazole (0.78 g, 12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.86 g, 5.7 mmol) was added, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with hexane, and subsequently the extract was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to afford the title compound (1.1 g, 3.1 mmol) as a colorless oil (yield 70%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][OH:17])[CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][O:17][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cccc(Cl)n1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cccc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Into 3 g of N,N-dimethylformamide were dissolved 251 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 188 mg of 6-chloro-2-pyridylmethyl alcohol, 72 mg of sodium hydride (60% in oil) was added thereto at room temperature, and the reaction mixture was stirred for 30 minutes. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 44 mg of 5-(6-chloro-2-pyridylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (35)).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:37][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH2:6][N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C)C(C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 43.1 %

Procedure:
N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide was prepared following the procedure for Example 100, but staring from ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol) and 2M trimethylaluminium in toluene (1.875 mL, 3.75 mmol). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (0.301 g, 43.1%) as a white solid.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([OH:45])[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[CH:46]1([S:49]([C:52]2[CH:57]=[CH:56][C:55](F)=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:48][CH2:47]1>>[C:26]([O:30][C:31]([C:33]1[CH:44]=[C:43]([O:45][C:55]2[CH:56]=[CH:57][C:52]([S:49]([CH:46]3[CH2:48][CH2:47]3)(=[O:50])=[O:51])=[CH:53][CH:54]=2)[C:36]2[CH2:37][C:38]([CH2:41][OH:42])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: O=S(=O)(c1ccc(F)cc1)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(=O)(=O)C3CC3)cc2)c2c(c1)OC(C)(CO)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227c) and 1-cyclopropanesulfonyl-4-fluoro-benzene. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.59 Hz, 2 H) 7.23 (s, 1H) 7.07 (d, J=8.59 Hz, 2 H) 3.73 (dd, J=11.87, 5.81 Hz, 1 H) 3.62 (d, J=7.58 Hz, 1 H) 3.16 (d, J=16.67 Hz, 1 H) 2.78 (d, J=16.67 Hz, 1 H) 2.48 (td, J=8.02, 4.67 Hz, 1 H) 1.55-1.58 (m, 12H) 1.45 (s, 2 H) 1.36 (dd, J=4.67, 1.89 Hz, 2 H) 0.97-1.13 (m, 2 H); LCMS for C24H27O7S m/z 460.80 (M+H)+.