Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1([C:40]2[S:41][CH:42]=[C:43]([CH2:45]O)[N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.ClCCl.C1C=CC=CC=1>[F:1][C:2]1[CH:13]=[C:12]([O:14][CH2:45][C:43]2[N:44]=[C:40]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[S:41][CH:42]=2)[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1cc2c(O)cc(F)cc2o1
Reactant: OCc1csc(-c2ccccc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(=O)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
Benzene was added to 1-(6-fluoro-4-hydroxybenzofuran-2-yl)ethanone (Example 36C, 178 mgs, 0.917 mmol) and the mixture was sonicated for 30 sec. and concentrated in vacuo to remove traces of water in the starting material. Triphenylphosphine (373 mgs, 1.421 mmol) was added and the mixture was dried on high vacuum for 10 min. (2-Phenylthiazol-4-yl)methanol (Example 3B, 175 mgs, 0.917 mmol) and THF (15 mL) were added and the mixture was sonicated/heated for 5 min. Diisopropyl azodicarboxylate (275 L, 1.412 mmol) in THF (2 mL) was added dropwise over 1 h and the resulting yellow solution was sonicated for 15 min. and stirred overnight at r.t. The mixture was diluted in dichloromethane, washed with saturated. NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified on silica gel chromatography (ISCO 24 g gold column, using 5% ethyl acetate in hexanes to 40% (10% increments)) to give the title material (132 mgs, 32%) as a white solid. LC (Method B): 2.613 min. LCMS (APCI) calcd for C20H15FNO3S [M+H]+ m/z 368.07, found 368.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94-8.02 (m, 2H), 7.62-7.67 (m, 1H), 7.44-7.51 (m, 3H), 7.38 (s, 1H), 6.91-6.96 (m, 1H), 6.64-6.72 (m, 1H), 5.39 (d, J=0.78 Hz, 2H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([NH:18][NH2:19])[CH:9]=1.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[N:11]2[C:12]3[C:17]([C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:9][C:10]2=[N:18][N:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: NNc1cc(-c2ccccc2Cl)c2ccccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3ccccc3n12

Procedure:
In the manner given in Example 2, 4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[C:21]([CH3:28])[C:19]=2[N:20]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:25]([C:23]3[CH:22]=[C:21]([CH3:28])[C:19]4[N:20]=[C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])[NH:17][C:18]=4[CH:24]=3)=[O:27])=[CH:42][CH:43]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)O)cc3[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)Nc4ccc(CCN5CCN(C)CC5)cc4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of the crude of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-7-methyl-3H-benzoimidazole-5-carboxylic acid (estimated 0.4 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (88 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) in DMF (5 mL) was added DIEA (0.5 mL, 371 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 15 h, and then evaporated to dry under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (34.5 mg, 11% from two steps from 3,4-diamino-5-methyl-benzoic acid). 1H NMR (MeOH-d4) δ 2.77 (s, 3H), 2.90 (s, 3H), 2.97-3.43 (12H), 3.97 (s, 3H), 7.09 (m, 1H), 7.22 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.82-7.84 (2H), 7.91 (s, 1H), 8.17 (m, 1H), 8.20 (s, 1H), 8.31 (s, 1H). ESI-MS m/z 577.5 (MH+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:26]=[C:27]([CH2:34][OH:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(#N)C>[OH:35][CH2:34][C:27]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (7.09 g, 32.1 mmol) and DIPEA (15 mL, 88 mmol) in ACN (50 mL) was added (3-fluoro-4-nitrophenyl)methanol (5 g, 29.2 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, loaded onto a silica-gel pre column, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as an orange foam (7.0 g, 71.4% yield). MS, m/z (C17H25N3O4): calcd, 335.2. found, 336.0 [M+H].
Reaction SMILES: Cl[CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH2:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCC(C)Cl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCCn3ccnc3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e 456.5 (M+Ht), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-pentyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][C:10]([O-])(C)[CH3:11].[K+].C([O-])([O-])=O.[K+].[K+].IC(C)C>COCCOC.O>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:11])[CH3:9])[CH:7]=1
Reactant: Oc1ccc(I)cn1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: COCCOC
Solvent: O
Product: CC(C)n1cc(I)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a stirred solution 5-iodopyridin-2-ol (0.4 g, 1.80 mmol) in DME (10 mL) was added t-BuOK (0.604 g, 5.4 mmol). The mixture was stirred for 30 min at rt, K2CO3 (0.621 g, 4.5 mmol) and 2-iodopropane (0.35 mL, 3.6 mmol) were added, and the reaction was heated at reflux for about 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane as eluent to afford 5-iodo-1-isopropylpyridin-2(1H)-one as an off-white solid (0.41 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.90 (s, 1H), 7.49 (dd, 1H), 6.21 (d, 1H), 4.94 (t, 1H), 1.25 (t, 6H), LC-MS m/z calcd for [M+H]+ 263.98. found 264.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:19].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].P([O-])([O-])([O-])=O>CO>[ClH:19].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CNCc1ccccc1)CC3
Reaction time: 4.5 h
Yield: 41.2 %

Procedure:
To a solution of 9-bromo-5-formyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (154 mg, 0.5 mmol) and benzylamine hydrochloride (79 mg, 0.55 mmol)in methanol (3 mL) was added sodium cyanoborohydride (100 mg, 1.6 mmol) by portions at 0° C. The mixture was stirred for 4.5 h at 0° C. ~ room temperature and poured into 1/15M phosphate buffer (pH 7.4, 50 mL). The precipitates formed were collected by filtration and dried in vacuo. The solids were dissolved in dichloromethane and saturated hydrogen chloride in isopropanol was added. The resulting mixture was concentrated and the residual solid was rinsed with dichloromethane to give 90 mg of the title compound (41%): 1H NMR (270 MHz, DMSO-d6) δ12.13 (bs, 1H), 9.13 (s, 1H), 9.09 (s, 1H), 7.40~7.59 (m, 5H), 7.24 (d, 1H, J=2 Hz), 7.20 (d, 1H, J=2 Hz), 5.33~5.23 (m, 1H), 4.20 (d, 1H, J=13.0 Hz), 4.10 (d, 1H, J=13.0 Hz), 3.18~3.29 (m, 2H), 2.73~2.99 (m, 2H), 2.27 (dm, 1H, J=12.9 Hz), 1.77~2.00 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([NH2:41])(=[O:40])=[O:39])[N:35]=[C:34]1[CH3:42]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:36]3[N:35]=[C:34]([CH3:42])[N:33]([CH3:32])[CH:37]=3)(=[O:40])=[O:39])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cn(C)c(C)n3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 1,2-dimethyl-1H-imidazole-4-sulfonamide: 1H-NMR (CDCl3) δ 7.50-7.27 (10H, m), 3.62 (3H, s), 3.46-3.41 (2H, m), 2.87-2.82 (2H, m), 2.37 (3H, s), 2.32 (3H, s), 2.27 (3H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:19]#[N:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.[I-].[Zn+2].[I-]>[NH2:20][CH2:19][C:13]1([OH:16])[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC(COCc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Product: NCC1(O)CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of EXAMPLE 341D (5 g), zinc iodide (0.183 g) and anhydrous ether (50 mL) was cooled in an ice bath and trimethylsilanecarbonitrile (3.45 mL) was added dropwise. The reaction was allowed to warm to ambient temperature with stirring continued 45 minutes. The reaction mixture was added via a syringe to a suspension of lithium aluminum hydride (2.78 g) in ether (75 mL) dropwise and the reaction mixture was then heated at reflux for 2 hours. The reaction was cooled in an ice bath and quenched very slowly by careful addition of water (2.8 mL), keeping the temperature below 5° C. Ether (100 mL) was added, followed by 4N aqueous sodium hydroxide (2.8 mL) and water (8.4 mL). The mixture was further diluted with ether (150 mL) and anhydrous sodium sulfate (70 g) was added. The resulting suspension was stirred for 18 hours and filtered. The solids were washed with ether (4×150 mL). The combined organics were dried with Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([S:20]([NH:23][C:24]([NH:1][C:2]2[N:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:25])(=[O:21])=[O:22])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1nc(N)nc2ccccc12
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)nc2ccccc12

Procedure:
To a dry, stirred solution of 8.0 g of 2-amino-4-methylquinazoline in 200 ml of methylene chloride at ambient temperature and pressure is added 13 g of 2-chloropyridin-3-sulfonylisocyanate. The resulting mixture is stirred at reflux for 2 hours and then concentrated at reduced pressure. The residue is triturated with 1-chlorobutane and filtered to yield the desired solid product.
Reaction SMILES: [O:1]1[C@H:10]2[C:5](=[CH:6][CH2:7][CH2:8][C@H:9]2[CH2:11][OH:12])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>O>[C:23]([Si:27]([O:12][CH2:11][C@H:9]1[C@@H:10]2[C:5]([CH2:4][CH2:3][CH2:2][O:1]2)=[CH:6][CH2:7][CH2:8]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CCC=C2CCCO[C@@H]21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1CCC=C2CCCO[C@@H]21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 360 mg (8S,8aR)-3,4,6,7,8,8a-hexahydro-2H-chromen-8-ylmethanol added 2.2 mL DMF, then 224 mg imidazole followed by 0.66 mL tert-butyl(chloro)diphenylsilane. The reaction was stirred overnight at RT, then added to water and extracted with diethyl ether. The crude extract was dried over Na2SO4, filtered, concentrated, then purified on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ=1.05 (s, 9H), 1.37-1.46 (m, 1H), 1.54-1.58 (m, 1H), 1.63-1.73 (m, 2H), 1.86-2.09 (m, 3H), 2.16-2.24 (m, 1H), 2.25-2.31 (m, 1H), 3.53 (m, 1H), 3.60 (dd, J1=9.8 Hz, J2=7.7 Hz, 1H), 3.80 (d, J=5.1 Hz, 1H), 3.90 (dd, 10.0 Hz, J2=7.4 Hz, 1H), 3.94-3.98 (m, 1H), 4.49-5.52 (m, 1H), 7.35-7.42 (m, 6H), 7.67-7.72 (m, 4H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH3:34])[C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[C:27]([CH3:34])=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CCOC(N)=N2)c1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 5-chloro-3-methyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=377.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1(=[O:24])(=[O:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16](=[O:24])(=[O:23])[CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCS(=O)(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C1NC2(CCS(=O)(=O)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a stirred solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol) in acetic acid (3 mL) were added tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.068 g, 0.46 mmol) and p-toluenesulfonic acid (0.0040 g, 0.023 mmol). The mixture was heated at 80° C. overnight. Then, the solvent was removed and the obtained residue was taken up in methanol (20 mL). Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for 10 min. The cloudy suspension was filtered and the collected solids were washed with methanol (20 mL) followed by water (30 mL) to give the title compound (0.0195 g, 24%) as a yellow solid:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([Cl:24])=[N:7][C:8]2[N:9]([N:21]=[CH:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:32]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33].Cl>C(Cl)Cl>[Si:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([Cl:24])=[N:7][C:8]2[N:9]([N:21]=[CH:22][CH:23]=2)[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH3:20])=[CH:16][CH:17]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CCOc1ccc(Nc2c(CCCO)c(Cl)nc3ccnn23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(Nc2c(CCCO[Si](C)(C)C(C)(C)C)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.9 %

Procedure:
To a methylene chloride (14 mL) solution containing [6-(3-hydroxypropyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)amine (1.43 g, 4.12 mmol), triethylamine (861 μL, 6.18 mmol) and tert-butylchlorodimethylsilane (808 mg, 5.36 mmol) were added with ice-cooling, and this mixture was stirred at room temperature for 16 hr. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (10 to 15% ethyl acetate-hexane) to obtain the title compound (2.03 g, yield 100%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1nc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 1H-1,2,4-triazol-3-amine (66.6 g) and 1,4-dioxaspiro[4.5]decan-8-one (175 g) in acetic acid (1.25 L) was gradually added sodium triacetoxyborohydride (252 g) under ice-cooling. After stirring at room temperature for 16 hr, water (1 L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate (1 L). The mixture was neutralized with sodium bicarbonate, and extracted 3 times with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1, 2 L). The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with diisopropyl ether (500 mL), and the resulting solid was collected by filtration, washed twice with diisopropyl ether (250 mL), and dried to give the title compound (166 g, 94%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:13]=2[S:12][C:11]=1C(OCC)=O.Cl>O1CCOCC1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[CH:24][CH:25]=3)[C:13]=2[S:12][CH:11]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(N3CCN(C)CC3)cc2)c1-c1ccc(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(-n3c(=O)ccc4c(-c5ccc(F)cc5F)csc43)cc2)CC1
Reaction time: 5 h
Yield: 104.9 %

Procedure:
To a solution of the compound of Example 112 (310 mg, 0.61 mmol) in dioxane (35 mL) was added 4M HCl(aq) (20 mL) and the mixture heated at reflux for 18 h. Reaction had not reached completion and so a few drops of concentratedHCI were added and reflux continued for 5 h. The reaction was quenched with saturated Na2CO3(aq) and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product contained a small amount of residual ester starting material. The product was therefore dissolved in EtOH (15 mL) and heated at reflux with NaOH (50 mg) for 16 h. Solvent was removed in vacuo and the residue partitioned between DCM and saturated Na2CO3(aq). The DCM layer was washed with Na2CO3(aq) (×3), dried (Na2SO4) and concentrated in vacuo to give the pure title compound as an off-white solid (280 mg). δH (DMSO-d6) 8.10–7.95 (2H, m), 7.86 (1H, dt, J 9.5, 2.6 Hz), 7.74–7.63 (4H, m), 7.55–7.52 (2H, m), 6.92 (1H, d, J 9.5 Hz), 3.72–3.67 (8H, m), 2.67 (3H,s). LCMS (ES+) RT 2.47 minutes, 438 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:13]([O:15][C:16]([CH2:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([CH3:35])[C:23]([CH3:34])=[C:24]([S:30](Cl)(=[O:32])=[O:31])[C:25]=2[CH3:29])[O:20]1)=[O:17])[CH3:14].Cl>CC(C)=O.CCOC(C)=O.O>[CH2:13]([O:15][C:16]([CH2:18][C:19]1([CH3:36])[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([CH3:35])[C:23]([CH3:34])=[C:24]([S:30]([NH:9][C:2](=[NH:10])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)(=[O:31])=[O:32])[C:25]=2[CH3:29])[O:20]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)Cl)c(C)c(C)c2O1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)NC(=N)c3ccccc3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
To a suspension of benzamidine hydrochloride (2.72 g) in acetone (70 ml) was added 1N aqueous sodium hydroxide (1N NaOH) (17.3 ml) under ice-cooling. To the mixture of a solution of 2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl chloride (3.25 g) in acetone (15 ml) was added dropwise over 15 minutes under ice-cooling, and stirred at room temperature for 20 hours. Acetone was removed under reduced pressure to give a residue. To the residue was added a mixture of water and AcOEt and the mixture was acidified with 1N HCl. The separated organic phase was washed with water and brine, and dried over MgSO4. After filtration, the filtrate was evaporated and purified by chromatography over silica gel (AcOEt-hexane 50:50 as eluent) to give N-(2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl)benzamidine as a glass (1.60 g).