Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:27]3[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=3)[CH:12]=2)(O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:35]=[N+:36]=[N-:37].[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:27]3[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=3)[CH:12]=2)([N:35]=[N+:36]=[N-:37])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N1CCC(O)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC(N=[N+]=[N-])(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 94.8 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-4-hydroxy-piperidin-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 35, 40.0 mg, 0.0867 mmol) and NaN3 (56.3 mg, 0.0867 mmol) in 2 mL of DCM at 0° C. under Ar was added TFA (100 μL, 1.30 mmol). The resulting mixture was stirred at 0° C. for 0.5 h, at RT for 2 d under Ar. Treated with 20 mL of EtOAc, the mixture was washed with saturated NaHCO3 aqueous solution (10 mL), brine (5 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% MeOH/DCM) gave 40.0 mg (95%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C26H30N8O2, 487.3 (M+H). found 487.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:59]([O-:73])([O:61][CH2:62][C@H:63]([O:69][N+:70]([O-:72])=[O:71])[CH2:64][CH2:65][CH2:66][CH2:67]O)=[O:60].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:70]([O:69][C@@H:63]([CH2:62][O:61][N+:59]([O-:73])=[O:60])[CH2:64][CH2:65][CH2:66][CH2:67][O:49][C:48]([C@@H:46]1[CH2:47][C@H:45]1[CH2:44][O:43][C:42]1[CH:41]=[C:40]([CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=1)[CH2:39][N:35]([CH:36]1[CH2:37][CH2:38]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)=[O:34])=[O:50])([O-:72])=[O:71]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.17 M) was added (2R)-6-hydroxyhexane-1,2-diyl dinitrate (1.5 eq., prepared according to the procedure described in WO2005070868/Example 2, incorporated by reference), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.), and 4-dimethylaminopyridine (1.5 eq.). The reaction was stirred at rt for 18 h and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 40% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:9].C(#[N:12])C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CN>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[ClH:1].[ClH:1].[NH2:12][O:9][CH2:8][C:7]1[NH:6][CH:5]=[N:4][C:3]=1[CH3:2]
Reactant: CC#N
Reactant: Cc1nc[nH]c1CO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1CON
Temperature: 25 °C

Procedure:
To 2.04 g of (4-methyl-1H-imidazol-5-yl)methanol hydrochloride was added 20 ml of acetonitrile, and 2.1 ml of triethylamine, 3.14 g of di-tert-butyl dicarbonate, and 0.17 g of DMAP were added thereto under ice-cooling, followed by stirring at room temperature. After concentrating the reaction solution under reduced pressure, ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was reacted with N-hydroxyphthalimide in accordance with Production Example 14, reacted with methylamine in accordance with Production Example 9, and then subjected to deprotection of a Boc group in accordance with Production Example 26 to obtain 0.53 g of 5-[(aminooxy)methyl]-4-methyl-1H-imidazole dihydrochloride as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)N.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46])[N:38]=[CH:37][N:36]=[C:35]2[S:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([S:47][C:35]3[C:34]4[C:39](=[CH:40][C:41]([O:42][CH2:43][CH2:44][O:45][CH3:46])=[C:32]([O:31][CH3:30])[CH:33]=4)[N:38]=[CH:37][N:36]=3)[CH:49]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: NC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react carbamate phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A (151 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (107 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours the reaction was concentrated to dryness. The resulting solid was triturated with 1:1 dichloromethane/hexane and the solid removed by filtration to give 26 mg. 1H (DMSO-d6) 9.23 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 7.79 (s, 1H), 7.55 (m, 4H), 7.40 (m, 5H), 7.25 (s, 1H), 6.35 (s, 1H), 4.33 (m, 2H), 3.99 (s, 3H), 3.75 (m, 2H), 3.34 (s, 3H), 1.25 (s, 9H); LCMS (ESI) m/z 599 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][NH2:19])[O:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[CH:28][C:29]5[CH:30]=[CH:31][C:32](=[O:36])[O:33][C:34]=5[CH:35]=4)[O:14][C:13]=3[CH:20]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2ccc(OCc3ccccc3)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(OCc5ccccc5)cc4O3)cc2o1
Yield: 25.7 %

Procedure:
2,3-Dihydro-7-benzyloxy-1,4-benzodioxin-2-methanamine (1.47 g, 5.42 mmole), 7-(3-chloropropoxy)coumarin (1.30 g, 5.45 mmole), diisopropylethylamine (4.0 ml, 23 mmole) and sodium iodide (4.17 g, 28 mmole) were combined in 150 ml of DMF and heated at 80°-100° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using first dichloromethane, then 0.5% methanol/dichloromethane, and finally 1% methanol/dichloromethane as eluant. The fractions containing material with Rf=0.26 on silica gel tlc (2.5% methanol/chloroform) were combined and concentrated in vacuum and the residue crystallized from 50 ml of isopropanol with the addition of 4.0 ml of 4N isopropanolic HCl to give 0.66 g of title compound as an off-white solid, monohydrochloride, m.p. 179°-181° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)C)c3n1)nn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 78.6 μmol) in dichloromethane (2 mL) was added TFA (2.96 g, 2000 μL, 26.0 mmol, Eq: 330), the reaction mixture turned bright orange and was stirred at 25° C. for 3 h, then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. overnight then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in a small amount of dichloromethane/MeOH, added cyclohexane and some solvents evaporated to allow solid formation, which was separated by filtration and dried to give N-tert-butyl-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 66.1 μmol, 84.0%) as an off-white solid. MS (M+H)+=379 (>90% purity); 1H NMR (CDCl3) δ: 9.11 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.22 (s, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.26 (br. s., 2H), 7.17-7.23 (m, 1H), 4.18 (s, 3H), 3.92 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([NH2:6])(=[O:5])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42](O)=[O:43])[O:39][C:40]=3[CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]3[CH:37]=[C:38]([C:42]([NH:6][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])=[O:43])[O:39][C:40]=3[CH3:41])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: CN(C)S(N)(=O)=O
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)N(C)C)oc3C)cc2)cc1
Reaction time: 18 h
Yield: 35.7 %

Procedure:
N,N-Dimethylsulphamide (73 mg, 0.59 mmoles), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (31 mg, 0.162 mmoles) and dimethyl-pyridin-4-yl-amine (1 mg) were added to a stirred solution of 4-(4′-methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4)(50 mg, 0.148 mmoles) in dichloromethane (20 ml). The mixture was stirred under an argon atmosphere for 18 hours. After evaporation of the solvent, the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined extracts were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried (MgSO4). Evaporation of the solvent afforded the crude product, which was purified by HPLC (gradient: 30% acetonitrile/70% water containing 0.1% trifluoroacetic acid to 98% acetonitrile/2% water at a rate of 1%/min) to afford compound 122 (23.5 mg) as a white solid. LC/MS System C: Rt=3.67 mins, m/z (ES−)=443 ((M−H) for C22H24N2O6S).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]([CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>C1C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]([CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(C)cc(C(=O)O)c(N)c1C
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(C(=O)O)c(NC(C)=O)c1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a mixture consisting of 1 g of 2-amino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid, 20 ml of dry benzene, and 0.7 ml of pyridine in a flask cooled with ice water was added dropwise with stirring a solution of 450 mg of acetyl chloride in 5 ml of benzene. The reaction mixture was stirred overnight, and then shaken with dilute hydrochloric acid. The layers were separated. The acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, and dried over sodium sulfate. The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to afford 0.84 g of 2-acetylamino-4-ethoxycarbonyl-3,5-dimethylbenzoic acid melting at 164° C.
Reaction SMILES: C([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[N:9]1)C1C=CC=CC=1.C(O)=O>CCO.[Pd]>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[C:10]1[CH:11]=[C:12]([C:13]([F:15])([F:16])[F:14])[NH:8][N:9]=1)[CH2:22][CH3:23]
Reactant: CCCN(CCC)c1cc(C(F)(F)F)n(Cc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CCCN(CCC)c1cc(C(F)(F)F)[nH]n1
Temperature: 78 °C
Yield: 93.1 %

Procedure:
To a 1 dram pressure vial containing 1-benzyl-N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (597 mg, 1.83 mmol) in EtOH (9.2 mL) was added 10% Pd/C (585 mg, 5.50 mmol) followed by dropwise addition of formic acid (3.9 mL, 101.0 mmol). The vial was capped, and the resulting black reaction mixture was heated at 78° C. for 1 h. The reaction mixture was filtered through a pad of CELITE® and concentrated in vacuo to give the title compound (401 mg, 93%) as a white solid. 1H NMR (CDCl3) δ 5.58 (s, 1H), 3.18-3.11 (m, 4H), 1.69-1.50 (m, 4H), 0.94 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 236.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=1
Reactant: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1

Procedure:
A solution of 8.59 g of trans-4-(4-benzyloxyphenoxy)-1-methyl-3-phenylpiperdine in a mixture of 100 ml of absolute ethanol and 50 ml of tetrahydrofuran is hydrogenated overnight over 5% palladium-on-carbon at room temperature under 45 pounds per square inch of hydrogen. The catalyst is filtered and washed with ethanol and ether. The filtrate is concentrated in vacuo to a nearly colorless, partially solidified foam. Trituration of the foam with ether followed by recrystallization from 270 ml of chloroform gives product as a colorless solid, mps 169.5° C., 170°-172° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.ClCCl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3](=[O:12])[N:4]([CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CI
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(F)(F)F)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 3-bromo-2-hydroxy-5-(trifluoromethyl)pyridine (1.0097 g, 4.1724 mmol) in chloroform (20 mL) was added silver carbonate (1.1964 g, 4.3388 mmol) and methyl iodide (0.40 mL, 6.4 mmol). The reaction mixture was stirred at room temperature for two hours and then at 40° C. for 24 hours. Additional methyl iodide (0.40 mL, 6.4 mmol) was added and the reaction kept at 40° C. for an additional 15 hours. The reaction mixture was then diluted with dichloromethane, filtered through celite, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 80% ethyl acetate in heptanes) to yield 0.5297 g (50%) of 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J=0.9, 1H), 8.22 (d, J=2.5, 1H), 3.56 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH3:17])=[O:7])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:9]1[CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
General Procedure 11.-To a mixture of sodium hydride (0.28 g, 60% in mineral oil, 0.17g, 7.0 mmol) in 10 ml of tetrahydrofuran stirring at 0° C. under argon, was added 2-methyl-1H-indole-3-carboxylic acid ethyl ester (1.17 g, 5.8 mmol) and the solution was stirred at 0° C. for 15 min. Benzyl bromide (0.80 ml, 1.15 g, 6.7 mmol) was then added and the reaction allowed to warm to room temperature and stirred for 24 h. The reaction was cooled to 0° C., quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexanes) to yield 1-benzyl-2-methyl-1H-indole-3-carboxylic acid, ethyl ester (Compound 57) as a tan solid (1.13 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-oxobutanoate (1.526 g, 4.778 mmol) was dissolved in anhydrous ethanol (15 ml), and the solution was mixed with sodium borohydride (94.6 mg, 2.50 mmol)under ice-cooling and stirred at the same temperature for 1 hour. Under ice-cooling, the reaction solution was mixed with water (20 ml) and then ethanol was evaporated under a reduced pressure. The thus obtained residue was mixed with chloroform (50 ml) and stirred, and then the thus separated chloroform layer was washed with saturated sodium chloride aqueous solution (30 ml) and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness under a reduced pressure, thereby obtaining 1.509 g (98.3%) of the title compound as a colorless oil. This product was used in the subsequent reaction without purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[F:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[F:21][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(F)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(F)c2)cc1
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-1-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)ethanone (30-6, 0.60 g) and thiourea (0.160 mg, 2.05 mmol) in 95% EtOH (12.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-fluoro-4-(4-methoxyphenoxy)-6-methylphenyl)thiazol-2-ylamine (30-7, 0.450 g, 1.36 mmol) as yellow solids in 80% yield: 1H NMR (500 MHz, CDCl3) δ 6.98 (d, J=9.0 Hz, 2 H), 6.89 (d, J=9.0 Hz, 2 H), 6.60 (s, 1 H), 6.49 (d, J=10.9 Hz, 1 H), 6.41 (s, 0.1 H), 3.80 (d, J=3.4 Hz, 3 H), 2.26 (s, 3H). ESI-MS: m/z 331.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:32]N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:32][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound 3-(4-chlorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=O)[CH2:8][O:7][C:6]=2[N:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[S:28])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Yield: 65.8 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.26 g, 0.852 mmol) and Lawesson's Reagent (0.34 g, 0.852 mmol) in toluene (10 ml) was heated at 120 degree for 16 h. The reaction mixture was concentrated to dryness and was added DCM (5 ml) and diisopropyl ether (20 ml). The precipitate was filtered to give product (0.18 g). 1H NMR (500 MHz, DMSO-d6): 12.9 (br, 1H), 7.35-7.55 (m, 5H), 7.32 (s, 1H), 5.16 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:14])=[N-]>CCOCC>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCc1ccccc1
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1
Temperature: 0 °C
Yield: 83.1 %

Procedure:
To an ice-cooled and stirred solution of 3-phenylpropionic acid (8.0 g, 0.053 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl 3-phenylpropionate (7.25 g, 0.044 mol, yield 83.1%, b.p. 106°-108° C./10 mmHg), which was assigned the structure by the following data: