Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:34]([F:37])([F:36])[F:35])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:8]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:7]=[CH:6]2>C(O)=O.O>[CH3:1][O:2][C:3]1[C:4]([C:34]([F:35])([F:37])[F:36])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:8]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[CH:7]=[CH:6]2
Reactant: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O=CO
Solvent: O
Product: COC(=O)N(CC(=O)O)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
A suspension of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine, 1,1-dimethylethyl ester (5.86 g, 10.9 mmol) in formic acid (135 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 10 minutes, dissolution occurred. After 1 hour, the reaction mixture was diluted with water (1.5 L) and extracted with ether (2×400 mL). The extracts were combined and the ether was removed. The residue was suspended in water (100 mL) and filtered. The solid was washed with water (2×20 mL) and air dried. The crude product was recrystallized from chloroform to provide the title compound as a white powder (4.15 g, 79%), m.p. 186°-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:19][C:20](=[N:37][OH:38])[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)c1

Procedure:
In analogy to example 74, step 7, from 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carboxylic acid ethyl ester and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.4:1) as a white foam, MS (ESI+): m/z=479.2319 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc2cc(CCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(CCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propan-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl ester as yellow oil, MS: 428 (M+).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>O1CCCC1.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([OH:26])(=[O:8])=[O:25])=[CH:20][CH:19]=1.[C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccc(Br)cc1

Procedure:
The analogous reaction of 0.1 mole of benzoin with 0.105 mole of p-bromobenzenesulfonyl chloride in 30 ml of tetrahydrofuran and 5 ml of water with the addition of 0.11 mole of 30% NaOH yields the same compound.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:13][C:10]1[N:9]=[CH:8][C:7]([C:22]2[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=2)[C:16]([O:15][CH3:14])=[O:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cnc(Cl)nc2)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To 2 ml of N,N-dimethylformamide deaerated with argon for 10 minutes, 213 mg (1.10 mmol) of 5-bromo-2-chloropyrimidine, 181 mg (1.05 mmol) of 3-(methoxycarbonyl)phenylboronic acid, 315 mg (2.97 mmol) of sodium carbonate and 22.4 mg (0.100 mmol) of palladium acetate were added, and the mixture was stirred at 110° C. for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene three times. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=92/8-76/24 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 74 mg of the title compound as a white solid (yield: 28%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)Cc1ccc(I)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)Cc1ccc([C@H](O)c2c(C(C)C)nc3c(c2I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C3)cc1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-4-isobutylbenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:38])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[N:12]([C:13]([CH:18]3[CH2:19][CH2:20][C:21]([OH:24])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:38])[CH2:22][CH2:23]3)=[N:14][N:15]=2)[C:11]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(=O)CC2)C1
Reactant: Cc1ccccc1[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)CCC(c2nnc3n2-c2ccc(Cl)cc2CN(C(=O)OC(C)(C)C)C3)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 8-chloro-1-(4-oxo-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol) in dry tetrahydrofuran (5 ml) was added a 1M o-tolylmagnesium chloride solution in tetrahydrofuran (0.5 ml, 0.5 mmol) at room temperature. After stirring for 2 h the reaction mixture was quenched with aqueous saturated ammonium chloride solution and extracted with two portions of ethyl acetate. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.17 g, 70%) as white solid. MS m/e: 509 ([[M+H]]+)
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][N:13]1[C:17]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:12][N:13]1[C:17]([C:18]2[S:19][C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:24])[F:25])=[N:14]1
Reactant: CCOC(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2cc(C(F)(F)F)nn2C)s1
Reaction time: 1.5 h

Procedure:
An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50° C. or below, followed by stirring at −50° C. or below for 90 minutes. Ethyl chloroformate was added to the reaction solution at −20° C. or below. After stirring at −20° C. or below for 15 minutes, it was subjected to purification in the usual way to give ethyl 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate. This was hydrolyzed with a base in the usual way to give 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][C:25]([CH3:32])([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][C:25]([CH3:32])([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)Cc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2NC1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2NC1=O
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
A Parr shaker was charged with PtO2 (0.12 g) and EtOAc (25 mL) was added under N2. The catalyst was shaken under a H2 atmosphere (50 psi) for 10 min and a suspension of 7-{5-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,3-dimethyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.54 g, 1.15 mmol) in EtOAc (125 mL) was added. The mixture was shaken under H2 (50 psi) for 1.5 h. The reaction was filtered through Celite washing with MeOH and the filtrate was concentrated to give an oily residue. Hexanes was added and the mixture was concentrated to give the title compound as a white solid (0.54 g, 99%). MS: ESI: m/z: 475.32 (Exact Mass: 474.20).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2ccc(C(=O)OC(C)(C)C)c(N)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc(OC(=O)OC(C)(C)C)cc3)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 62 mg of tert-butyl 2-amino-4-(4-(tert-butoxycarbonyl)oxyphenyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,3-dimethylbenzamido)-4-(4-(tert-butoxycarbonyl)oxyphenyl)benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:29]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:26][CH2:27][CH3:28])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CCCNCC1CC1
Product: CCCN(Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-nitro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with propyl(cyclopropylmethyl)-amine to give 8-nitro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 35 8-Fluoro-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])=[CH:27][CH:26]=2)=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16]C(=O)OC(C)(C)C)[CH2:11]2)=[N:8][CH:9]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[C:5]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])=[CH:27][CH:26]=3)[C:4]([C:1]([NH2:2])=[O:3])=[CH:9][N:8]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(Nc3ccc(C(=O)N4CCOCC4)cc3)c(C(N)=O)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cnc(N2CCC[C@@H](N)C2)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
A solution of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (110 mg, 0.210 mmol) in CH2Cl2 (2 mL) was treated with TFA (4 mL, 51.9 mmol) and stirred at rt for 4 hrs. The mixture is evaporated to dryness and the residue was dissolved in CH2Cl2 and washed with bicarbonate, water, and brine. Concentrated to give 72 mg of (R)-6-(3-aminopiperidin-1-yl)-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14]C2C(OC3C=CC=CC=3OC)=C(OCCCN)N=C(C3CC3)N=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.C(S(Cl)(=O)=O)C>>[C:8]1([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCCN
Agent: CCS(=O)(=O)Cl
Product: NS(=O)(=O)c1ccccc1

Procedure:
According to the procedure described in Example 4a) 200 mg p-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide was reacted with ethanesulfonylchloride to give 220 mg p-tert.-butyl-N-[6-(3-ethansulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide. LC-MS: tR=5.74 min, [M+1]+=619.22, [M−1]−=617.24.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[OH-:31].[Na+].O.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([OH:31])[N:13]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(O)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 33.0 mg, 0.077 mmol, 1.0 eq.) in 1,4-dioxane (0.8 mL) was added 2 M NaOH in H2O (0.39 mL, 0.78 mmol, 10 eq.), and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was neutralized by the addition of aqueous concentrated HCl and the resulting precipitate was filtered, washed with 1,4-dioxane (2.0 mL) and dried to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-2-ol (20) as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (br s, 1H), 7.54 (br d, 11-1, J=7.5 Hz), 7.51 (br d, 1H, J=7.5 Hz), 7.22 (br t, 1H, J=7.5 Hz), 7.17 (br t, 1H, J=7.5 Hz), 6.73 (br s, 1H), 3.85 (s, 3H), 3.04 (m, 1H), 2.76 (s, 3H), 2.64 (m, 1H), 2.30 (s, 3H), 1.94-1.80 (m, 2H). LRMS m/z (M+H) 362 found, 362 required.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH:27]2[N:20]3[C:21]4[C:17]([CH:18]5[CH2:31][NH:30][CH2:29][CH2:28][CH:19]53)=[CH:16][C:15]([NH2:14])=[CH:23][C:22]=4[CH2:24][S:25][CH2:26]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Nc1cc2c3c(c1)C1CNCCC1N3C(Cc1ccc(F)cc1C(F)(F)F)CSC2

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)Carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 154. 1H NMR (CDCl3) δ: 9.30 (broad s, 1H), 9.15 (broad s, 1H), 7.60-7.52 (m, 1H), 7.38-7.25 (m, 1H), 7.13 (broad t, 1H, J=8.0 Hz), 6.30-6.15 (broad m, 2H), 4.45-4.25 (broad m, 2H), 4.17-3.98 (broad m, 2H), 3.70-3.30 (m, 4H), 3.30-2.70 (broad m, 5H), 2.60-2.47 (m, 1H), 2.20-2.00 (m, 2H). LRMS (ES)+: 438.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Fluoro-2-nitrophenol (6 g, 38.2 mmol) was dissolved in anhydrous DMF (20 ml). Potassium carbonate (5.3 g, 38.2 mmol) was added, followed by iodomethane (2.28 ml, 38.2 mmol). The reaction was stirred at room temperature for 16 h, then partitioned between dichloromethane and water. The organic layer was washed three times with 1M sodium hydroxide and once with brine, then dried over sodium sulfate. Removal of the solvent in vacuo afforded the title compound as a yellow oil, which solidified upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[I:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[I:25])=[C:9]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[I:25])[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccccc1I
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccccc2I)c(Nc2ccccc2I)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 5.3 g (24 mmol) of 2-iodoaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concentration by evaporation is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation, yielding the title compound in the form of a yellow foam: 1H-NMR (DMSO-d6): δ=7.91 (dxd, J1 =8, J2 =1, 2H), 7.39 (dxdxd, J1 =10, J2 =8, J3 =1, 2H), 7.32 (br s, 2H), 7.22-7.05 (m, 2H), 7.01 (s, 2H), 6.88 (txd, Jt =8, Jd =1, 2H), 3.73 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:16])[CH:4]=1)#[N:2]>C(O)(=O)C.[Fe]>[NH2:13][C:12]1[C:3]([C:1]#[N:2])=[CH:4][C:5]([CH3:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1C
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(C#N)cc1C
Temperature: 45 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of methyl 4-cyano-2-methyl-5-nitrobenzoate (14.8 g, 0.0672 mol) in acetic acid (250 mL) was added iron powder (22.5 g, 0.40 mol). The reaction mixture was heated to 45° C. and stirred for 1 h, at which time it was cooled to room temperature. The reaction mixture was filtered through a bed of celite, and the filter cake rinsed with ethyl acetate. The volume of the filtrate was reduced by half and then partitioned between water and ethyl acetate. The organic layer was washed with 10% lithium chloride followed by saturated aqueous sodium bicarbonate. The organic layer was further washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with hexanes to afford methyl 5-amino-4-cyano-2-methylbenzoate (11.7 g, 91%) as a bright yellow powder. 1H NMR (400 MHz, CDCl3): 7.28 (s, 1H), 7.26 (s, 1H), 4.35 (br s, 2H), 3.89 (s, 3H), 2.43 (s, 3H). MS (EI) for C10H10N2O2: 191 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[C@@H:19]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][C@@H:19]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 3-(3-methylindazol-5-yl)-5-[(S)-4-Boc-3-benzylpiperazin-1-yl]-[1,2,4]triazine 124 (0.012 g, 0.025 mmol) was added a solution of trifluoroacetic acid in dichloromethane (20% v/v, 2 mL). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. Methanol (1 mL) and dichloromethane (9 mL) were added. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-5-[(S)-3-benzylpiperazin-1-yl]-[1,2,4]triazine 12 (0.0041 g, 0.0106 mmol).