Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[CH3:37][N:38]1[CH:43]2[CH2:44][CH2:45][CH:39]1[CH2:40][C:41](=O)[CH2:42]2>>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]1[CH:3]=[C:2]([NH:1][CH:41]2[CH2:42][CH:43]3[N:38]([CH3:37])[CH:39]([CH2:45][CH2:44]3)[CH2:40]2)[CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: CN1C2CCC1CC(=O)C2
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NC4CC5CCC(C4)N5C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]-3,4-dihydroquinazolin-2(1H)-one was prepared from 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one by a procedure analogous to that described in EXAMPLE CCC18, STEP A. Mass spectrum (ESI) 661 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:33]=[C:32]([C:34](=[NH:37])[NH:35]O)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27]>>[Cl:17][C:18]1[CH:33]=[C:32]([C:34]2[N:37]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:35]=2)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H](O)CNC(=O)CO
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Product: COc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(Cl)c3)no2)cc(C2CCCC2)n1
Yield: 57.8 %

Procedure:
The title compound (135 mg) is prepared in analogy to Example 6 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid (100 mg, 452 μmol) and (S)—N-(3-[2-chloro-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (150 mg, 452 μmol): LC-MS**: tR=0.85 min, [M+H]+=517.21; 1H NMR (CDCl3): δ1.69-1.80 (m, 2H), 1.83-1.95 (m, 4H), 2.06-2.15 (m, 2H), 2.42 (s, 3H), 3.19-3.29 (m, 1H), 3.53-3.61 (m, 1H), 3.81 (ddd, J=14.1, 6.5, 3.5 Hz, 1H), 3.97-4.01 (m, 1H), 4.01 (s, 3H), 4.06 (dd, J=9.5, 4.8 Hz, 1H), 4.21 (s, 2H), 4.21-4.26 (m, 1H), 7.12 (t br, J=6.0 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H).
Reaction SMILES: C([CH:8]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][NH:21][C:22]([CH:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[N:26]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]3[NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:25]2[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=2[Cl:53])=[O:23])[N:14]=1)[C:9]([O-:11])=[O:10])C1C=CC=CC=1.CN(C=O)C>[Pd].C(O)C>[Cl:53][C:47]1[CH:48]=[C:49]([Cl:52])[CH:50]=[CH:51][C:46]=1[CH:25]1[CH:24]([C:22]([NH:21][CH2:20][CH2:19][C:15]2[N:14]=[C:13]([O:12][CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:17][CH:16]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[NH:41][S:42]([CH3:45])(=[O:43])=[O:44]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OC(Cc3ccccc3)C(=O)[O-])n2)C1c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)O)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a mixed liquid of 420 mg of benzyl({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([N:33]3[CH2:34][CH2:35][N:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:38]3)(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide and ethyl 2-(4-{[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-1-piperazinyl)acetate in substantially the same manner, as described in Example 50. The product was obtained as a light yellow solid; mp: 91-92° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.08-1.17 (t, 3H), 1.49-1.56 (m, 2H), 2.02-2.07 (m, 2H), 2.45-2.50 (m, 4H), 2.52-56 (m, 2H), 2.74-80 (m, 2H), 2.86-3.01 (m, 5H), 3.20 (s, 2H), 3.24-3.36 (m, 4H), 3.96-3.99 (d, 2H), 4.01-4.07 (q, 2H), 4.69-4.71 (m, 1H), 6.86-6.88 (d, 2H), 7.05-7.09 (m, 3H), 7.23-7.24 (m, 1), 7.47-7.50 (d, 2H), 8.20 (brs, 4H); MS m/z 640 (M+H)+; Analysis for C28H41N5O8S2×1.0 F3CCO2H×0.18 CH2Cl2 Calc'd: C, 47.13; H, 5.55; N, 9.11; Found: C, 47.02; H, 5.75; N, 8.67.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH3:12])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH3:20]I.[OH-].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[N:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:10]=1[CH2:11][CH3:12])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][CH3:12])=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:8]([CH3:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(-c2ccc(Cl)cc2)c1CC
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1c(CC)c(-c2ccc(Cl)cc2)nn1C
Product: CCOC(=O)c1nn(C)c(-c2ccc(Cl)cc2)c1CC

Procedure:
In analogy to the procedure described for example 2 a], 5-(4-chloro-phenyl)-4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester was reacted with methyl iodide in the presence of potassium hydroxide to to give 5-(4-chloro-phenyl)-4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as yellow crystals and 5-(4-chloro-phenyl)-4-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C)[CH:7]=[C:6]2[C:13]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][CH:23]=O)[N:20]=[C:15]2[CH:14]=1.[CH3:34]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1([CH3:34])[CH:11]=[CH:10][C:9]2[C:5]([C:6]([C:13]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[C:16]4[N:17]=[CH:18][C:19]5[N:20]([CH:23]=[N:22][CH:21]=5)[C:15]=4[CH:14]=3)=[CH:7][N:8]=2)=[CH:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC=O)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC1(C)C=CC2=NC=C(c3cc4c(ncc5cncn54)n3COCC[Si](C)(C)C)C2=C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.10 g, 0.22 mmol) in 1,4-dioxane (4 mL) was treated with Lawesson's Reagent (0.053 g, 0.13 mmol) and heated to about 80° C. in an oil bath for about 15 min. The mixture was cooled and mercuric acetate (0.073 g, 0.23 mmol, Fluka) was added. The mixture was stirred for about 30 min at ambient temperature and another portion of mercuric acetate (0.073 g, 0.228 mmol, Fluka) was added and stirring was continued for about 2 h at ambient temperature. The mixture was diluted with EtOAc (20 mL) and filtered. The solvent was evaporated under reduced pressure then the material was purified by silica gel chromatography eluting with DCM/MeOH (95:5). The material obtained after concentration of the product-containing fractions was further purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-5-methyl-5H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 49%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 448 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ClCCl.[NH2:60][CH2:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][OH:72])[CH2:66][CH2:65]1>C(N(CC)CC)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:60][CH2:61][CH2:62][CH2:63][N:64]5[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][OH:72])[CH2:68][CH2:69]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCN1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a mixture of 0.051 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0494 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.6 mL of dichloromethane, 0.6 mL of dimethylformamide, 0.12 mL of triethylamine was added followed by 0.0235 g (0.13 mmole) of 2-[4-(3-amino-propyl)-piperazin-1-yl]-ethanol. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0054 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-3-methoxy-benzamide (I-96).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[SH:10].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:3][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:1]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2c([nH]1)CCCC2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2c([nH]1)CCCC2
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-2-thiol (500 mg) in acetone (5 mL) were added K2CO3 (1344 mg) and MeI (0.223 mL) at room temperature. After stirring for 1 h, the mixture was quenched with water, and extracted with ethyl acetate, and the extract was washed with brine and dried over magnesium sulfate. The residue was purified by column chromatography (silica gel, eluted with 40%-90% EtOAc in hexane) to give 2-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-benzimidazole (545 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)[CH:2]=[CH2:3].C(=O)(OCC=C)O[CH2:17][CH:18]=[CH2:19]>Cl[Pd]Cl>[CH2:19]([N:8]1[C:7]([CH3:14])([CH3:13])[CH2:6][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH2:10][C:9]1([CH3:12])[CH3:11])[CH:18]=[CH2:17]
Reactant: C=CCOC1CC(C)(C)NC(C)(C)C1
Reactant: C=CCOC(=O)OCC=C
Agent: Cl[Pd]Cl
Product: C=CCOC1CC(C)(C)N(CC=C)C(C)(C)C1
Temperature: 110 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
4-allyloxy-2,2,6,6-tetramethyl-piperidine (150 g, 0.76 mol), di-allyl carbonate (115 g, 0.8 mol) and PdCl2 (1.35 g, 1.6 mmol) are charged under nitrogen atmosphere into a 3-necked 500 ml-flask equipped with a thermometer and a reflux condenser. The solution is heated under stirring to 110° C. for 24 hours. Gas-chromatographic analysis of the reaction mixture then shows that the reaction produced the desired 1-allyl-4-allyloxy-2,2,6,6-tetramethyl-piperidine in 63% yield (calculated on the starting 4-allyloxy-2,2,6,6-tetramethyl-piperidine) and >97% selectivity.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.O.[NH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2cccc3nsnc23)CC1

Procedure:
The title compound was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 2.57 (t, J=6.21 Hz, 2H), 3.77 (t, J=6.21 Hz, 2H), 7.60-7.84 (m, 1H), 8.25-8.32 (m, 1H), 8.40-8.46 (m, 1H); MS (ES) m/z 297.9 (MH+). C11H11 N3O3S2
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([N+:34]([O-:36])=[O:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([N+:34]([O-:36])=[O:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c([N+](=O)[O-])cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c([N+](=O)[O-])cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-nitrobenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]1)=[O:38]>C(N(CC)CC)C>[CH3:35][O:36][C:37]([CH:39]1[CH2:44][CH2:43][CH:42]([CH2:45][NH:46][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([CH2:17][S:14]([CH:13]=[C:11]3[CH2:12][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:10]3)(=[O:16])=[O:15])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: COC(=O)C1CCC(CN)CC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(CNC(=O)c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Yield: 38.2 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 39 mg of 4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride. 47 mg of 4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl ester are thus obtained in the form of a pale yellow paste [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 0.90 to 1.05 (mt, 2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt, 1H), from 1.70 to 2.00 (mt, 4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12 (t, J=6.5 Hz, 2H), 3.60 (s, 3H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.50 (t, J=6 Hz, 1H)].
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C@@H:27]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][N:29](CC3C=CC(OC)=CC=3OC)[C:28]2=[O:47])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C@@H:27]2[CH2:33][C:32]([F:34])([F:35])[CH2:31][CH2:30][NH:29][C:28]2=[O:47])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
A cocktail containing 40% trifluoroacetic acid, 1% trifluoromethanesulfonic acid in CH2Cl2 (20 ml) was added to 4-chloro-N-[(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-benzenesulfonamide (0.5 g, 1.0 mmol). After 30 min the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water, NaHCO3 solution, 1 M KHSO4 solution, brine, dried (MgSO4.2H2O), filtered, concentrated under reduce pressure and purified over silica gel (CH2Cl2/MeOH 95:5 v/v): white solid 0.74 g (78%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Solvent: ClCCl
Solvent: CCO
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 52 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and 1N aqueous solution of sodium-hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 90 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (170 mg, 91%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:14][O:15][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:16][O:17][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:12][C:7]=2[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:20])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:23]=1)#[N:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (0.600 g, 1.21 mmol, as prepared in the previous step) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated with Et3N (421 μL, 3.02 mmol) and methanesulfonyl chloride (190 μL, 2.42 mmol). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded the title compound (0.551 g, 70%) as a white solid. Mass spectrum (APCI, m/z): Calcd. for C28H40N4O8S2Si, 653.2 (M+H). found 652.8.
Reaction SMILES: [C:1](Cl)(=[O:15])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2>>[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[N:20]([C:1]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH2:19][CH2:18]2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=C(Cl)Oc1ccccc1-c1ccccc1
Product: O=C(Oc1ccccc1-c1ccccc1)N1CCN2CCC1CC2
Yield: 14.7 %

Procedure:
Biphenyl-2-yl carbonochloridate (83.0 mg, 0.358 mmol) was treated with 1,4-diazabicyclo[3.2.2]nonane (113 mg, 0.896 mmol) using the same procedure reported in example 46 to afford the title compound as an off-white solid (17 mg, 15%). Purity: >99% UPLCMS (210 nm); retention time 0.75 min; (M+1) 323.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc2c(c1)NCCO2
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
To a 1.0 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-2-one (100 mg, 0.436 mmol) was dissolved in tetrahydrofuran (1.0 ml). To the reaction mixture, 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (0.524 ml, 0.524 mmol) was added dropwise at 0□, and then stirred for 20 minutes. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with ethyl acetate and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and diisopropyl ether to obtain white solid (63 mg, 67%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19](=[N:22]O)([NH2:21])[CH3:20].[F:24][C:25]([F:42])([F:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35](C(O)=O)=[CH:34][CH:33]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:22]=[C:19]([CH3:20])[N:21]=2)[N:8]([C:6]([C:35]2[CH:34]=[CH:33][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([F:24])([F:41])[F:42])=[CH:37][CH:36]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(N)=NO
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Product: CON=C1C[C@@H](c2nc(C)no2)N(C(=O)c2ccc(-c3ccccc3C(F)(F)F)cc2)C1
Yield: 44 %

Procedure:
Following the general methods as outlined in Example 1 (Method B), starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), N′-hydroxyethanimidamide (Intermediate 7) and 2′-(trifluoromethyl) [1,1′-biphenyl]-4-carboxylic acid (Intermediate 10), the title compound was isolated, after flash-chromatography, as a mixture of E-/Z-isomers as an oil in 44% yield (88.2% purity by HPLC).