Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:29](=[O:31])[NH2:30])[CH2:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([C:29](=[O:31])[NH2:30])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)O)C(N)=O
Yield: 101 %

Procedure:
Benzyl t-butyloxycarbonyl-L-valyl-D-isoglutaminate (7.5 g, 17.2 mmol) was catalytically hydrogenated in methanol (150 ml) using palladium black as a catalyst at room temperature for 6 hours. The catalyst was filtered and the solvent was evaporated. Petroleum ether was added to the residue. After trituration, the resulting powder was filtered. Reprecipitation from ethyl acetate/petroleum ether gave t-butyloxycarbonyl-L-valyl-D-isoglutamine (6.0 g). m.p. 89°-90° C. (dec.). [α]D23 +9.46° (C 0.5, DMF). Rf2 =0.32.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8](Cl)[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[Mg].[S:19](Cl)(Cl)=[O:20]>C1COCC1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([S:19]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:7]=2)=[O:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)Oc1ccc(Cl)cc1OC(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(S(=O)c2ccc(OC(C)(C)C)c(OC(C)(C)C)c2)cc1OC(C)(C)C
Yield: 64 %

Procedure:
A Grignard reagent was conventionally prepared using 3,4-di-tert-butoxyphenyl chloride, magnesium, and THF and further reacted with thionyl chloride, obtaining bis(3,4-di-tert-butoxyphenyl) sulfoxide in a yield of 64%. Then 58.9 g (0.12 mol) of bis(3,4-di-tert-butoxyphenyl) sulfoxide was dissolved in 120 g of THF and cooled in an ice water bath. Then 12.1 g (0.12 mol) of triethylamine was added thereto and 68.3 g (0.31 mol) of trimethylsilyl triflate was added dropwise in a controlled manner at less 10° C. To this solution, a Grignard reagent which was conventionally prepared using 61.6 g (0.24 mol) of 1,2-di-tert-butoxy-4-chlorobenzene, 5.8 g (0.24 mol) of magnesium, and 100 g of THF was added dropwise in a controlled manner at less 10° C. With the reaction temperature controlled at 0° to 10° C., reaction ripening was carried out for 30 minutes. A 20% ammonium chloride aqueous solution, 700 g, was added to the reaction solution to terminate reaction, followed by separation. 300 g of chloroform was added to the organic layer. The organic layer was washed twice using 300 g of water and then evaporated, obtaining an oily residue. The oily residue was worked up by column chromatography (silica gel, eluent: chloroform/methanol), obtaining tris(3,4-di-tert-butoxyphenyl)sulfonium trifluoromethanesulfonate of 99% purity in a yield of 20%. The final percent yield of this two-steps synthesis process was 13%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32]Cl)=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:57])([F:56])[C:38]1[CH:39]=[C:40]([CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1)[CH2:41][NH:42][C:43]1[N:44]=[N:45][N:46]([CH3:48])[N:47]=1.CC(C)([O-])C.[K+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32][N:42]([C:43]3[N:44]=[N:45][N:46]([CH3:48])[N:47]=3)[CH2:41][C:40]3[CH:39]=[C:38]([C:37]([F:36])([F:56])[F:57])[CH:51]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:49]=3)=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: Fc1cc2cc(CCl)c(N3CCC[C@@H]3C3CCC(CCOCc4ccccc4)CC3)nc2cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CCOCc3ccccc3)CC2)n1
Reaction time: 1 h

Procedure:
Methaneslufonyl chloride (5.5 mL, 71 mmol) is added dropwise to a mixture of [2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-yl]methanol (13.7 g, 28.5 mmol) and N,N-diisopropylethylamine (DIPEA, 12.4 mL, 71 mmol) in toluene (150 mL) at 5° C., and the reaction mixture is stirred at ambient temperature for 2 hours. To the mixture, water and ethyl acetate are added and the organic layer is washed with sat. NaHCO3 aq, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give crude 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-3-(chloromethyl)-6,7-difluoroquinoline. To a mixture of 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-3-(chloromethyl)-6,7-difluoroquinoline and N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine (13.9 g, 43 mmol) in DMF (120 mL) is added potassium tert-butoxide (4.80 g, 43 mmol) at 5° C. The resulting mixture is stirred for 1 hour at the same temperature. After adding sat. NH4Cl aq., the mixture is extracted with ethyl acetate. The combined organic layer is washed with water, brine, dried over magnesium sulfate, filtrated, and concentrated. The resulting mixture is purified by silica gel column chromatography to give trans-N-[2-((R)-2-{-4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinolin-3-ylmethyl]-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine as a yellow amorphous.
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH:8]=[CH:9][C:10](C#N)=[C:11]4[C:24]=3[C:15]([C:16]3[C:21]=2[C:20]=1[C:19](C#N)=[CH:18][CH:17]=3)=[CH:14][CH:13]=[C:12]4C#N)#N.[C:29]([C:31]1[CH:32]=[CH:33][C:34]2[C:35]3[CH:36]=[CH:37][C:38]([Br:55])=[C:39]4[C:52]=3[C:43]([C:44]3[C:49]=2[C:48]=1[C:47]([C:50]#[N:51])=[CH:46][CH:45]=3)=[CH:42][CH:41]=[C:40]4[C:53]#[N:54])#[N:30].BrC1C=CC2C3C=CC(Br)=C4C=3C(C3C=2C=1C(Br)=CC=3)=CC=C4Br>[N+](C1C=CC=CC=1)([O-])=O>[C:29]([C:31]1[CH:32]=[CH:33][C:34]2[C:35]3[CH:36]=[CH:37][C:38]([Br:55])=[C:39]4[C:52]=3[C:43]([C:44]3[C:49]=2[C:48]=1[C:47]([C:50]#[N:51])=[CH:46][CH:45]=3)=[CH:42][CH:41]=[C:40]4[C:53]#[N:54])#[N:30].[CH:8]1[C:7]2=[C:24]3[C:15]([C:16]4[C:21]5[C:20](=[CH:3][CH:4]=[CH:5][C:6]2=5)[CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: N#Cc1ccc2c3ccc(C#N)c4c(C#N)ccc(c5ccc(C#N)c1c25)c43
Agent: Brc1ccc2c3ccc(Br)c4c(Br)ccc(c5ccc(Br)c1c25)c43
Agent: N#Cc1ccc2c3ccc(C#N)c4c(C#N)ccc(c5ccc(Br)c1c52)c43
Solvent: O=[N+]([O-])c1ccccc1
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
DE 340091 describes the preparation of 3,4,9,10-tetracyanoperylene from 3,4,9-tricyano-10-bromoperylene. 3,4,9-tricyano-10-bromoperylene was prepared from 3,4,9,10-tetrabromo-perylene, which was obtained by bromination of perylene in nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][C:17]([NH:19][CH2:20][C@H:21]2[O:25][C@@H:24]([N:26]3[CH:33]=[C:32]([CH2:34][CH3:35])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[CH2:23][C@@H:22]2[OH:36])=[O:18])=[C:11]([CH3:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([O:36][C@@H:22]1[C@@H:21]([CH2:20][NH:19][C:17](=[O:18])[CH2:16][C:12]2[C:11]([CH3:37])=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[CH3:15])[O:25][C@@H:24]([N:26]2[CH:33]=[C:32]([CH2:34][CH3:35])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:23]1)(=[O:40])[CH3:39]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(C)cc(OCc4ccccc4)cc3C)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CNC(=O)Cc3c(C)cc(OCc4ccccc4)cc3C)O2)c(=O)[nH]c1=O

Procedure:
0.25 g of 5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine was stirred as a slurry in 5 ml of dry pyridine with 0.4 ml of acetic anhydride for 72 hours. The resulting solution was evaporated in vacuo and the residue was re-evaporated three times with toluene. After trituration with diethyl ether and filtration there was obtained 0.22 g of crude product of melting point 188°-191° C. Recrystallization from a mixture of 4 ml of methylene chloride and 4 ml of petroleum ether gave 0.20 g of pure 3'-O-acetyl-5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine of melting point 194°-196° C. (dec).
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O.C(OCC)(=O)C>[N+](CC)([O-])=O.O>[C:21]([C:7]1[N:2]=[C:3]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1)#[N:22]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)CCc1cccc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
tert-Butyl 3-(1-oxido-2-pyridyl)propanoate (0.88 g, 3.9 mmol) was dissolved in nitroethane (5 ml). Trimethylsilyl cyanide (0.78 g, 7.9 mmol) and N,N-dimethylcarbamoyl chloride (0.85 g, 7.9 mmol) were added thereto. The reaction mixture was stirred at room temperature for 48 hrs, combined with ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel (50 g) column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to give the titled compound (0.75 g, 82%). 1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.74 (2H, t, J=7.1 Hz), 3.12 (2H, t, J=7.1 Hz), 7.41 (1H, d, J=7.8 Hz), 7.52 (1H, d, J=7.8 Hz), 7.72 (1H, t, J=7.8 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:36])[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([CH3:25])[CH3:24])=[N:18][C:17]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:23]([CH3:25])([C:22](=[O:36])[NH:21][C:19]2[S:20][C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[C:17]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:18]=2)[CH3:24])=[O:35])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-{2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (120 mg) and TFA (3 mL) in dichloromethane (3 mL) was stirred at RT for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4 and concentrated. The residue was taken up in dichloromethane-methanol (3:1 v/v), and 2 M HCl (in ether, 100 uL) was added. The mixture was stirred at RT for 10 min and concentrated to give hydrochloride salt of the title compound. LCMS method A, retention time 1.0 min. m/z 496.1 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[CH2:13]([O:15][C:16](=[O:34])[C@H:17]([NH2:33])[CH2:18][CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]OS(C)(=O)=O)[CH3:14].O>CN(C)C=O>[CH2:13]([O:15][C:16](=[O:34])[C@H:17]([NH2:33])[CH2:18][CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][S:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:14]
Reactant: CCOC(=O)[C@H](N)CC(COS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](N)CC(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (5.5 g, 137.8 mmol) and 4-methoxybenzylmercaptan (15.4 mL, 110.2 mmol) were dissolved in N,N-dimethylformamide (150 mL), and the mixture was stirred for 10 min at 0° C. To the resulting solution was added in drops (R)-4-BOC-amino-5-methanesulfonyloxy-pentanoic acid ethyl ester (46.7 g, 137.8 mmol) prepared in Step B, and the mixture was stirred for 4 h at 0° C. Water was added thereto to quench the reaction, and the reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([C:11]2[N:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=2)([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][C:29]=2[F:38])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:38][C:29]1[CH:30]=[C:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH:32]=[CH:33][C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([OH:10])([C:11]3[N:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=3)[CH3:9])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(O)(c1cn(CCO)nn1)c1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(C)(O)c4cn(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 1-(6-bromopyridin-2-yl)-1-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]ethanol (128 mg, 0.41 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (120 mg, 0.41 mmol) according to the general procedure in Example 1.
Reaction SMILES: C(OC([N:8]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1)[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[NH:19][CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=2)[CH:10]=1)=O)(C)(C)C>C1(C)C=CC=CC=1>[N+:30]([C:26]1[CH:25]=[C:24]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[NH:19][CH:18]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=3)[CH:10]=2)[CH:29]=[CH:28][CH:27]=1)([O-:32])=[O:31]
Reactant: COC(=O)c1c[nH]c(-c2cc(N(C(=O)OC(C)(C)C)c3cccc([N+](=O)[O-])c3)ccn2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c(-c2cc(Nc3cccc([N+](=O)[O-])c3)ccn2)c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (0.40 g, 0.91 mmol) was taken up in toluene (38 mL) and SiO2 (9.0 g) was added. The mixture stirred at reflux for 20 h. The mixture was cooled to rt and filtered over celite, washing with EtOAc. The filtrate was concentrated to a bright orange color. The solid was taken up in hexanes and filtered. The solid was then washed with CH2Cl2/hexanes to afford methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (0.15 g, 49% yield) as a bright yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[N:15][C:16]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[B-][N+](C)(C)C>C(O)(=O)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [B-][N+](C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 97 %

Procedure:
A solution containing 2-(1-Boc-piperidin-4-yl-methylidene)amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide from above (6.0 g, 13 mmol) and borane trimethylamine complex (2.9 g, 39 mmol) in glacial acetic acid (100 mL) was heated at 70° C. for 24 h. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo, and the residue was partitioned between dichloromethane (200 mL) and water (100 mL). The biphasic mixture was treated with 2 N NaOH until neutral; then the organic layer was separated and the aqueous layer was washed again with dichloromethane (100 mL). The combined organic layers were washed with brine (100 mL), dried with MgSO4, and filtered. The filtrate was concentrated in vacuo to give 5.85 g (97%) of the title compound as an orange foam which was used directly in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][N:17]=1.C(OCC)(=O)C>C1COCC1.O>[C:1]([NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][N:17]=1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(Nc2nc(NCCN)ncc2C(N)=O)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCNc1ncc(C(N)=O)c(Nc2cccc(C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An 87 μl portion of acetyl chloride and −170 μl of triethylamine were added to a mixture of 318 mg of 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide and 20 ml of ethyl acetate, followed by stirring at room temperature for 30 minutes. Water and THF were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from a mixed solvent of THF and ethyl acetate, thereby obtaining 198 mg of 2-[(2-acetylaminoethyl)amino]-4-(3-methylanilino)pyrimidine-5-carboxamide (colorless crystals).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=2)(=[O:25])=[O:24])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([S:23]([NH:22][CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:25])=[O:24])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)c(Cl)c2)(c2ccc(I)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NCC1(c2ccc(I)cc2)CCNCC1)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of 4-[(3-chloro-4-fluoro-benzenesulfonylamino)-methyl]-4-(4-iodo-phenyl)-piperidine-1 carboxylic acid tert-butyl ester (0.09 g, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL, to give a 25% v/v solution). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum for 1 h to give 3-chloro-4-fluoro-N-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-benzenesulfonamide as a reddish solid (0.021 g, ˜0.04 mmol). MS: 509/511 (M+1).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]2([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]2)[CH2:4][CH2:3]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][CH2:4][C:5]32[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]3)=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)C2(CCC(O)c3ccc(F)cc32)N1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2(CC=Cc3ccc(F)cc32)N1
Yield: 87 %

Procedure:
3',4',-Dihydro-4'-hydroxy-7'-fluorospiro[imidazolidine-4,1'(2'H)-naphthalene]2,5-dione (3.2 g., 0.013 mole) was added to 75 ml. of toluene containing a trace of -toluenesulfonic acid and the mixture heated to reflux for 5 hours. The toluene was removed in vacuo and the residue triturated with diethyl ether and filtered, 2.6 g. (87% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f6) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)1-(4-methyl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)1-(4-methyl-benzyl)-piperidine-4-carboxylic acid ethyl ester (4.3 g, 9.9 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (40%). white solid mp 207-208° C., MS: 404.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].[H][H].Cl>CO.C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[CH:24]=4)=[CH:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: [H][H]
Reactant: O=C1C=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CCOCC
Solvent: CO
Product: O=C(c1ccc(C2=CC(O)CCC2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 99.7 %

Procedure:
3-[4-(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-cyclohex-2-enone of Example 24 (0.100 g, 0.261 mmol) and cerium (III) chloride (0.064 g, 0.261 mmol) were dissolved in methanol (1.3 mL) followed by addition of solid sodium borohydride (0.010 g, 0.261 mmol). After hydrogen evolution ceased (approximately 5 minutes), 0.1 N hydrochloric acid (50 mL) was added and the resulting mixture extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. A slightly yellow solid was isolated which was dissolved in boiling diethyl ether and filtered. The product was precipitated from the filtrate by addition of pentane and the precipitate filtered and dried to afford the title compound (0.100 g) as an amorphous white solid.