Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[OH2:26].NN.Cl>C(Cl)(Cl)Cl.CO.O1CCCC1>[CH2:16]([C:14]1[CH:13]=[CH:12][C:3]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:1][CH:2]([CH3:15])[C:3](=[O:26])[NH:1][C:2]=2[CH:15]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: O
Agent: Cl
Agent: NN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2c(c1)NC(=O)C(C)N=C2c1ccccc1
Temperature: 25 °C
Yield: 132.9 %

Procedure:
2-Amino-4-decylbenzophenone (4.16 g) was dissolved in chloroform (40 ml) and phthaloylalanyl chloride (3.22 g) was added thereto with stirring at room temperature. The mixture was stirred for 0.5 hour. The reaction mixture was washed with 5% aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and the oily substance obtained was dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (40 ml). Thereto was added hydrazine monohydrate (1.56 g) with stirring under ice-cooling and the mixture was stirred for 2 hours. Conc. hydrochloric acid (1 ml) was added thereto with stirring at room temperature and the mixture was stirred at 60° C. for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was extracted with chloroform and washed with 5% aqueous sodium hydrogencarbonate and water. The residue was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Isopropyl alcohol (60 ml) and acetic acid (1 ml) were added to the concentrate and the mixture was stirred at 70° C. for 1 hour. After cooling, the residue obtained by concentration under reduced pressure was extracted with chloroform and washed with 5% aqueous sodium hydrogencarbonate and water. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 3.2 g of 8-decyl-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccccc2Cl)c2ccsc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are sitrred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of o-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate, whereupon the solvent is distilled off. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-chlorophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 168°-170° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (55 mg, 79%), MS (ISP) m/z=435.4 [(M+H)+], mp 221° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) and benzoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[O:13])=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(C(=O)C(=O)c2ccc(N)cc2)cc1
Temperature: 0 °C

Procedure:
3.8 g of 4,4′-dinitrobenzil was reduced under hydrogen with 3.8 g 10% Ru on C in EtOH. The mixture was filtered through Supracel and the filtrate concentrated under vacuum to dryness. The residue was dissolved in 50% denatured ethanol in water, treated with Darco and filtered. The filtrate was cooled to 0° C. and the resulting crystals were collected and washed with 50% denatured ethanol in water. The crystals were then dried under a heat lamp to give the title compound as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:31][CH2:30][NH:29][C@H:28]2[CH2:32][NH:33][CH2:34][C@@H:27]12>>[O:26]1[CH2:31][CH2:30][NH:29][C@H:28]2[CH2:32][N:33]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[N:5]=[C:4]([N:13]4[CH2:19][C:18]5[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=5[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]4)[CH:3]=3)[CH2:34][C@@H:27]12
Reactant: C1CO[C@@H]2CNC[C@@H]2N1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H]4NCCO[C@@H]4C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (4aS,7aR)-octahydropyrrolo[3,4-b][1,4]oxazine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.26 Hz, 1 H), 7.85 (d, J=7.33 Hz, 1 H), 7.81 (s, 1 H), 7.63 (td, J=7.52, 1.39 Hz, 1 H), 7.50-7.41 (m, 2 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 4.51 (m, 2 H), 4.02-4.15 (m, 3 H), 3.86 (d, J=10.8 Hz, 1 H), 3.68-3.47 (m, 6 H), 3.238 (m, 1 H), 2.72 (m, 1 H), 2.41 (s, 3 H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CN1CCOCC1.[CH:32]([O:35][C:36](Cl)=[O:37])([CH3:34])[CH3:33]>ClCCl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:36]([O:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)s1
Reactant: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)CC1

Procedure:
To a suspension N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-(piperidin-4-yl)thiophene-2-carboxamide (0.103 g, 0.249 mmol) in dichloromethane (2 ml) was added N-methylmorpholine (0.110 ml, 0.997 mmol) followed by isopropylchloroformate (0.374 ml, 0.374 mmol). A second portion of isopropylchloroformate (0.4 ml) was added and after 1 hour the mixture was directly purified by normal phase chromatography to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.05 (t, J=6.0 Hz, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 6.96 (d, J=3.8 Hz, 1H), 6.88 (dd, J=7.0, 1.7 Hz, 1H), 4.78 (hept, J=6.2 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.05 (d, J=12.9 Hz, 2H), 3.10-2.97 (m, 1H), 2.98-2.81 (m, 2H), 2.01-1.88 (m, 2H), 1.57-1.38 (m, 2H), 1.19 (d, J=6.2 Hz, 6H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:36][CH:37]=1
Reactant: CCCCCC(=O)Cl
Reactant: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
In a stream of nitrogen and at 0° C., 0.15 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-(4-methoxybenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 6 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 98.8%) of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH:15][C:10]=3[N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[O:29][CH3:30])[C:8]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Ni]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:9]2[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=3[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:31])=[C:21]([O:29][CH3:30])[CH:22]=1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc([N+](=O)[O-])cc1OC
Agent: [Ni]
Solvent: CCO
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(N)cc1OC
Yield: 83 %

Procedure:
A mixture of 3.5 g of the compound obtained in Example 5 in 350 ml of absolute EtOH, in the presence of Raney nickel, is hydrogenated for 20 hours at RT and at a pressure of 60 bar. The reaction mixture is filtered on Celite and the filtrate is evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM/EtOAc mixture (90/10; v/v). 2.7 g of the expected product are obtained after crystallization from an iso ether/EtOAc mixture, mp=191° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.[CH:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29](=[O:32])[NH:30]/[N:31]=[C:5]2/[C:6](=[O:20])[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8]3[C:4]/2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Reactant: NNC(=O)NC1CCCCC1
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NC2CCCCC2)c2cc(Br)ccc21)C(C)C
Yield: 89.9 %

Procedure:
By using 5-bromo-1-(2-diisopropylaminoethyl)isatin and 4-cyclohexylsemicarbazide, a method analogous to that described in Example 16 was carried out to obtain (E)-5-bromo-1-(2-diisopropylaminoethyl)isatin 3-(4-cyclohexylsemicarbazone) having a melting point of 155°-156° C. (yield: 89.9%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[F:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[F:41]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:42]([C:37]2[CH:38]=[CH:39][C:40]([F:41])=[C:35]([F:34])[CH:36]=2)(=[O:44])=[O:43])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(F)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.8 g, 3.92 mmol) in DMF (3 mL) is added BEMP (1.81 mL, 6.27 mmol). After 1 hour, the reaction mixture is cooled to 0° C. and a solution of 3,4-difluoro-benzenesulfonyl chloride (0.83 mL, 6.27 mmol) in DMF (3 mL) is added. The reaction mixture is allowed to warm to room temperature, stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 30% EtOAc in iso-hexane to afford [1-(3,4-difluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=381.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1(C=O)[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([CH:14]3[CH2:16][CH2:15]3)[CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH2:5]1.C([Li])CCC>O1CCCC1>[CH:14]1([N:9]2[CH2:8][C:7]([CH3:17])([CH3:18])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]#[CH:2])[CH:5]=3)[CH2:10]2)[CH2:16][CH2:15]1
Reactant: CC1(C)CN(C2CC2)CC2=C1CC(C=O)(C=C(Br)Br)C=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-(2,2-dibromo-vinyl)-2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 26, 0.18 g, 0.47 mmol) in tetrahydrofuran (2 mL) was treated with 1.6M solution of n-butyl lithium (0.6 mL, 0.96 mmol) under argon. The reaction mixture was allowed to warmn to −20° C. over 1.5 h, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as an oil (0.1 g, 94%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:18])[C@@H:13]([CH3:32])[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@@H:13]2[CH3:32])=[O:18])[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNCCN1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.9 %

Procedure:
(S)-1-Benzyloxycarbonyl-4-[1-(tert-butoxycarbonyl)-piperidine-4-carbonyl]-3-methylpiperazine (D20)(0.38 g) was dissolved in ethanol (10 ml) and hydrogenated at atmospheric pressure over 10% Palladium on charcoal (10% water paste, catalytic quantity). After 16 h the catalyst was removed by filtration and the filtrate was evaporated to give the title compound (D21) as a white powder (0.26 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[O:5][C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C@@H:3]1[CH2:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[N:27]1.[O:37]1CCCC1.I([O-])(=O)(=O)=O.[Na+].[K]>C(O)(C)(C)C>[CH:6]([O:5][C@H:4]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C@H:3]([CH2:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[N:27]1)[C:2]([OH:37])=[O:1])=[O:7]
Reactant: COc1ccc(-c2ccc(CC[C@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Reactant: C1CCOC1
Agent: [K]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Product: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound obtained from step d above (8 g) in tert-butanol:tetrahydrofuran (40 mL:40 mL) at 0° C., a solution of sodium metaperiodate (14 g in 40 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature, and potassium permangnate (518 mg) was added at 0° C. After stirring the reaction mixture for an additional 6 hours at room temperature, the reaction mixture was evaporated on a rotary evaporator. The residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under the reduced pressure, to afford the title compound (8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:27](O)=[O:28])[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[C:25]=1[F:26])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:27](=[O:28])[NH:73][CH2:72][C:71]2[CH:70]=[CH:69][C:68]([S:65]([CH3:64])(=[O:67])=[O:66])=[CH:75][CH:74]=2)[C:7]2[NH:11][C:10]([NH:12][C:13]([C:15]3[N:16]=[CH:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:14])=[N:9][C:8]=2[C:25]=1[F:26])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCOc1cc(C(=O)O)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 42.3 %

Procedure:
30 mg (0.08 mmol) of 6-ethoxy-7-fluoro-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid and 100 mg (0.25 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.3 mL of DIEA and treated with 30 mg (0.14 mmol) of 4-methanesulfonyl-benzylamine hydrochloride as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 19 mg (45%) of isoquinoline-3-carboxylic acid [5-ethoxy-4-fluoro-7-(4-methanesulfonyl-benzylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 562 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][O:19]CC.B(Br)(Br)Br>ClCCl>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][OH:19])[N:4]([CH2:3][C:2]([CH3:27])([CH3:1])[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(Cn1c(CO)nc2c(N)nc3ccccc3c21)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a suspension of 1-[2,2-dimethyl-3-(methylsulfonyl)propyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.02 mmol) in dichloromethane (5 mL) was added boron tribromide (5.1 mL, 1M solution in dichloromethane). An exotherm was observed upon addition and the mixture turned light purple. After stirring at ambient temperature for 20 hours, the remaining starting material was consumed by adding boron tribromide (2.5 mL, 1M solution in dichloromethane). The reaction was quenched with aqueous hydrochloric acid (1N, 20 mL) to afford a homogeneous mixture. The layers were separated and the aqueous layer washed with dichloromethane (20 mL). The pH of the aqueous layer was adjusted to 12 by addition of aqueous sodium hydroxide (50%) at which time a solid precipitated out of solution. The solid was stirred for 18 hours, collected by filtration and washed with water. The crude product was purified by chromatography over silica gel (eluting with CMA) to afford a white powder. The powder was triturated with methanol (20 mL). The resulting solid was isolated by filtration, washed with methanol and dried for 4 hours at 65° C. to provide 150 mg of {4-amino-1-[2,2-dimethyl-3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-2-yl}methanol as a white powder, mp 230-232° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I.[Cl-].[NH4+]>C1COCC1>[I:37][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: II
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
15 g of 4-nitrophenylethanol, 28.1 g of triphenylphosphine and 9.2 g of imidazole are dissolved in 500 ml of THF, mixed in portions with 27.77 g of iodine and stirred for 2 hours at room temperature. The reaction mixture is mixed with ammonium chloride solution and extracted with dichloromethane. The organic phase is washed in succession with sodium thiosulfate solution and water and dried on sodium sulfate. After purification by chromatography on silica gel, 23.22 g of the title compound is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH:27][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1cc(-c2ccccc2)ccc1O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared by the method of Example 15b), from 3-nitro-4-chlorobenzoyl chloride (5.28 g, 24.0 mmol) and 4-phenyl-2-aminophenol (3.92 g, 21.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22]([C:34]([CH3:36])=[CH2:35])[C:21]=2[O:37][CH3:38])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[NH2:8][C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:34]([CH3:36])[CH3:35])[C:21]=2[O:37][CH3:38])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2
Reactant: C=C(C)c1c(OCc2ccccc2)ccc(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1c(Oc2c(C)cc(N)c3c2CCC3)ccc(O)c1C(C)C
Yield: 98.9 %

Procedure:
To a solution of dibenzyl[7-(4-benzyloxy-3-isopropenyl-2-methoxyphenoxy)-6-methylindan-4-yl]amine (7.97 g) in tetrahydrofuran (80 mL) was added 10% Pd/C (4.00 g). The mixture was stirred at room temperature under an atmospheric pressure of hydrogen overnight. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness to give the title compound (4.33 g).