Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:33]C(=O)OC(C)(C)C)[C:5](=[O:32])[NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:20][C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[S:27][C:23]=5[CH:22]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:31][C:10]=2[CH2:9]1.O1CCOCC1.Cl>C(N(CC)CC)C>[O:28]=[C:26]1[NH:25][C:24]2[CH:29]=[CH:30][C:21]([NH:20][C:19]3[C:14]4[C:11]5[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:5](=[O:32])[C@H:4]([CH2:3][CH2:2][OH:1])[NH2:33])[CH2:9][C:10]=5[S:31][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:22][C:23]=2[S:27]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N[C@@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 23.2 %

Procedure:
A mixture comprising 32.5 mg (56 μmol) tert-butyl {(2R)-4-hydroxy-1-oxo-1-[({(7RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)amino]butan-2-yl}carbamate (prepared according to example 27), 1.0 mL 1,4-dioxane and 42.7 μL hydrochloric acid (4M in 1,4-dioxane) was stirred at 23° C. overnight. 1 mL N,N-diethylethanamine was added, the solvents removed and the residue purified by chromatography to give 6.3 mg (22%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.I[C:22]1[N:23]=[CH:24][N:25]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:26]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:22]3[N:23]=[CH:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH:26]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(I)c2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Cl)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (2.95 g, 17.39 mmol) in THF (60 ml) at −15° C. was added n-BuLi (2.5M, 6.96 ml, 17.39 mmol). After 30 min, a solution of ZnCl2 in Et2O (1M, 17.39 mL, 17.39 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.268 g, 0.232 mmol) and 304 (4.71 g, 11.59 mmol) in THF (18 ml) was added and the mixture was heated to reflux for 1 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with a mixture of MTBE/Hexane, to afford the title compound 305 (3.75 g, 8.37 mmol, 72% yield) as a beige solid. MS (m/z): 448.46 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([O:29]CC)=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:33]=[CH:32][C:15]([C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5]3)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccc(-c5ccccc5)cc4)ccc32)cc1

Procedure:
The title compound was prepared from ethyl N-{4-[(5-amino-1H-indol-1-yl)methyl]benzoyl}phenylalaninate and biphenyl 4-sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 630; MS (ESI) m/z 628.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:35])[C:3]1=[O:25])[CH3:24]
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 228°-229° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([Cl:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>O.[OH-].[Na+]>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=3)[C:8]([Cl:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: Fc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(F)cc2)n(C)c1=O

Procedure:
A solution of 43 g 1,3-dimethyl 8-chloro xanthine in 200 ml water and 20 ml sodium hydroxide 10N is heated to 70°-80° C., to which 27.6 ml 4-fluorobenzyl chloride are portion-wise added at this temperature within 4 hours. During this addition, 20 ml sodium hydroxide 10N are added by small portions to maintain the pH at an alkaline value. After achievement of this addition, the solution is further heated at 70°-80° for 2 hours then let to revert to room temperature under stirring. The precipitate is filtered, dried, washed with water until neutral, then dried. Thereafter it is recrystallized from acetone to recover 19 g of pure compound. It melts at 183°-184° C.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([OH:38])([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (39 ml, 63 mmol) was added to a stirred solution of 4-bromobiphenyl (11.7 g, 50 mmol) in anhydrous tetrahydrofuran (50 ml), under nitrogen, at about −50° C., whilst ensuring that the reaction temperature was kept below −40° C. After a further 1 hour, a solution of 1-benzyl-4-oxopiperidine (10.4 g, 55 mmol) in anhydrous tetrahydrofuran (30 ml) was added at such a rate that the reaction temperature was maintained below −40° C. The cooling bath was then removed and, after a further 1 hour, the reaction mixture was partitioned between dichloromethane (400 ml) and brine (200 ml). The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure, then the residue crystallised from ethyl acetate to provide the title compound (13.9 g) as a colourless solid. δ(DMSOd6): 1.80 (d,2H), 2.52 (m,2H), 3.24 (m,4H), 4.33 (d,2H), 7.28-7.75 (m,14H), 11.30 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:20][N:21]([CH3:23])[CH3:22])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step A, 4.0 g, 20.0 mmol) in dimethylformamide (40 mL) was added tert-butoxybis(dimethylamino)methane (4.35 mL, 22 mmol). This mixture was stirred at reflux for 15 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate (5×). The combined organic extracts were washed with water (3×) and brine (1×), dried over sodium sulfate, filtered, and evaporated to give 3.64 g (72%) of the title compound of Example 101, Step B as a brown oil that was sufficiently pure to carry on to the next step. 1H NMR (CDCl3, 400 MHz) δ 7.47 (s, 1H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H), 2.43 (t, 2H), 1.46 (s, 9H); MS (APCI) 255 (MH+).
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][N:32]([CH2:35][C@@H:36]([C@H:39]([OH:41])[CH3:40])[CH2:37][OH:38])[C:31](=[O:42])[N:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH2:37][C@@H:36]([CH2:35][N:32]2[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[N:30][C:31]2=[O:42])[C@H:39]([OH:41])[CH3:40])=[CH:3][CH:4]=1
Reactant: CC(=O)Nc1ccn(C[C@H](CO)[C@@H](C)O)c(=O)n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
DMTCl (0.9 g, 2.66 mmol) was added to a stirred solution of 21 (0.6 g, 2.35 mmol) in 25 ml of anhydrous pyridine. After being stirred at room temperature for 4 hrs the reaction was quenched with MeOH (2 ml) and concentrated to an oil. The oil was partition between dichloromethane and 10% citric acid. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The resulting material was chromatographed on silica eluting with a gradient of methanol (5-7.5%) in ethyl acetate. Concentration of the pure product fractions afforded 1.2 g (91%) of 22 as a white amorphous solid. 1H NMR (DMSO-d6): δ 10.78 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.27 (m, 5H), 6.97 (d, J=7.2 Hz, 1H), 6.84 (m, 4H), 4.66 (d, J=4.8 Hz, 1H), 4.01 (m, 1H), 3.78 (m, 2H), 3.73 (s, 6H), 3.73 (m, 1H), 3.09 (m, 2.89 (m, 1H), 2.12 (m, 1H), 2.09 (s, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[CH:6]=2.[Cl:30]N1C(=O)CCC1=O>C(#N)C.O>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:7]1[C:6]([Cl:30])=[C:5]2[C:9]([CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4]2)=[N:8]1)#[N:15]
Reactant: CC(C#N)(Cn1cc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)ccc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A mixture of N-[2-(6-chloro-2H-indazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (50 mg, described in Example 143), and N-chlorosuccinimide (16 mg) in acetonitrile (1 mL) was heated to 60° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound (46 mg, 85%). MS (ES): M/Z [M+H]=457. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.80 (d, J=14.3 Hz, 1H), 5.03 (d, J=14.3 Hz, 1H), 7.15 (dd, J=9.0, 1.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.93 (d, J=8.7 Hz, 2H) and 8.65 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[NH2:12].OS(O)(=O)=O.[CH3:18]O>>[NH2:12][C:3]1[C:4]([CH3:11])=[C:5]([CH:9]=[CH:10][CH:2]=1)[C:6]([O:8][CH3:18])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(C)c1N
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1C
Temperature: 70 °C
Yield: 91 %

Procedure:
To stirred solution of methyl 3-amino-2-methylbenzoic acid (5 g, 33.1 mmol) in methanol (50 mL), was added conc. H2SO4 (5 mL) at 0° C. and the mixture was heated at 70° C. for 22 h. On completion, methanol was removed under reduced pressure, and then sat. sodium bicarbonate solution was added and the product extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to yield methyl 3-amino-2-methylbenzoate (5 g, 91%).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([OH:20])(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:23]=1[OH:38]>N1C=CC=CC=1>[OH:38][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:37])([C:29]([F:30])([F:31])[F:32])[C:33]([F:34])([F:35])[F:36])=[CH:27][C:22]=1[NH:21][C:12](=[O:20])[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 76.4 %

Procedure:
To a mixture of 0.58 g of WSC and 5 ml of pyridine, 0.37 g of isonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60° C. for three hours. The mixture was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.79 g of N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OCC)=O)[CH2:21][CH2:20]2)=[CH:5][CH:4]=1.[OH-].[K+]>C(O)(C)C>[OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1

Procedure:
According to the procedure of European Patent Application 0 393 738 A1, hydrolyze (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine using potassium hydroxide in isopropanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:8][C:6]2[CH:5]=[CH:4][C:3]([S:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=3)=[C:2]([NH2:1])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(Sc3ccc(NC(C)=O)cc3)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
A mixture of the product from Example 232b (28 mg, 0.085 mmol), 4-carbomethoxybenzyl bromide (22 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (35 mg, 100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CC(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)C)nc1Cl
Yield: 86.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-isobutoxypiperidine-1-carboxylate obtained in Example (117d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.02 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.71 g of the title compound as a colorless solid (87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10](OC)OC)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: COC(CSc1ccc(Br)cc1)OC
Solvent: Clc1ccccc1
Product: Brc1ccc2sccc2c1
Yield: 50.9 %

Procedure:
A mixture of polyphosphoric acid (10 g) in chlorobenzene (260 mL) was heated to reflux and added, under nitrogen, dropwise in one hour 1-bromo-4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE12; 9.71 g, 35 mmol). The reaction mixture was then heated for 4 h until reaction is complete, cooled, quenched with water (150 mL) and extracted into methylene chloride. Combined organic layer was dried over Na2SO4 and concentrated to give a crude residue that was purified by flash chromatography (silica, eluting solvent: petroleum ether) to give 3.8 g of 5-bromo-benzo[b]thiophene (white solid) (Yield=51%).
Reaction SMILES: C(O[C:6]([N:8]([CH3:39])[C@H:9]([CH2:23][O:24][C:25](=[O:38])[NH:26][C:27]1[N:28]=[CH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([F:37])=[CH:32][CH:31]=2)[CH2:10][C:11]1[N:12]=[CH:13][N:14](C(OC(C)(C)C)=O)[CH:15]=1)=[O:7])(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[C:70]([F:71])=[CH:69][CH:68]=[CH:67][C:52]=1[CH2:53][NH:54]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:30](=[CH:35][CH:34]=1)[CH:29]=[N:28][C:27]([NH:26][C:25](=[O:38])[O:24][CH2:23][C@@H:9]([N:8]([CH3:39])[C:6]([NH:54][CH2:53][C:52]1[CH:67]=[CH:68][CH:69]=[C:70]([F:71])[C:51]=1[Cl:50])=[O:7])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=[CH:36]2
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1cn(C(=O)OC(C)(C)C)cn1
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of (S)-tert-butyl 4-(2-(tert-butoxycarbonyl(methyl)amino)-3-(6-fluoroisoquinolin-3-ylcarbamoyloxy)propyl)-1H-imidazole-1-carboxylate (280 mg, 0.51 mmol) in THF (10 mL) was added HCl (4 N in 1,4-dioxane, 2.55 mL, 10.2 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (20 mL). To the suspension were added DIEA (0.27 mL, 1.53 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (166 mg, 0.51 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to dryness. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(1H-imidazol-4-yl)propyl 6-fluoroisoquinolin-3-ylcarbamate (35 mg, 13%). LRMS (M+H+) m/z 529.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][CH:25]([C:27]([O:29]CC)=[O:28])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(COc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 80 °C
Yield: 78.7 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-2′-(2,5-difluoro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg), NaOH (111 mg), H2O (5 mL) and THF (10 mL) was heated at 80° C. for 1 h. Then THF was removed by vacuum. The water solution was acidified by concentrated hydrochloric acid to “pH” 1. The white precipitate was collected by filtration to give title compound as a white solid (300 mg).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@H:35]1[CH2:41][N:40]2[C:42]([CH:45]=[O:46])=[CH:43][N:44]=[C:39]2[C@H:38]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:37][CH2:36]1>>[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C@H:35]1[CH2:41][N:40]2[C:42]([CH:45]([OH:46])[C:2]([F:4])([F:3])[F:1])=[CH:43][N:44]=[C:39]2[C@H:38]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C(F)(F)F)cnc21
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
(Trifluoromethyl)trimethylsilane (0.5 M in tetrahydrofuran; 2.15 mL, 1.07 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 0.107 mL, 0.107 mmol) were sequentially added to neat tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (0.14 g, 0.36 mmol). After 15 min, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (110 mg). MS 462.1 (M+1).