Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C1[C:62]2(OCCC[O:63]2)[CH2:61][C@@H](C(OC)=O)N1C(OCC1C=CC=CC=1)=O>>[C:62]([N:38]1[CH2:37][C:36]2([CH2:40][CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:2]([CH3:57])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[N:34]([C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[CH2:35]2)[CH2:39]1)(=[O:63])[CH3:61]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCCO2
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)CN(C(C)=O)C2)C(C)C
Yield: 83 %

Procedure:
This compound was prepared in an analogous fashion to Example 21 from methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate Example 24 (40 mg, 0.05 mmol) to afford the title compound as a yellow solid (35 mg, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67-12.33 (m, 1H) 7.19-7.99 (m, 12H) 5.07 (br. s., 1H) 3.92-4.25 (m, 4H) 3.67-3.94 (m, 4H) 3.45-3.66 (m, 8H) 2.20-2.46 (m, 3H) 2.17 (br. s., 2H) 1.80-2.06 (m, 5H) 1.60-1.82 (m, 3H) 0.78-1.02 (m, 12H). HRMS for C44H56N9O7 (M+H)+ calc: 822.4303, found: 822.4300. Purity (LC-MS): 91%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl:13][C:11]1[N:12]=[C:8]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(Oc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
42 g (0.036 mol) of anhydrous potassium carbonate are added to a solution of 72.0 g (0.36 mol) of 2,4-dichloro-5-nitrothiazole in 300 ml of acetonitrile. A solution of 28.2 g (0.3 mol) of phenol in 300 ml of acetonitrile is then added dropwise at 15° C. to 20° C. in the course of about 1.5 hours and the mixture is subsequently stirred at the same temperature for a further 0.5 hour. It is then heated at the reflux temperature for 15 minutes, cooled to room temperature and then stirred into 3 liters of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 500 ml of petroleum ether at about 20° C., filtered off, washed with petroleum ether and dried. 75.4 g (98.0% of theory) of 4-chloro-5-nitro-2-phenoxythiazole are thus obtained. Melting point 96° C. (from petroleum ether).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.C(Cl)Cl.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:30](=[O:31])([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A stirred solution of 2.54 g (0.01 mol) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol of Example 1, 20 ml of sieve dried CH2Cl2 and 1.55 g (0.013 mol) of phenylisocyanate was heated 20 hours under reflux with exclusion of moisture. The cooled solution was concentrated on a rotary evaporator to afford an oil which was dissolved in 10 ml of hot toluene. The solution was seeded with product (previously obtained by the method described herein), stirred until a thick suspension formed and allowed to stand overnight (about 16 hours) at ambient temperature. Filtration and drying in vacuo afforded 2.53 g (67.8%) of a colorless solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl carbanilate, m.p. 98°-99° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3]1.[CH:26](OCC)=[O:27].[O-]CC.[Na+].Cl>C(O)C>[OH:27][CH:26]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C1Cc2ccc(Cc3cccc(NC(=O)c4cccs4)c3)cc2N1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(Cc3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Temperature: 78 °C
Yield: 52.9 %

Procedure:
Thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.110 g, 0.306 mmol) and ethyl formate (0.075 mL, 0.918 mmol) were dissolved in anhydrous ethanol (0.6 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.85 mL, 1.53 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale brown precipitate. The suspension was filtered yielding a tan solid as the pure Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.061 g, 0.162 mmol, 53%).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].C([Li])CCC.C(Br)C=CC>O>[CH3:13][C:12]1[CH2:7][C:8]([CH:1]([CH3:5])[CH2:2][CH2:3][OH:4])([O:18][CH3:19])[C:9]([CH3:17])=[C:10]([CH3:16])[C:11]=1[O:14][CH3:15]
Reactant: C1CCOC1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: CC=CCBr
Agent: [Li]CCCC
Solvent: O
Product: COC1=C(C)CC(OC)(C(C)CCO)C(C)=C1C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A THF solution (50 ml) of 2-bromo-3,5,6-trimethyl-1,4-dimethoxybenzene (10 g, 40 mmole) was cooled to -70° C. under an atmosphere of argon, and n-butyllithium (20%, hexane solution) was added dropwise to the solution, followed by stirring at -70° C. for 10 minutes. Subsequently, cuprous bromide (5.70 g, 40 mmole) was added to the mixed solution, and the temperature of the reaction solution was raised to 0° C. The reaction solution was cooled again to -70° C., and crotyl bromide (5.4 g, 40 mmole) was added. Stirring was effected until the reaction solution reached the room temperature, and the reaction was suspended by adding 100 ml of water. The reaction solution was extracted with IPE, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in THF (50 ml), and sodium boron hydride (1 g) was added to the solution. Boron trifluoride etherate (1.5 ml) was added dropwise to the reaction solution, and after stirring was effected for 1 hour and 50 ml of water was added, 3N aqueous potassium hydroxide solution (50 ml) was added dropwise to the mixed solution. 30% Aqueous hydrogen peroxide solution was added to the reaction solution under cooling, followed by stirring under the same conditions for 18 hours. The reaction solution was extracted with IPE, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solution: IPE) to give 3-(3,5,6-trimethyl-1,4-dimethoxyphenyl)-butan-1-ol (3 g, 30%).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:20])[CH2:3][CH2:4]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: Nc1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC4CCC(F)(F)CC4)ncnc23)c1F
Yield: 28.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (Intermediate-9, 75 mg, 0.27 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 116 mg, 0.41 mmol), oxalyl chloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (105 mg, 0.81 mmol) in CH2Cl2 (5 mL) to afford 42 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.69-8.66 (d, J=7.8 Hz, 1H), 8.49 (s, 1H), 8.12-8.09 (m, 2H), 7.53 (t, 1H), 7.40-7.32 (m, 2H), 4.28 (m, 3H), 2.09-1.98 (m, 6H), 1.73 (m, 2H), 1.12 (s, 9H); MS [M]+: 548.33.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([NH:16][NH2:17])=[O:7])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1ccccc1OCC
Solvent: O
Solvent: CCO
Product: CCOc1ccccc1C(=O)NN
Temperature: 25 °C

Procedure:
Ethyl 2-ethoxybenzoate (100 g, 128.7 mmol) and hydrazine hydrate (100%, 25 ml, 128.7 mmol) are dissolved in 200 ml of ethanol and heated under reflux for 5 hours. A further 12.5 ml (64.3 mmol) of hydrazine hydrate are added and the reaction mixture is heated under reflux for a further 7 hours. For working up, the reaction mixture is extensively concentrated and then stirred with 300 ml of cyclohexane at room temperature. After cooling to 0° C., the crystals are filtered off with suction, washed twice with 50 ml of cold cyclohexane each time and finally dried in a vacuum oven at 35° C. and 300 mbar overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:31]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:31])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c21
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-indazole (35 mg, 0.083 mmol) and sodium cyanoborohydride (10.4 mg, 0.166 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (42%). 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.29 (s, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.98 (s, 3H), 3.44 (s, 2H), 2.50 (m, 2H), 2.00-2.25 (m, 7H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.2, 160.2, 139.4, 133.9, 128.62, 128.56, 124.8, 124.6 (q, J=272 Hz), 124.5 (q, J=2.9 Hz), 122.6 (q, J=33 Hz), 121.1, 119.7 (q, J=4.8 Hz), 115.0, 114.9, 78.7, 70.5, 51.8, 46.2, 40.2, 38.3, 32.6. Mass spec.: 436.15 (MH)+. Accurate mass spec.: m/z 436.2008 [MH]+, Δ=0.9 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-6-hydroxyquinoline-3-carbaldehyde (2.35 g, 11.3 mmol) in N,N-dimethylformamide (15 mL) was added tert-butyl 2-bromoacetate (2.0 mL, 13.6 mmol) and potassium carbonate (3.13 g, 22.6 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with water (100 mL) and allowed to stir for 1 hour. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.62 g, 99%) as an off-white solid. +ESI (M+H) 322.1; 1H NMR (400 MHz, CDCl3, δ): 10.54 (s, 1 H), 8.60 (s, 1 H), 7.99 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.17, 2.93 Hz, 1 H), 7.11 (d, J=2.73 Hz, 1 H), 4.65 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1N
Yield: 89 %

Procedure:
A mixture of 118.8 g of 2-amino-4-nitro-benzoic acid, 1000 ml of methanol and 120 ml of concentrated sulfuric acid is heated at the boiling point for 16 hours. The mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed with saturated NaHCO3 solution. After drying over Na2SO4, the organic phase is concentrated. 114.2 g (89%) of methyl 2-amino-4-nitro-benzoate are thus obtained with a melting point (m.p.) of 156-158° C.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:21]1[CH:22]=[CH:23][S:19][CH:20]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1-c1ccsc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Under an argon atmosphere, a suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (656 mg), 3-thiopheneboronic acid (511 mg), dichloro[bis(triphenylphosphine)]palladium (70 mg) and sodium carbonate (636 mg) in 1,2-dimethoxyethane (10 mL)-water (3 mL) was stirred at 100° C. for 2 hr. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a colorless oil (yield 549 mg, 83%).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:26]([CH3:28])[CH3:27])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.[CH2:34]1[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:34]1([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]([CH:26]([CH3:27])[CH3:28])[C:10]([C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:29])[CH2:3][CH2:4]3)=[O:9])=[CH:18]4)[CH2:21][CH2:22]2)[CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCNCC3)ccc21
Reactant: C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C4CCC4)CC3)ccc21
Temperature: 55 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a mixture of (1,1-dioxo-1λ6-thiomorpholin-4-yl)-[1-isopropyl-5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone (268 mg, 1.0 eq.) in acetic acid (115 mg, 3.0 eq.) was added a solution of cyclobutane (90 mg, 2.0 eq.) in tetrahydrofuran (8 mL). The mixture was stirred for 2 h at 55° C. Then the mixture was cooled to room temperature and sodium triacetoxyborohydride (279 mg, 2.0 eq.) was added. The reaction mixture was stirred overnight at 65° C. The residue was partitioned between water and ethyl acetate. The organic layer was washed with a sodium hydrogenocarbonate aqueous solution, dried over sodium sulfate, filtered and dried in vacuo. Then the residue was purified on silica eluting with a gradient of dichloromethane/methanol to yield 97 mg (32%) of the desired product as off-white oil. MS (m/e): 474.5 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=C(C3N=C(N4CCOCC4)C4SC(CN5CCN(S(C)(=O)=O)C(CO)C5)=CC=4N=3)C=CC=2)[CH:22]=N1.[H-].[Na+].IC>C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([CH2:18][O:19][CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1CO
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
Amine preparation: to a THF (5 mL) solution of 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, described for the production of 174) was added sodium hydride (0.043 g). The reaction mixture was stirred for 20 min and then iodomethane (0.19 mL) was added. After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-methanesulfonyl-3-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester (0.254 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH:12]1([CH:15]=O)[CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH:12]1([CH2:15][N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:1][CH2:2]2)[CH2:14][CH2:13]1
Reactant: O=CC1CC1
Reactant: C1CCC2(CC1)CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C1CCC2(CC1)CCN(CC1CC1)CC2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-azaspiro[5,5]undecane (0.34 g, 2.2 mmol), cyclopropanecarbaldehyde (0.14 g, 2 mmol) and NaBH(OAc)3 (0.64 g, 3 mmol) in dichloroethane (10 mL) were added AcOH (0.12 mL, 2 mmol), the resulting suspension was stirred overnight, quenched with NaHCO3 and extracted with CH2Cl2 twice, the combined organic layer was washed with brine, and dried with MgSO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography. The compound was converted to the hydrochloride by passing HCl gas into the ether solution of 3-(cyclopropylmethyl)-3-azoniaspiro[5,5]undecane at 0° C., followed by decanting the ether supernatant, the final white solid (0.39 g, 80% yield) was dried in vacuo. 1H NMR (360 MHz, CDCl3) δ 2.45 (t, J=5.66 Hz, 4H), 2.23 (d, J=6.51 Hz 2H), 1.49 (t, J=5.66 Hz, 4H), 1.48-1.40 (m, 6H), 1.38-1.30 (m, 4H), 0.92-0.82 (m, 1H), 0.52-0.47 (m, 2H), 0.11-0.17 (m, 2H); 13C NMR (90 MHz, CDCl3) δ 64.55, 49.67, 36.47, 35.46, 31.00, 27.12, 21.73, 8.74, 4.19; ESI-MS: Calculated for C14H25N (M+H)+ 208.4, Found: 208.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:11]=[N:10][N:9]=1
Reactant: Brc1ccccc1-c1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 0.50 g of 5-(2-bromophenyl)-1H-tetrazole in 20 ml of CH2Cl2 is added 0.65 g of triphenylmethyl chloride followed by 0.37 ml of triethylamine. The solution is refluxed for 2.5 hours, cooled to room temperature and then washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography eluting with ethyl acetate/hexanes (1:5) to provide the desired product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[CH:15]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to −40° C. Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at −40° C. for 1 h, then cooled to −78° C. A solution of 1-bromo-4-fluorobenzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at −78° C. for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0° C. over an hour. The reaction was quenched with NH4Cl (aq. sat), and extracted with EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone.