Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[CH3:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:20]([O:12][CH2:11][CH:10]=[CH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:19]
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 96.8 %

Procedure:
Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH2Cl2 (250 mL) at 0° C. with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCl (6.48 mL, 74.75 mmol, 1.1 5 eq). Allow the mixture to warm to 23° C., pour into 1M HCl (100 mL) and wash the resulting organic layer again with 1M HCl (100 mL), followed by water (5×100 mL; pH=6.5-7). Dry the organic layer (Na2SO4) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol acetate as a colorless oil.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.3.). Starting with 7.66 g (19.62 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-yl methanesulfonate, prepared in step 10.3., and 3.83 g (58.85 mmol) of sodium azide in 28 mL of N,N-dimethylformamide. After evaporating off the solvent, 6.60 g of product are obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:9][C:8]=12.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[C:8]=12
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1nccc2c(-c3ccccc3)n[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc2c(-c3ccccc3)nn(Cc3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (193 mg) obtained in Step C of Example 10 in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. 4-(Bromomethyl)benzenesulfonamide (220 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 3 days, and then overnight at 60° C. Sodium hydride (60% dispersion in mineral oil, 70 mg) and 4-(bromomethyl)benzenesulfonamide (220 mg) were added thereto, and the mixture was stirred at 60° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (173 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[NH:13][C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[N:13]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3c([N+](=O)[O-])cccc32)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(=O)n(S(=O)(=O)c2ccc(C)cc2)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4-nitro-1,3-dihydro-2H-benzimidazol-2-one from Step B (500 mg, 1.50 mmol) in DMF (50 mL) was added potassium carbonate (207 mg, 1.50 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Methyl bromoacetate (252 mg, 1.65 mmol) was added dropwise and the reaction mixture was stirred for 1 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=406 (M+1).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[C:12]([N:31]1[CH:35]=[C:34]([C:36]([OH:38])=O)[N:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:52][CH2:53][C:54]1[CH:79]=[CH:78][C:57]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][C:63]([C:66](=[O:72])[CH2:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[C:62]([OH:73])[C:61]=2[C:74]([F:77])([F:76])[F:75])=[CH:56][CH:55]=1.C(N(CC)CC)C>C(#N)C>[CH3:69][C:68]([CH3:71])([CH3:70])[CH2:67][C:66]([C:63]1[CH:64]=[CH:65][C:60]([O:59][CH2:58][C:57]2[CH:78]=[CH:79][C:54]([CH2:53][NH:52][C:36]([C:34]3[N:33]=[CH:32][N:31]([C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:35]=3)=[O:38])=[CH:55][CH:56]=2)=[C:61]([C:74]([F:75])([F:76])[F:77])[C:62]=1[OH:73])=[O:72]
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Add 1-hydroxybenzotriazole hydrate (63.8 mg; 417 μmol), 1-trityl-1H-imidazole-4-carboxylic acid (148 mg, 417 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79.9 mg, 417 μmol) to anhydrous acetonitrile (7 mL). Stir the reaction mixture at room temperature for 1 hr. Then add 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-3,3-dimethyl-butan-1-one hydrochloride (150 mg, 347 μmol) and triethylamine (97 μL, 695 μmol). Stir the reaction mixture at room temperature overnight. Quench the reaction with water and the solid, filter the solid and dry to give the title compound (220 mg, 301 μmol). MS (m/z): 730 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[NH:10]1[CH2:14][CH2:13][N:12]=[C:11]1S(O)(=O)=O.C(O)C(C)C>C(Cl)(Cl)Cl>[CH:7]1[CH:8]=[C:2]([Cl:1])[C:3]([NH:4][C:11]2[NH:12][CH2:13][CH2:14][N:10]=2)=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: ClC(Cl)Cl
Solvent: CC(C)CO
Product: Clc1cccc(Cl)c1NC1=NCCN1
Temperature: 125 °C
Yield: 64 %

Procedure:
A mixture of 2,6-dichloroaniline (0.162 g, 1 mmol), imidazoline-2-sulfonic acid (0.30 g, 2 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at this temperature for 16 hours. The mixture was then cooled to room temperature, diluted with CHCl3 (10 ml) and washed twice with 2 ml of aqueous 1 N NaOH. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to yield a solid which was chromatographed (silica gel, 10:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.147 g (a yield of 64%) of the title compound as a white solid, which was characterized spectroscopically.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:34][CH3:35])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[ClH:13].[CH3:35][O:34][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4ccccc43)c2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
A solution of oxindole (200 mg, 1.5 mmol) in THF (3 ml) was added dropwise under nitrogen to sodium hydride (60 mg, 1.5 mmol, prewashed with hexane) in THF (3 ml). After stirring for 20 minutes at ambient temperature, a solution of 4-chloro-6(3-morpholinopropoxy)-7-methoxyquinazoline (169 mg, 0.5 mmol) in DMF (3 ml) was added. The mixture was heated at 75° C. for 1 hour, allowed to cool and the volatiles removed by evaporation. The mixture was partitioned between water and ether. The aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether, the solid was collected by filtration and dried under vacuum to give 7-methoxy-6-(3-morpholinopropoxy)-4-(oxindol-3-yl)quinazoline hydrochloride (175 mg, 69%).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])O.C1[N:8]=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[CH2:51](OP(O)(O)=O)[C@H:52]1O[C@@](O)(COP(O)(O)=O)[C@@H](O)[C@@H:53]1O.C([O-])(=O)C(C)=O>>[NH2:8][C@H:2]([C:1]([OH:6])=[O:5])[CH2:4][CH:52]([CH3:53])[CH3:51]
Reactant: O=P(O)(O)OC[C@H]1O[C@@](O)(COP(=O)(O)O)[C@@H](O)[C@@H]1O
Reactant: CC(O)C(=O)[O-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: CC(=O)C(=O)[O-]
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Lactate dehydrogenase was measured by monitoring the oxidation of NADH at 340 nm in a reaction mixture with the following composition: 50 mM Tris-acetate buffer (pH 6), 0.5 mM fructose-1,6-diphosphate, 25 mM pyruvate and 0.5 mM NADH.
Reaction SMILES: C[N:2]1CCOCC1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([OH:25])=O.O.OC1C2N=NNC=2C=CC=1.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[NH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:45][CH2:44][CH2:43][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:25]
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: N
Product: O=C(NCCN1CCCCC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-methylmorpholine (0.085 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (95.5 mg) [see Preparation 3], hydroxybenzotriazole hydrate (89.0 mg), 2-piperidinoethylamine (50 mg) [see J. Chem. Soc, (1935), 1421-1426] and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (140 mg) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature for 18 hours, after which time the mixture was diluted with water and the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by coloumn chromatography on silica gel eluting with a solvent gradient of 4:1:0, changing to 0:95:5, by volume, hexane: ethyl acetate: 0.88 aqueous ammonia solution solution to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2 -(2-piperidinoethyl)-2-piperidinecarboxamide (109 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([CH2:14][CH:15]([OH:18])CO)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([CH2:14][CH2:15][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC(O)CO)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a solution of 4-cyano-4-(2,3-dihydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (3.65 g) in tetrahydrofuran (100 ml) was added 10% aqueous sodium periodate solution (100 ml), and the mixture was stirred at room temperature for 40 min. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue (3.3 g) was dissolved in tetrahydrofuran (100 ml) and sodium borohydride (360 mg) and methanol (20 ml) were added with ice-cooling, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) and dried under reduced pressure to give the title compound (3.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: Cc1ccc(S(=O)(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-methylbenzenesulfonamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and p-toluene sulfonyl chloride in a similar manner as described above to give a tan solid (60% yield). 1H-NMR (CDCl3): δ 8.63 (s, 1H), 7.85 (d, 2H), 7.57 (m, 1H), 7.37 (d, 2H), 7.25 (m, 1H), 7.18 (d, 1H), 4.74 (d, 1H), 4.46 (m, 1H), 2.61 (m, 2H), 2.48 (s, 3H), 2.00-1.82 (m, 2H), 1.80-1.60 (m, 2H); MS m/z 419 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-bromomethyl-4-chloro-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][C:7]=1[S:18]([Cl:17])(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
A mixture of 4-fluoro-1-nitro-2-[(2,2,2-trifluoroethyl)oxy]benzene (10 g, 41.8 mmol) in chlorosulfonic acid (82 mL, 125.5 mmol) was stirred at 50° C. for 8 hours before being poured into ice and extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to give 2-fluoro-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonyl chloride (15 g, crude) as a brown oil, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(Cl)(Cl)Cl.[C:15](Cl)(Cl)=[S:16].C(=O)(O)[O-].[Na+]>O>[N:1]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1ccsc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccsc1N=C=S
Reaction time: 1 h
Yield: 65.1 %

Procedure:
In a sulfonation flask, 50.2 g (0.32 mol) of methyl 2-aminothiophene-3-carboxylate are added to 480 ml of chloroform and 320 ml of water. Then 40.5 g (0.35 mol) of thiophosgene and 1000 ml of saturated aqueous sodium bicarbonate solution are added simultaneously in 40 minutes under stirring. The stirring continued for 1 h at room temperature and then the organic phase is separated. The water phase is extracted twice with chloroform and the organic phase dried over sodium sulfate. After removal of the chloroform in the water-jet vacuum 61.3 g of a dark oil is obtained, which is further purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5). 41.5 g of methyl 2-isothiocyanatothiophene-3-carboxylate are obtained in the form of a brown powder having a melting point of 63-65° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:37]3[C:43]4[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:42]=4[CH:41]=[C:40]([C:50]([OH:52])=O)[CH2:39][N:38]3[C:53]=2[CH:54]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[CH3:63][N:64]1[CH2:70][CH:69]2[NH:71][CH:66]([CH2:67][CH2:68]2)[CH2:65]1>CN(C=O)C.O>[CH:55]1([C:36]2[C:35]3[CH:34]=[CH:33][C:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])=[CH:54][C:53]=3[N:38]3[CH2:39][C:40]([C:50]([N:71]4[CH:66]5[CH2:67][CH2:68][CH:69]4[CH2:70][N:64]([CH3:63])[CH2:65]5)=[O:52])=[CH:41][C:42]4[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=4[C:37]=23)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: CN1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
HATU (680 mg, 1.8 mmol) was added to a stirring solution of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (670 mg, 1.37 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane di HCl salt (560 mg, 2.81 mmol) in DMF (6 mL) and TEA (1.2 mL, 8.2 mmol) and the reaction was stirred for 30 min (complete by LCMS). The reaction mixture was diluted with water (˜35 mL) (precipitate formed) and stirred ON. The precipitate was collected by filtration, flushed with water and dried under high vacuum at 55° C. to yield tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (775 mg, 1.30 mmol, 95% yield) as a light yellow solid. The material was used without further purification. 1HNMR (300 MHz, CDCl3) δ ppm 1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82 (s, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8.4, 1.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.02 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: N.O1CCOCC1.C([N:10](CC)CC)C.[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[N:28]2[CH3:47])=[C:21]([S:23](Cl)(=[O:25])=[O:24])[CH:22]=1)#[N:16]>>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C@@H:27]2[C:32]([C:33]#[N:34])=[C:31]([CH3:35])[N:30]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[C:29](=[O:46])[N:28]2[CH3:47])=[C:21]([S:23]([NH2:10])(=[O:25])=[O:24])[CH:22]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: N
Solvent: C1COCCO1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(N)(=O)=O)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Under an atmosphere of argon protective gas, a 0.5 M solution of ammonia in dioxane (4000 μl, 2021 μmol; 10 eq.) and triethylamine (20.4 mg, 202 μmol; 1 eq.) were added to 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (100 mg, 202 μmol) at room temperature, and the mixture was stirred for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (56 mg, 58% of theory).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC1>ClCCl>[OH:2][CH:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cl[Mg]c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-formylbenzoate (2.83 g, 17.2 mmoles) at −78° C. in 60 mL of dichloromethane is added 10 mL a 2.0 M solution of phenylmagnesium chloride in tetrahydrofuran (20.0 mmoles) over 7 minutes. After stirring for an additional 20 minutes, the reaction was quenched with methanol then with saturated aqueous ammonium chloride. The aqueous layer was acidified with 1N hydrochloric acid and the phases were separated. The organic portion was washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Removal of the volatiles under reduced pressure and purification over silica gel afforded the title ester.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][Si:8]([Si:11]([Si:19]([CH3:22])([CH3:21])[CH3:20])([Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][CH2:13][OH:14])([CH3:10])[CH3:9].N1C=CC=CC=1>O1CCCC1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:1]([O:14][CH2:13][CH2:12][Si:11]([Si:19]([CH3:22])([CH3:21])[CH3:20])([Si:15]([CH3:18])([CH3:17])[CH3:16])[Si:8]([CH3:7])([CH3:9])[CH3:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)[Si](CCO)([Si](C)(C)C)[Si](C)(C)C
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Yield: 63 %

Procedure:
Methacryloyl chloride (2.50 grams, 0.024 mole) in 25 ml tetrahydro-furan was added dropwise into a solution of 2-tris(trimethylsilyl) silyl ethanol (6.5 grams, 0.022 mole), pyridine (2.0 grams, 0.025 mole) and 25 mg of phenothiazine in 50 ml tetrahydrofuran at room temperature. Stirred at room temperature for two more hours. The solids were filtered off and the solution was washed with 100 ml brine. The solution was then diluted with 100 ml ether and washed with 5% hydrochloric acid, followed by deionized water, and then with brine. It was dried over anhydrous magnesium sulfate and was concentrated in vacuo. Fractional distillation under reduced pressed gave 5 grams of the product at 105-115° C. at 0.5 mm.