Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.COC[C:14]([O:16][CH3:17])=[O:15]>O1CCCC1>[CH3:1][S:2]([CH2:5][C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL) was added 1.59 M n-butyl lithium (36.3 mL) in a dryice-acetone bath under a nitrogen atmosphere. After stirring for 0.5 hour, a solution of methyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. The resulting mixture was stirred for 2 hours in the bath and allowed to warm to room temperature over 2 hours. The mixture was partitioned between EtOAc and 4 N hydrochloric acid. The reaction was quenched by adding 4 N hydrochloric acid in EtOAc (15 mL). The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was washed with EtOAc (100 mL, five times). The organic layer was combined, and the combined extracts were dried over MgSO4, and evaporated. Flash silica gel column chromatography (EtOAc-hexane=50-200 to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorless oil (2.24 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)[C:7]([CH:11]([OH:24])[C:12](C)([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:13]([O:15][CH3:16])=[O:14])=[C:8](C)[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:32](OC(=O)C)(=[O:34])[CH3:33].O.[CH2:40]([Cl:42])Cl>CN(C)C1C=CN=CC=1.C(=O)(O)[O-].[Na+]>[C:32]([O:24][CH:11]([C:7]1[N:6]([CH2:25][C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:40]=2[Cl:42])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)[CH:12]([C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:34])[CH3:33]
Reactant: CCCCc1nc(C)c(C(O)C(C)(C(=O)OC)c2ccncc2)n1-c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Reactant: ClCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCc1ncc(C(OC(C)=O)C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reaction time: 2 h

Procedure:
A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)-methylpropanoate (3.32 g, 7.5 mmol)methylene chloride (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol ethyl acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26](=[O:27])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)=[C:24]([CH3:38])[N:23]=[C:22]1[CH2:39][CH2:40][CH3:41]>O>[F:13][C:14]1[CH:15]=[C:16]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26](=[O:27])[C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=2)=[C:24]([CH3:38])[N:23]=[C:22]1[CH2:39][CH2:40][CH3:41]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:17][O:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Reaction time: 17 h
Yield: 59.5 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.56 g, 8.38 mmol) and oxetan-3-one (500 mg, 6.94 mmol) DCE (60 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (2.34 g, 11.04 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2) to afford 4-Oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester as a white solid (1.0 g, 59%). 1H NMR (CDCl3, 400 MHz) δ 4.69-4.58 (m, 4 H); 3.51-3.44 (m, 5 H); 2.27 (m, 4 H) and 1.46 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N(C)c2nc(C(=O)O)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate (560 mg, 1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25 mL of methanol and water (1:3) was stirred at room temperature for 5 h. The solvents were removed under vaccum, and the residue was dissolved in 50 mL of water and acidified to pH 3. The white precipitate was collected and washed with water and dried (380 mg, 1.23 mmol, 74%). 1H NMR (CDCl3): 8.02-8.05 (m, 1H), 7.68 (ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H), 7.02-7.05 (m, 1H), 6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].[C:21](O)(=[O:27])[CH2:22][CH2:23][C:24](O)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:27]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Reactant: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)CCC2=O)C1
Product: Cl
Temperature: 135 °C
Reaction time: 4 h

Procedure:
(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (100 mg; enantiomer B, preparation as described in WO2004085404) was initially charged in a flask together with succinic acid (58 mg). To this was added polyphosphoric acid (approx. 2 ml). The reaction mixture was subsequently stirred at 135° C. After 4 hours, a little more succinic acid (˜9 mg) was added. After a further 2 h at 135° C., the mixture was left to stand at room temperature overnight. For workup, the mixture was poured onto ice-water, and the acidic phase was adjusted to pH 10 with saturated potassium carbonate solution and then extracted three times with ethyl acetate. The combined organic phases were washed once with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC. The fractions comprising product were combined, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. It was dried over magnesium sulfate, then filtered and concentrated to dryness. The residue was taken up with aqueous hydrochloric acid and freeze-dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: Clc1ccccc1N1CCc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH:11]=[CH2:12].[NH2:14][CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)=[N:18][N:17]=1>C(Cl)Cl>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)=[N:18][N:17]=1)[CH2:6][CH:4]=[CH2:5])[CH:11]=[CH2:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCBr
Reactant: NCc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)o1
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)o1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
2.4 ml (13.8 mmol) of N-ethyldiisopropylamine and 0.97 ml (8 mmol) of allyl bromide were added to a solution of 0.600 g (1.75 mmol) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo [5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 30 ml of methylene chloride, whereupon the mixture was stirred at 70° for 12 hours. The reaction solution was diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.580 g (78%) of (S)-1-(5-diallylaminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.56 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]1=[O:21])[O:7][CH2:6]2.[CH2:23]=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:13]1=[O:21])[O:7][CH2:6]2
Reactant: C1CCNCC1
Reactant: CN(C)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C=O
Solvent: CCO
Product: CN(C)c1ccc2c(c1)COC2=C1C(=O)N(CN2CCCCC2)c2ccccc21
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of 3-(5-Dimethylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (550 mg, 1.88 mmol), paraformaldehyde (141 mg, 4.7 mmol) and piperidine (240 mg, 2.82 mmol) in 20 mL of EtOH was stirred at reflux for overnight and cooled to room temperature. The solid which formed on cooling was collected by filtration, washed with EtOH (5 mL) and dried under vacuum to give the title compound (655 mg, 89%) as bright yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([NH2:10])[CH2:5][C:4]=2[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@@H:19]1[CH2:23][CH:22](O)[O:21][C:20]1=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(#N)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:15]=[C:16]([Cl:26])[C:17]=1[CH2:18][C@H:19]([CH2:23][CH2:22][NH:10][C@H:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:20]([OH:25])=[O:21]
Reactant: N[C@H]1CCc2[nH]ncc2C1
Reactant: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@@H](CCN[C@H]1CCc2[nH]ncc2C1)Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
To a solution of 0.30 g (2.2 mmoles) of (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine in 15 mL of ACN at 43° C., add 0.732 g (2.05 mmoles) of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxy-dihydro-furan-2-one. Heat the mixture at 50° C. for 0.5 h and allow to cool to room temperature. Add 0.70 g (3.3 mmoles) of sodium triacetoxyborohydride. After 2.5 h, add an additional charge of sodium triacetoxyborohydride (100 mg). After 1 h, heat to 50° C. and add 15 mL of water slowly. Allow to cool to room temperature and stir the slurry overnight. Collect the solids by filtration and rinse with water (2×5 mL). Stir the wet cake with 15 mL of acetonitrile and filter. Rinse the cake with acetonitrile (2×5 mL) and dry in a vacuum oven to afford 0.65 g (62%) of the title compound as a solid. MS (m/z): 476 (M+1, 35Cl), 478 (M+1, 37Cl).
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[N:23]([CH3:25])[CH3:24]>>[CH3:24][N:23]([CH3:25])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH2:20][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: CN(C)c1ccccc1CCl
Product: CN(C)c1ccccc1CSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 26.9 %

Procedure:
The title compound was prepared in a yield of 26.9%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and 2-chloromethyl-N,N-dimethylaniline in place of 2-choromethylpyridine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][S:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:13][C:3]1[S:4][CH:5]=[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cscc1C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C2CCCCC2)csc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To an icebath-chilled solution of 3-methyl-4-cyclohexylthiophene (10 g, 55.55 mmol) in DMF (60 mL) was added solid N-bromosuccinimide (9.89 g, 55.55 mmol). After addition, the mixture was allowed to warm to room temperature and was stirred for about 1 hr at which point HPLC analysis indicated the reaction was complete. The product mixture was poured into 200 mL of cold water and the aqueous phase was extracted with ether (3×125 mL). The combined ether extracts were washed with water (3×250 mL) and brine (1×200 mL), then passed through a cone of DRIERITE. Solvent was removed by rotary evaporation to afford the crude product 2-bromo-3-methyl-4-cyclohexylthiophene (13.6 g, 94%) as a light amber oil which was judged to be of greater than 95% purity product. 1H NMR (CDCl3) δ 6.88 (s, 1, ArH), 2.53 (m, 1, cyclohexylmethine) 2.19 (s, 3,ArCH3), 1.9 and 1.35 ppm (m, 10, cyclohexyls).13C NMR 147.81, 135.93, 118.32, 109.44 (thiophene carbons), 39.27, 33.55, 26.86, 26.24 and 13.73 (aliphatic carbons). 2D NMR confirmed that the bromine was bonded to the carbon adjacent to the 3-methyl substituent.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=NC2CCCCC2)CC1.[C:16]1(/[CH:22]=[CH:23]/[CH2:24][O:25][C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=O)=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC2N([OH:47])N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[C:16]1(/[CH:22]=[CH:23]/[CH2:24][O:25][C:26](=[O:27])[NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([N:7]2[CH2:4][CH2:5][CH:6]([CH2:1][OH:47])[CH2:8]2)=[O:33])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccccc1C(=O)O)OC/C=C/c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(=O)N1CCC(CO)C1)OC/C=C/c1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of DCC (4.54 g, 22 mmol) dissolved in the minimum of CH2Cl2 was added dropwise to compound 73 (6 g, 0.020 mol) in CH2Cl2 at −5C, whilst stirring, with a catalytic amount of DMF (10 drops). The reaction mixture was stirred for a further five minutes before HOBt (3.0 g, 22 mmol) in CH2Cl2 was added. The reaction mixture was allowed to stir for 1 hour at −5° C., then left to stir for 12 hours at room temperature. The colourless precipitate of DCU was removed by filtration and the remaining reaction mixture cooled to −5° C. (S)-pyrrolidinemethanol (2.37 mL, 24 mmol) was added and the reaction mixture allowed to warm to room temperature and, stirred for 12 hours. TLC (70% Pet ether/EtOAc) revealed reaction completion. The reaction mixture was washed with NaHCO3 (4×100 mL), NH4Cl (4×100 mL), H2O (4×100 mL), brine (4×100 mL) and dried over MgSO4. Purification was achieved via flash column chromatography (60% pet ether/EtOAc) to furnish compound 74 as a stiff brown oil (95%). 1H NMR (250 MHz, CDCl3); δ 8.69 (s, 1H, NH), 8.13 (d, 1H, J=8.2 Hz, aromatic H), 7.42-7.22 (m, 6H, Coc aromatic H and aromatic H), 7.06 (ddd, 1H, J=1.07, 7.6, 7.5, aromatic H), 6.70 (d, 1H, J=16 Hz, 3′-H), 6.34 (dt, 1H, J=6.4, 18 Hz, 2′-H), 4.81 (dd, 2H, J=1.1, 6.4, 1′-H), 4.40 (br, s, 1H, H-11a), 3.85-3.42 (m, 4H, H-11, H-3), 2.06-1.70 (m, 4H, 1-H, H-2); 13C NMR (62.9 MHz, CDCl3) δ 171.3 (ester carbonyl), 136.6 (aromatic quat), 134.6 (methine), 131.3 (methine), 129.0 (methine), 128.5 (methine), 128.0 (methine), 127.1 (methine), 123.9 (alkenic methine), 122.7 (methine), 121.3 (methine), 67.0 (Coc, C-1), 66.2 (methylene Coc), 61.1 (methine, C-11a), 51.9 (methine, C-3), 28.8 (methine, C-1), 25.5 (methine, C-2); MS m/z; 381 (M+. +1), 363, 337, 308, 279, 261, 247, 229, 203, 117.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13][C@H:12]1[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[Na+].O.C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:30]#[N:31])[CH2:13][C@H:12]1[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Yield: 48.6 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methyl-4-methanesulfonyloxypyrrolidine (10.246 g) and sodium cyanide (3.6 g) in dimethyl sulfoxide (100 ml) was heated for three hours at 92° C. The reaction mixture was poured into a mixture of water (300 ml) and ethyl acetate (300 ml). The organic layer was separated, and the remaining aqueous layer was reextracted with ethyl acetate (200 ml). The organic layers were combined, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S,4S)-1-benzyloxycarbonyl-2-(tert-butyldimethylsilyloxy)methyl-4-cyanopyrrolidine (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[C:11]([CH:20]=O)[C:10]=2[OH:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>>[ClH:1].[C:23]([NH:27][CH2:20][C:11]1[CH:12]=[C:13]([O:15][C:16]([F:17])([F:19])[F:18])[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[OH:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(OC(F)(F)F)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(C)(C)NCc1cc(OC(F)(F)F)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
3-((tert-Butylamino)methyl)-3′,4′-dichloro-5-(trifluoromethoxy)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 3′,4′-dichloro-2-hydroxy-5-(trifluoromethoxy)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]1[C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13][CH2:12][N:11]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:20][CH:19]=[CH:18]3>C1COCC1>[Cl:1][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:10]([CH3:9])[C:16]3=2)[NH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-chlorosuccinimide (13 mg, 0.10 mmol) was added to a solution of tert-butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 0.030 g, 0.099 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (17.5 mg) as a white solid. MS m/z 337 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)[C@@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 78.4 %

Procedure:
The procedure described in Example 180 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (3.0 g) and ethyl 4-aminophenylacetate (1.40 g) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.93 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (3.34 g).