Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH2:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH:25][C@H:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:46])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (10.0 g, 24.9 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 mL, 74.6 mmol) at 0° C. After stirred for 10 min, ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour. Additional triethylamine (10.4 mL, 74.6 mmol) and ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester (10.6 g). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.27 (d, 3H, J=6.8 Hz), 1.89 (bs, 1H), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J=6.8, 14.8 Hz), 3.69 (dd, 1H, J=7.1, 7.1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J=12.1 Hz), 5.12 (d, 1H, J=12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 7.35 (dd, 1H, J=7.6, 7.6 Hz), 7.41-7.46 (m, 3H), 7.53 (dd, 1H, J=1.5, 1.5 Hz); MS: m/z (MW) 466.
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:34][CH2:33]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=S)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 88 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:15]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:14]=2[CH:26]=1
Reactant: Clc1ccccn1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccc(C)cc3)c2c1
Product: COC(=O)CCCCCOc1ccc2nc(Sc3ccccn3)n(-c3ccc(C)cc3)c2c1

Procedure:
200 mg of 6-[[1-(4-methylphenyl)-2-mercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was heated to 150° C. with 80 μl of 2-chloropyridine for 14 hours. After another 200 μl of 2-chloropyridine was added, it was heated for 3 hours to 170° C. After cooling, it was purified by column chromatography on silica gel. 40 mg was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:24][O:23][C:21](=[O:22])[C:18]1[CH:17]=[CH:16][C:15]([N:14]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COC(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1

Procedure:
Using general procedure H with 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 85) (1.0 g) and benzylbromide (0.54 mL, 4.50 mmol) and then using general procedure C afforded 4-(benzyl-piperidin-4-yl-amino)-benzoic acid methyl ester as a white solid (620 mg, 63% over 2 steps).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]([F:34])([F:36])[F:35])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (5.00 g) and 37% formalin (3.0 mL) in the same manner as in the synthesis of Example 1 was dissolved in chloroform (50 mL), and triethylamine (11.1 mL) and 3-cyano-4-methoxy-5-trifluoromethylbenzoylchloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:25])[F:26])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([NH:30][CH3:29])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Reactant: CN
Agent: Cl
Product: CNC(=O)C(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and methanamine hydrochloride as starting materials and isolated (28 mg, 54%); MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)=[O:22])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.C1COCC1.[Li+].[OH-]>CO>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([NH:20][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[O:22])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 4-(((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)carbamoyl)benzoate (135 mg, 0.280 mmol, Example 140) and THF (7 mL):MeOH (3 mL) was added 1M LiOH (1 mL, 1.000 mmol). After 2 h, the reaction was concentrated in vacuo. The off-white solid was taken up in a minimum of DCM and eluted through a Redi-Sep® pre-packed silica gel column (4 g) with EtOAc to provide the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) δ ppm 8.91 (d, J=4.8 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.53-7.66 (m, 5H), 6.93 (s, 1H). MS (ESI pos. ion) m/z: 469.0 (M+H).
Reaction SMILES: BrC1CCCC1.[N+](C1NC=CN=1)([O-])=O.[CH:15]1([N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[N+:25]([O-])=O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1nccn1C1CCCC1
Agent: BrC1CCCC1
Agent: O=[N+]([O-])c1ncc[nH]1
Product: Nc1nccn1C1CCCC1

Procedure:
Bromocyclopentane (14 mmol) and 2-nitroimidazole (10 mmol) were used to prepare 1-cyclopentyl-2-nitro-1H-imidazole following the alkylation procedure described for Example 181. The product, thus obtained was reduced under hydrogenation conditions as described in general procedure F to afford 1-cyclopentyl-2-amino-1H-imidazole. This aminoimidazole derivative was converted to 1-cyclopentyl-2-isothiocyanato-1H-imidazole following the general procedure A.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([N:33]=[N:34][C:3]2[C:2]([CH3:1])=[C:8]([OH:9])[C:7]3[N:10]4[CH2:11][CH:12]5[NH:23][CH:13]5[C:14]4([O:21][CH3:22])[CH:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=3[C:4]=2[OH:5])=[O:32])=[CH:29][CH:28]=1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: NNC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC12C(COC(N)=O)c3c(O)c(N=NC(=O)c4ccc(N)cc4)c(C)c(O)c3N1CC1NC12
Yield: 40.2 %

Procedure:
In a similar manner to that described in Example 17, mitomycin A (302 mg), 4-aminobenzoylhydrazine (389 mg) and potassium carbonate (150 mg) are used to obtain the desired product (163 mg) with a yield of 40.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Mg].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>CCOCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 ml of ether is added dropwise to a mixture of 2.8 g of magnesium in 20 ml of ether, the reflux being maintained once it has started. At the end of the addition, the mixture is heated at reflux for one hour. A mixture of 7.5 g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at a temperature below 40° C., followed by refluxing for one hour. After cooling to RT, the reaction mixture is poured into an ice/concentrated HCl mixture and extracted with EtOAc, the organic phase is washed with water, with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 6.5 g of the expected product are obtained after crystallization from a DCM/iso ether mixture (20/80; v/v),
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36]O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36][O:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(O)c1-c1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a solution of 7-chloro-4-hydroxy-6-nitro-3-thiophen-2-yl-1H-quinolin-2-one (50 mg in 2.5 mL of tetrahydrofuran) at 0° C. was added 44 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 63 mg of triphenylphosphine followed by 0.04 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 24 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 90:10; then 80:20; then 60:40) to give the title compound (44 mg).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][C@H:5]([CH3:9])[N:4]1C(OC(C)(C)C)=O)[CH3:2]>Cl.CO>[CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][C@H:5]([CH3:9])[NH:4]1)[CH3:2]
Reactant: CC[C@H]1COC[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC[C@H]1COC[C@H](C)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.2 %

Procedure:
(3S,5S)-tert-Butyl 3-ethyl-5-methylmorpholine-4-carboxylate (1.8 g, 7.8 mmol) was dissolved in ca. 10 M HCl in CH3OH and allowed to stir at ambient temperature. After 2.5 h, the solution was concentrated under reduced pressure. To the residue was added 1 N NaOH (20 mL) and this was extracted with CH2Cl2 (2×20 mL). The combined organics were dried (Na2SO4) and carefully concentrated under reduced pressure to give (3S,5S)-3-ethyl-5-methylmorpholine (1.0 g, quantitative). 1H NMR consistent.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]1[CH2:9][C@H:8]([O:10]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1)=[O:4].O.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C@H:6]1[CH2:9][C@H:8]([OH:10])[CH2:7]1
Reactant: COC(=O)C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.7 %

Procedure:
To a solution of trans-4-nitro-benzoic acid 3-methoxycarbonylmethyl-cyclobutyl ester (540 mg, 1.84 mmol) in MeOH (20 mL) is added H2O (2.4 mL), THF (10 mL), and K2CO3 (255 mg, 1.84 mmol) at room temperature. The mixture is stirred at room temperature for 45 minutes. The solvent is removed under reduced pressure. Water is added to the obtained residue, and the mixture is extracted with dichloromethane. The organic layer is concentrated under reduced pressure then purified by silica gel column chromatography to give trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (230 mg, 87%); TLC (hexane/AcOEt, 1:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm 1.69-1.70 (m, 1H), 2.07-2.19 (m, 4H), 2.44-2.46 (d, 2H), 2.41-2.69 (m, 1H), 3.66 (s, 3H), 4.39-4.47 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([CH3:19])[C:3]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([Li])CCC.CCCCCC.B(OC)(OC)[O:39]C.OO>O1CCCC1.O.C(O)(=O)C>[OH:39][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([CH3:19])[C:3]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COB(OC)OC
Reactant: Cn1c(C(=O)OC(C)(C)C)c(Br)c2cc(OCc3ccccc3)ccc21
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(C(=O)OC(C)(C)C)c(O)c2cc(OCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 1,1-dimethylethyl 3-bromo-1-methyl-5-(phenylmethoxy)-1H-indole-2-carboxylate (18.6 g, 45 mmol) in 200 mL of tetrahydrofuran is cooled to -78° C. in a dry ice-acetone bath and treated dropwise with a solution of 1.6M n-butyl lithium in hexane (29 mL, 46 mmol). After 15 minutes a solution of trimethyl borate (5.2 mL, 4.8 g, 46 mmol) in 25 mL of tetrahydrofuran is added dropwise. The mixture is stirred for 1 hour, and 4.0 mL of acetic acid is slowly added. The mixture is stirred for an additional 10 minutes, and a solution of 30% hydrogen peroxide in water (5.4 mL, 1.8 g, 53 mmol) is slowly added. After 30 minutes, an additional 4.5 mL (1.5 g, 44 mmol) of peroxide solution is added, and the mixture is stirred at room temperature for 20 hours. The mixture is added to 1.0 L of water and extracted with ethyl acetate. The combined organic layers are washed with brine, 5% aqueous sodium bicarbonate solution, and brine again, then dried (anhydrous sodium sulfate) and evaporated to an oil residue. Purification of the residue by flash chromatography (silica gel, 50% dichloromethane in hexane elution) gives 8.2 g (52%) of product suitable for further synthesis. A sample recrystallized from hexane has mp 101°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:29]([CH2:28][C@@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]5)[C:27]=4[C:26]2=3)=[O:30])=[N:38][CH:39]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Reactant: Nc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv) in distilled DMF (8 mL) at room temperature under nitrogen was added 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg). The resulting solution was stirred for 2 h at room temperature and quenched with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to give tert-butyl N-(4-[[(3S)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (23.1, 195 mg, 81%) as a yellow oil. MS: m/z 556 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([CH:39]([NH:42][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCC(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-phenylpropylamine (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated under vacuum, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:12]O>CO>[O:1]([CH3:12])[C@H:2]1[O:10][CH2:9][C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: CO
Agent: Cl
Product: CO[C@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 201.4 %

Procedure:
To a suspension of L-arabinose (100 g, 667 mmol) in anhydrous MeOH (450 mL) was added a HCl/MeOH solution (7.3 g dry HCl in 50 mL MeOH) at room temperature under argon atmosphere. The mixture was refluxed for 2 h and cooled down to room temperature. The solution was concentrated to about ¾ of its volume to give a suspension. The solid precipitated was filtered and washed with cold MeOH (20 mL) to give the first crop as a crystalline powder (35.23 g). The filtrate was concentrated (35° C.) to ¼ of its volume. The solid precipitated was filtered, washed and dried as above to givc the second crop (9.66 g) as a colorless crystalline powder. The concentration and filtration were repeated to afford additional 28.31 g of the product (total 73.2 g, 67%). 1H NMR (D2O) δ 3.30 (s, OCH3, 3H), 3.56 (dd, 1H, H5), 3.73 (m, 1H, H4), 3.77 (dd, 1H, H5), 3.82 (bs, 1H, H2), 4.73 (m, 1H, H1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:3]1[CH:5]=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: CS(=O)(=O)c1ccc(Cl)c(N)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a slurry of 2-chloro-5-methanesulfonyl-aniline (4.50 g, 21.9 mmol) in 48% HBr (12 mL) at 0° C. was added dropwise a solution of sodium nitrite (2.28 g, 33 mmol) in H2O (8 mL) at such a rate that the temperature never exceeds 5° C. The resulting yellow mixture was allowed to stir 20 min at 0° C. and then charged with copper(I) bromide (3.3 g, 23 mmol). After 30 min the resulting mixture was extracted with EtOAc (2×100 mL) and the combined extracts were washed successively with satd NH4Cl, 3N HCl and brine, then dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (4.92 g, 83%) as a white solid. GC-MS (EI): 268, 270.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[O:16]=[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)/[CH:13]=[CH:12]/[C:9]1[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: CS(=O)(=O)Oc1ccc(/C=C/C(=O)N2CCC[C@H]2CN2CCCCC2)cc1

Procedure:
230 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.