Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:12]([CH3:18])[C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([C:14]1[C:15]([CH3:16])=[C:11]([C:9](=[O:10])[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]([CH3:18])[C:13]=1[CH3:17])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1c(C(=O)CCl)c(C)n(C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 87.7 %

Procedure:
A solution of 48.65 g (0.17 mole) of (2,4-dichlorophenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone (5) in 480 mL 1,2-dichloroethane was cooled in an ice bath and 53.5 g (0.425 mole) of AlCl3 was added in four portions. A 33.5 mL portion of (0.425 mole) chloroacetyl chloride was added dropwise. The ice bath was removed and the reaction allowed to stir for 3h under argon. A 10 g sample of AlCl3 was added and the reaction was stirred overnight. The mixture was poured into 1N HCl/ice and the organic layer was separated. The aqueous layer was extracted twice with methylene chloride. The organics were combined and washed with water, NaHCO3, water, brine, and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized from methylcyclohexane to give 53.50 g of product: mp 100-102° C.; mass spectrum (Cl—CH4) m/z=358 (M+1); NMR 300 MHz (CDCl3) d 7.55 (s, 1 H); 7.4 (s, 2 H); 4.4 (s, 2 H); 3.7 (s, 3 H); 2.5 (s, 3 H); 1.9 (s, 3 H). Anal Calcd for C16H14NO2: C, 53.58; H, 3.93; N, 3.91. Found: C, 53.48; H, 3.81; N, 3.93.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(C(F)(F)F)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.42 mmol) and triethylamine (88 μL, 0.63 mmol) in methylene chloride (15 mL) was added dropwise 3-(trifiuoromethyl)benzoyl chloride (93 mg, 0.44 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 130 mg (71%) of the title compound as a viscous oil: [α]21D -25° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 417 (25, M+).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:28]=[CH:27][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:20])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH:29]([C@@H:31]1[C@@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][N:33]([C@H:42]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:43]([O:45]CC2C=CC(OC)=CC=2)=[O:44])[CH2:32]1)=O>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]([N:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:29][C@@H:31]3[C@@H:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:34][N:33]([C@H:42]([CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]4)[C:43]([OH:45])=[O:44])[CH2:32]3)[CH2:25][CH2:26]2)[CH3:20])=[O:18])=[CH:27][CH:28]=1)([O-:10])=[O:9]
Reactant: CN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 60.8 %

Procedure:
The title compound was prepared from 4-(N-(N-(4-nitrobenzyl)carbamoyl)-N-methylamino)-piperidine trifluoroacetate (41 mg, 0.1 mmol, from Step A) and 2-(R)-(3-(R)-formyl-4-(S)-phenyl-pyrrolidin-1-yl)-2(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (26 mg, 0.05 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 18 mg (61%) of the title compound. ESI-MS: 592.4 (M+H); BPLC A: 2.12 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)c(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+].C(O)C>O1CCCC1>[Cl:17][C:12]1[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[O:8][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1c(-c2cccnc2Cl)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1onc(-c2cccnc2Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Combine 3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid methyl ester (1.90 g, 0.0075 mol) with aqueous sodium hydroxide (2N, 15.0 mL, 0.03 mol), ethanol (3 mL), and tetrahydrofuran (3 mL). Stir for 4 hours at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 3.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Eluted over silica gel with methanol/dichloromethane allowing for isolation of the desired isoxazole acid as an off white solid (0.98 g, 55%). MS(ES): (M+1)+ 238.97, 240.97 m/z.
Reaction SMILES: O[CH:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4].C(Cl)[Cl:25].Cl>O>[Cl:25][CH:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: ClCCl
Agent: Cl
Solvent: O
Product: CCC(Cl)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 26.7 g. (75.4 mmole) 4-chlorobenzenesulphonic acid-4-(1-hydroxypropyl)-phenethyamide], 200 ml. methylene chloride and 100 ml. concentrated hydrochloric acid is vigorously stirred for 1 hour, then diluted with water and the methylene chloride phase is separated off. It is washed with water and sodium bicarbonate solution, dried with anhydrous sodium sulphate and evaporated. Yield quantitative; m.p. 90°-91° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].N12CCCN=C1CCCCC2>O1CCOCC1>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][C:34](=[O:35])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)[nH]3)c2cc1C1CC1)S(C)(=O)=O
Yield: 60.1 %

Procedure:
A mixture of Example 10F (355 mg, 0.75 mmol), carbonyldiimidazole (146 mg, 0.900 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.124 mL, 0.825 mmol) in dioxane (6 mL) was refluxed for 1 hour, cooled and partitioned between ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 10-40% ethyl acetate in hexane to give the title compound as a solid (225 mg, 60%). MS (ESI−) m/z 498 (M−H)−.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:20][CH2:21][N:22]([C:1]([Cl:4])=[S:2])[CH2:23][CH2:24]1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCN(C(=S)Cl)CC3)c2cc1OC
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 3.06 ml (40.1 mmol) of thiophosgene in 100 ml of dichloromethane were slowly added a solution of 10 g (36.5 mmol) of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline obtained by the method described in South African Patent No. 67 06512 (1968) in 100 ml of dichloromethane and 12.4 ml (89.1 mmol) of triethylamine under ice-cooling. The resulting mixture was stirred at the same temperature in an atmosphere of argon for 2 hours. After the solvent was evaporated, the residue was purified by silica gel chromatography to give 6.65 g (52%) of the desired compound.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[Zn].O>[NH:10]([CH:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCNCC1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(NC2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
In a three neck round bottom flask equipped with mechanical stirrer and water condenser, 15.36 gm (0.10 moles) of 4-piperidone hydrochloride monohydrate and 16.43 gm (0.2 moles) of aniline were added. To this mixture, 130 gm (2.0 moles) of zinc and 120 gm (2.00 moles) of 90% acetic acid were added. The reaction mixture was stirred at room temperature for 24 hrs and at 50 to 70° C. for 24 hrs. Water was then added to the reaction mixture and filtered. Crushed ice was added to the filtrate and was neutralized with excess of aqueous sodium hydroxide solution. The crude 4-anilinopiperidine was obtained by filtration.
Reaction SMILES: [C:1](Cl)(=O)C.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([OH:11])=[O:10]>CO>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([O:11][CH3:1])=[O:10]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution prepared by the dropwise addition of 12 ml acetyl chloride to 150 ml methanol was added 7.0 grams 3-fluoro-4-nitrobenzoic acid and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 2% sodium carbonate solution. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 6 grams of methyl 3-fluoro-4-nitrobenzoate as an orange oil which gradually hardened to a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A solution of tert-butyl 3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynylcarbamate (300 mg, 0.78 mmol) in CH2Cl2 (10 mL) was treated with TFA (2 mL) and stirred at rt for 45 min. The mixture was concentrated under vacuum and the residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (180 mg, 80%) as a red oil. 1H NMR (DMSO-d6) δ 8.65 (s, 1H), 8.47 (d, 1H, J=5.6 Hz), 8.43 (dd, 1H, J=10.7, 2.5 Hz), 8.17 (d, 1H, J=8.6 Hz), 7.54 (t, 1H, J=8.6 Hz), 7.04 (d, 1H, J=5.6 Hz), 3.49 (s, 2H); MS(ESI+): m/z 288.17 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:17])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:18][CH2:19][CH3:20])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]2[CH2:18][CH2:19][CH3:20])=[CH:24][CH:23]=1
Reactant: CCCc1[nH]c2cc(C(N)=O)ccc2c1C(=O)C(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 66.6 %

Procedure:
A mixture of 3-isobutyryl-2-propylindole-6-carboxamide (100 mg), 4-chlorobenzyl bromide (113 mg) and potassium carbonate (152 mg) in dimethylformamide (2 ml) was heated at 60° C. for 2 hours, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was crystallized from a mixture of ethyl acetate and hexane. The crude crystals were recrystallized from a mixture of ethyl acetate and hexane to give 1-(4-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide (97 mg) as colorless crystals.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@H:64]([C:69]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:26])[NH:27][CH3:28])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: CNC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N-methylbenzamide (15, 150 mg, 0.38 mmol), DCC (94 mg, 0.45 mmol) and DMAP (5 mg, 0.038 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (133 mg, 0.38 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 100 mg (52%) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=O)[CH3:11])=[CH:4][C:3]=2[O:2]1.Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:10](/[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)\[CH3:11])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: Cl
Product: C/C(=N\OCc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)OCO2
Yield: 87 %

Procedure:
3′,4′-Methylenedioxyacetophenone (22) (150 mg, 0.914 mmol) was condensed with compound 19 (206 mg, 1.01 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the resulting solid filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30255 (250 mg, 87%) as a yellow solid, m.p. 158.7-160.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:22]([O:21][C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1cc(Br)cc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(C(=O)O)c2)CC1

Procedure:
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,3-difluorobenzoic acid was prepared as in Example 2 (Step ii) using 5-bromo-2,3-difluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10]([C:25]#[N:26])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline tert-butyl ester (889 mg, 2.43 mmol) and sodium cyanide (1.19 g, 24.3 mmol) in N,N-dimethylformamide (18 mL) was stirred for 4 days at 80° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting initially with 10% ethyl acetate/hexane. Fractions containing the TLC more mobile isomer were combined and evaporated to afford the desired title compound; yield 225 mg (31%).
Reaction SMILES: [P:1](Cl)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Br:9][C:10]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:19][C:16]1[CH:17]=[CH:18][C:10]([Br:9])=[C:11]2[C:15]=1[C:14](=[O:20])[CH2:13][CH2:12]2)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: O=C1CCc2c(Br)ccc(O)c21
Reactant: CCSP(=O)(Cl)OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCSP(=O)(OC)Oc1ccc(Br)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Methyl S-ethyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-bromo-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-methyl S-ethyl O-(4-bromoindan-1-on-7-yl) thiophosphate.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][C:41]([CH3:45])([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:40][C:41]([CH3:45])([CH3:44])[CH2:42][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)C=O
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 0.25 h
Yield: 12.7 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol) in 1,2-dichloroethane (3.0 mL) was treated with trimethylacetaldehyde (21 μL, 0.186 mmol) at ambient temperature. After stirring for 15 minutes, the mixture was treated with acetic acid (11 μL, 0.181 mmol) followed by sodium triacetoxyborohydride (53 mg, 0.248 mmol). After stirring at ambient temperature for 24 hours, the mixture was treated with aqueous 10% NaHCO3 (5.0 mL) and extract with ethyl acetate (3×10 mL). The ethyl acetate extracts were combined, wash with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with chloroform to provide the title compound (12.5 mg, 13%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.79 (s, 2H), 7.28-7.05 (m, 10H), 5.20 (s, 4H), 4.88-4.76 (br s, 2H), 3.90-3.66 (m, 2H), 2.87 (dd, 2H), 2.75-2.60 (m, 2H), 2.47 (d, 4H), 2.17 (s, 2H), 0.78 (s, 9H); MS (ESI+) m/z 636 (M+H)+.