Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH2:31][CH3:32])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH2:31][CH3:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC[C@@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H](CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Yield: 73 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-amino-pentanoic acid (82 mg, 0.7 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 1.4 mL, 0.7 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 150 minutes. The reaction mixture was diluted with water and treated with 1N hydrochloric acid. The crude precipitate was purified by MPLC (methylene chloride-ethyl acetate) to provide the title compound as an off-white solid in 73% yield. MS ESI(−) m/e: 403.9928 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=O)=[C:4]([F:20])[CH:3]=1.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8]2)=[C:4]([F:20])[CH:3]=1
Reactant: CCCCCCCCC1Cc2c(F)cc(Br)cc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC1Cc2cc(Br)cc(F)c2C1

Procedure:
This ketone is dissolved in trifluoro acetic acid and an excess of triethylsilane is added. After completion of the reaction, the mixture is poured into the 10-fold amount of water and extracted with dichloromethane. The combined dichloromethane extracts are washed as described above and dried afterwards. After removing of the solvent by distillation and chromatographic cleaning (silica gel; dichloromethane/heptane; gradient, starting with 1:1) 6-bromo-4-fluoro-2-octyl-indane is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH:20]=O)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH2:20][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1
Reaction time: 17 h
Yield: 24 %

Procedure:
A mixture of 1.25 g (4.00 mmol) of 3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propionaldehyde, 0.743 g (4.50 mmol) of ethyl p-aminobenzoate, 1.0 ml of glacial acetic acid, and 3A molecular sieves in 25 ml of methanol was stirred at room temperature for 3 hours under nitrogen before 0.28 g (4.47 mmol) of sodium cyanoborohydride was added during a 2 minute period. After stirring for 17 hours, the mixture was filtered. The filtrate was spin evaporated in vacuo to a yellow foam. The product was separated from a mixture by flash chromatography on Silica Gel 60 (100 g; 230-400 mesh, EM Reagents) with ethyl acetate. Appropriate fractions were combined on the basis of TLC correlation, and solent was removed by spin evaporation in vacuo. Recrystallization from ethyl acetate yielded 0.44 g (24% of theory) of ethyl 4-[3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propylamino]benzoate as a white solid, mp 197°-198°; TLC (ethyl acetate), Rf =0.5; NMR (DMSO-d6) δ 1.28 (t, J=7.1 Hz, 3H, CH3), 1.65 (m, 2H, CCH2C), 2.14 (s, 3H, Ac), 2.2 (m, 2H, CH2Het), 2.23 (s, 6H, 2Ac), 3.05 (m, 2H, CH2N), 4.22 (q, J=7.1 Hz, 2H, CO2CH2), 6.5 (br, 1H, AcNH obscured by Ar), 6.57 (d, 2H, ArH), 7.69 (d, 2H, ArH). Elemental analysis. Calculated for C22H27N5O6, 0.5 H2O (MW 466.49): C, 56.64; H, 6.05; N, 15.01. Found: C, 56.88; H, 6.01; N, 14.88.
Reaction SMILES: [CH3:1][S:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[NH:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26](O)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]([N:5]([C:3]([S:2][CH3:1])=[NH:4])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2noc(C)c2C(=O)O)cc1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2noc(C)c2C(=O)N(C(=N)SC)C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of tert-butyl methylthiocarbonoimidoylcarbamate (Preparation AU, 0.98 g, 5.16 mmol), 3-(4-methoxyphenyl)-5-methyl-4-isoxazolecarboxylic acid (Preparation Y, 1.17 g, 5 mmol), EDCI (1.2 g, 6.26 mmol) and DIPEA (1 g, 7.75 mmol) in DCM (30 mL) was stirred for 3 hours. The solvent was concentrated by rotovap and residue was purified by column with EtOAc/DCM (5/95) as the eluant. The product was obtained as a white solid (1.2 g, 60%). 1H NMR (CD3OD): δ 1.52 (s, 9H), 1.89 (s, 3H), 2.76 (s, 3H), 3.86 (s, 3H), 7.00, 7.02 (d, 2H), 7.47, 7.49 (d, 2H). MH+=406.19
Reaction SMILES: CCN(CC)CC.[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:14][CH2:13]1)=[O:11].[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.O>[O:11]=[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:26])[F:27])[CH2:16][CH2:17]1)[CH2:9][NH:8][S:36]([C:33]1[CH:32]=[CH:31][C:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CNS(=O)(=O)c1ccc(-c2ccccc2)cc1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
Et3N (42 mg, 0.42 mmol) was added to a stirred solution of 2-amino-1[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (80 mg, 0.19 mmol) in DCM (4 mL) at 0-5° C. 4-biphenylsulfonyl chloride (47 mg, 0.19 mmol) was then added and the mixture was stirred at 0-5° C. for 4 hrs. The reaction was then diluted with cold water and the product was extracted with DCM, washed with 5% NaHCO3, 5% HCl, then saturated brine solution. The DCM layer was dried over sodium sulphate and concentrated. The residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in hexane as eluent) to afford 33 mg (33.4% yield) of biphenyl-4-sulfonicacid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LC-MS purity: 90.35%. 1H-NMR (CDCl3) δ 7.9 (m, 2H), 7.7 (d, 3H,), 7.6-7.5 (m 4H), 7.5-7.4 (m, 3H), 7.3 (m, 1H), 5.6 (s, 1H), 4.0-3.7 (m, 5H), 3.7-3.5 (m, 3H), 3.4-3.3 (m, 2H), 3.25-3.1 (m, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Reactant: c1cncc(CN2CCNCC2)c1
Agent: Cl
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCN(Cc3cccnc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (methode C) (64%, white crystals). HPLC-MS m/z=437.4 (M+1), Rt: 2.38 min.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.O.[C:20](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4-bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2×250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78%)
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2>>[F:34][C:35]1[CH:44]=[C:43]([C:45]([NH:27][C@@H:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2
Reactant: O=C(O)c1cc(F)c2cnc(N[C@H]3CCOC3)nc2c1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(N[C@@H]4CCOC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-N-((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((R)-tetrahydrofuran-3-ylamino)quinazoline-7-carboxamide (I-62) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87e.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]C)=[O:20])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc(C(=O)O)c1
Temperature: -15 °C
Yield: 98.4 %

Procedure:
To a stifling solution of (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (98.6 g, 319.7 mmol) in MeOH (1000 mL) in a water bath at 15° C. add 10M NaOH aqueous solution (500 mL) portionwise over 5 min (exotherm to 37° C.) and stir the reaction at ambient temp for 20 h. Concentrate the reaction in vacuo at 35° C. to remove MeOH and give a suspension. Dilute the slurry with water (200 mL), cool to −15° C. in a dry ice/iPrOH bath and quench with addition of concentrated HCl (417 mL) over 1 h with vigorous mechanical stirring maintaining internal temp at −5° C., to a final pH of 1. Extract the cold suspension with EtOAc (2×1500 mL), and wash the organics with water (2×1000 mL) and brine (400 mL). Dry the organic layers (Na2SO4), and concentrate at 40° C. to a solid. Suspend this in hexane (750 mL) and filter to give 91.65 g of the product (R)-2-(3-Carboxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C1COCC1.CCCCCC>[OH:12][C:13]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
To a solution of 1-methyl-1H-imidazole (2 g) in THF (15 ml) was added 1.59 M n-butyllithium in n-hexane solution (18.4 ml) slowly under ice bath cooling, and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (5.8 g) in THF (15 ml) solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc and was washed with brine, and was dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by silica gel column (CHCl3:MeOH=95:5 to 90:10) to give tert-butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (4.02 g) as a pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[S:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNS(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 4.1 %

Procedure:
To a solution of 33 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 25 mg of 2,4-dichlorobenzenesulfonyl chloride in 0.8 ml of dichloromethane was added 40 μl of pyridine under ice-cooling, and stirring was continued at room temperature for 4 hours. After removing the solvent, to the residue were added 1.0 ml of ethanol and 0.3 ml of 2N aqueous sodium hydroxide, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, and neutralized with 2N hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. Then, the residue was purified by HPLC using a reverse-phase column by using an elution solvent of water-acetonitrile-trifluoroacetic acid system, to give 2.0 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[S:19](=[O:25])(=[O:24])[NH:20][C:21](=[O:23])[CH2:22]2)=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1
Reactant: Nc1ccccc1NC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(/C=C/c3nc4ccccc4[nH]3)cc2OCc2ccccc2)S(=O)(=O)N1

Procedure:
A solution of (E)-N-(2-aminophenyl)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylamide in acetic acid is stirred at 60° C. for 18 h. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:20]3[N:19]=2)[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:27]([C:26]2[CH:25]=[N:24][N:21]3[CH:22]=[CH:23][C:18]([N:14]4[CH2:15][CH2:16][CH2:17][C@@H:13]4[C:4]4[CH:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=[C:2]([F:1])[CH:3]=4)=[N:19][C:20]=23)=[O:29])[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: COCCOc1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1
Product: COCCOc1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)NC4CC4)c3n2)c1
Yield: 52 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropylamine to yield the title compound as a white solid (16 mg, 52% yield). MS (apci) m/z=440.1 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:10])[F:9])[CH2:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:41][O:42][C@H:43]1[C:48](=O)[CH2:47][CH2:46][O:45][CH2:44]1.[OH-].[Na+]>ClCCl.O>[C:23]([O:22][C:20]([N:16]1[CH2:15][C@@H:14]2[CH2:19][C@H:17]1[CH2:18][N:13]2[C:11]([C@@:4]1([CH2:7][CH:8]([F:9])[F:10])[CH2:5][CH2:6][C@@H:2]([NH:1][C@@H:48]2[C@H:43]([O:42][CH3:41])[CH2:44][O:45][CH2:46][CH2:47]2)[CH2:3]1)=[O:12])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CO[C@@H]1COCCC1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A 0° C. solution of tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.45 g, 9.2 mmol) in dichloromethane (50 ml) was treated with sodium triacetoxyborohydride (5.34 g, 25.2 mmol) and (3R)-3-methoxytetrahydro-4H-pyran-4-one (2.31 g, 17.8 mmol). The reaction was stirred under nitrogen at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 47 hours. The reaction was treated with 2.5N NaOH (35 mL) and stirred for 10 minutes. The reaction was diluted with water and the layers separated. The aqueous layer was extracted twice with ethyl acetate. The dichloromethane layer was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic layers were combined, washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol (2.13 g, 47%) which was used without further purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:2]
Reactant: CCOC(=O)CCCCCCOc1cccc(OC)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(O)cccc1OCCCCCCC(=O)O

Procedure:
To a stirred solution of ethyl 7-(2-formyl-3-methoxyphenoxy)heptanoate (4.15 g, 0.0135 M) in dry tetrahydrofuran (60 ml) was added dropwise a solution of magnesium iodide (5.82 g, 0.0202 M) in dry ether (97.5 ml). The mixture was then stirred under reflux (5 hr). The cooled mixture was poured into 10% hydrochloric acid (65 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solution were washed with water and evaporated to dryness. The residue, ethyl 7-(2-formyl-3-hydroxyphenoxyheptanoate, was dissolved in 2 N sodium hydroxide solution (50 ml) with stirring at room temperature (10 hr). The solution was decanted from a residue and acidified with concentrated hydrochloric acid with cooling. The precipitated solid was filtered off and washed well with water to give 7-(2-formyl-3-hydroxyphenoxy)heptanoic acid, m.p. 106°-107° C. from benzene/petrol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)=[CH:12]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[NH:25][CH:24]=[CH:23][N:22]=3)=[CH:12]2)=[CH:26][CH:27]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Yield: 53.9 %

Procedure:
1-(4-Ethoxycarbonylbenzyl)-3-(1-imidazolylmethyl)indole (1.53 g) was dissolved in ethanol (25 ml) and a solution of sodium hydroxide (0.2 g) in water (5 ml) was added. The solution was heated under reflux for 2 hours and then evaporated. The residue was taken up in water and the solution was just acidified with acetic acid. A gummy precipitate was formed which solidified on scratching. The solid was filtered off, washed with water and crystallised from ethanol to give 1-(4-carboxybenzyl)-3-(1-imidazolylmethyl)indole (0.76 g), m.p. 234°-235° C. Found: C, 72.32; H, 4.96; N, 12.67. C20H17N3O2 requires: C, 72.49; H, 5.17; N, 12.68.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Cu][C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14])#[N:17]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(Br)c(OC)c1C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC)c1C
Temperature: 150 °C
Yield: 67.6 %

Procedure:
To a sealed tube vessel was added methyl 4-bromo-2-methyl-3-(methyloxy)benzoate (280 mg, 1.08 mmol), copper (I) cyanide (97 mg, 1.08 mmol) and dimethylformamide (2 mL). The mixture was heated at 150° C. for 24 hours, then was cooled to room temperature and filtered through a pad of Celite. After washing the Celite with ethyl acetate, the combined filtrate was washed with 5% aqueous lithium chloride, and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% ethyl acetate in hexane, purified fractions were pooled and concentrated to afford 150 mg, 0.73 mmol (68%) of methyl 4-cyano-2-methyl-3-(methyloxy)benzoate. 1H NMR (400 MHz, CDCl3): 7.61 (d, 1H), 7.47 (d, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.49 (s, 3H). MS (EI) for C11H11NO3: 206 (MH+).
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:24])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 12.3 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride and 2.8 g. of methanesulfonamide in 150 ml. of pyridine is stirred at reflux for 2 hours and then evaporated in vacuo. The residue is partitioned between water and diethyl ether, the aqueous layer acidified with 1N hydrochloric acid, and the organic layer separated, dried with magnesium sulfate and evaporated. Crystallization of the residue affords the product as a white solid.