Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12][C:11]2=[O:21])=[CH:6][C:5]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O.[CH2:31]([OH:33])[CH3:32]>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:21])[CH2:12][CH:13]([C:17]([F:19])([F:20])[F:18])[CH2:14][C:15]([O:33][CH2:31][CH3:32])=[O:16])=[CH:6][C:5]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCO
Reactant: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)CC(C(F)(F)F)CC2=O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CC(=O)Nc1ccc(Cl)c(C=C(Cl)C(=O)OCC)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
0.13 g (34 mmol) of sodium borohydride was added in portions at room temperature to a solution of 4.2 g (10 mmol) of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)phenyl]-3-trifluoromethylglutarimide in 100 ml of ethanol. After stirring for 3 hours the reaction mixture was added to 100 ml of water, after which the aqueous phase was extracted twice with dichloromethane. The combined org. phases were dried over sodium sulfate and concentrated. Finally, the residue was purified by triturating with petroleum ether. Yield: 2 g (42%); m.p.: 115°-117° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:31])[C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-5-methylimidazolidine-2,4-dione (50 mg) described in Example 450 and methyl iodide (9.2 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (26 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N+:34]([O-:36])=[O:35])=[C:21]([CH:23](C(OCC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[N:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N+:34]([O-:36])=[O:35])=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:22]=2)=[N:14][N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.3 %

Procedure:
A mixture of diethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (165 mg, 242 μmol), water (4 μL, 242 μmol), and lithium chloride (51 mg, 1210 μmol) in DMSO (2 mL) was heated at 100° C. for 24 hours. The mixture was cooled to room temperature and partitioned between saturated aqueous NH4Cl (15 mL) and DCM (15 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 40% to 70% EtOAc/hexanes) to provide ethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)acetate (117 mg, 79%) as a white solid. LCMS (API-ES) m/z: 610.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].CS(C)=O>O>[N:14]([CH2:2][C@@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCl)COc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H](O)COc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of (S)-1-Chloro-3-(4-fluoro-phenoxy)-propan-2-ol (5.0 g, 24.5 mmol), sodium azide (3.19 g, 49.0 mmol) and DMSO (25 mL) was stirred at 80° C. for 6 h. Then the reaction mixture was poured into water (100 mL), extracted with hexane-Et2O (1:1) mixture (2×100 mL). Extracts were washed with brine (100 mL), dried over Na2SO4 and evaporated. The residue was dried under vacuum at RT. Colorless oil, 4.83 g (22.9 mmol, 93%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][N:17]1[C:21]2[CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:19]=[CH:18][N:17]([CH3:16])[C:21]=4[CH:22]=3)[OH:27])=[CH:3][N:4]=2)[N:7]=1
Reactant: Cn1cnc2ccc(C=O)cc21
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cnc2ccc(C(O)c3cnc4ccc(Cl)nn34)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (850 mg, 3.47 mmol) was dissolved in THF (50 mL) under Argon. Ethylmagnesium bromide solution (1 M, 3.47 mL) was added and the mixture was stirred at rt for 20 min. Then 3-methyl-3H-benzoimidazole-5-carbaldehyde in THF (10 mL) was slowly added and the mixture was stirred at rt for 18 h. The mixture was quenched with water and NaHCO3. It was extracted with EtOAc twice and some MeOH to dissolve the solids. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 25 min then up to 11% MeOH). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as a pink foam (tR 1.79 min (conditions 8), MH+=314).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 6-chloropyridin-3-ol.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:23]([NH:24][C:25](=[O:59])[C:26]([C:34]3[N:35]=[C:36]([NH:39]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:37][CH:38]=3)=[N:27][O:28]C(C)(OC)C)[C:22](=[O:60])[N:9]2[C:10]=1[C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])=[N+:2]=[N-:3]>C(O)=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:23]([NH:24][C:25](=[O:59])[C:26]([C:34]3[N:35]=[C:36]([NH2:39])[S:37][CH:38]=3)=[N:27][OH:28])[C:22](=[O:60])[N:9]2[C:10]=1[C:11]([O:13][CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(CN=[N+]=[N-])CS[C@@H]2C(NC(=O)C(=NO)c3csc(N)n3)C(=O)N12
Reaction time: 0.2 h
Yield: 44.4 %

Procedure:
A mixture of 753 mg of the product of Step B, 0.75 ml of 98% formic acid and 9.25 ml of 50% aqueous formic acid was stirred at 55°-60° C. for 12 minutes and the mixture was evaporated to dryness at a temperature not above 30° C. The residue was taken up in 5 ml of water and the mixture was vacuum filtered. The product was washed with water and then with isopropyl ether and dried. The 481 mg of product was chromatographed over silica gel and was eluted with a 1-1 acetone-methylene chloride mixture to obtain 211 mg of the pivaloyloxymethyl 3-azidomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccccc4F)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccccc3F)C2)n1
Temperature: 150 °C
Yield: 10.2 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(2-fluorophenyl)-3-piperidinecarboxamide (191 mg, 0.440 mmol), 3 mL of EtOH, Hunig's base (0.077 mL, 0.440 mmol), and hydrazine anhydrous (0.055 mL, 1.759 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 1H), 1.84 (m, 2H), 2.01-2.20 (m, 1H), 3.21-3.24 (m, 2H), 3.44-3.61 (m, 1H), 4.36-4.53 (m, 1H), 4.61-5.09 (m, 1H), 6.97 (m, 1H), 7.17 (m, 3H), 7.39 (s, 1H), 7.67-8.01 (m, 3H), 9.84 (m, 1H), 11.87-12.17 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](O)(=[O:11])[CH3:10]>>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 150 °C
Yield: 82.5 %

Procedure:
Proline (1 g, 8.68 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for two hours. The excess acetic acid was removed using a rotary evaporator. The residue was stirred in MTBE at ambient temperature until a solid precipitated. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (1.12 g, 82.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.77-1.95 (m, 4H), 1.97 (s, 2H), 2.0-2.19 (m, 1H), 3.35 (dt, 1H), 3.41-3.58 (m, 2H), 4.19 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9].[Li][CH2:21]CCC.IC>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[C:14]([CH3:21])[S:13][C:12]=1[C:16]([OH:18])=[O:17])(=[O:10])=[O:9]
Reactant: [Li]CCCC
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)O)s1
Temperature: 25 °C

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarboxylic acid (6 g, 18.60 mmol) in anhydrous tetrahydrofuran (240 mL) at −78° C. and under nitrogen was added nBuLi (2.5 M in hexane, 30 mL, 74.4 mmol). The mixture was stirred at this temperature for 2 h before the addition of iodomethane (6.6 g, 74.4 mmol). The mixture was then poured into crushed ice and then allowed to warm to room temperature. After acidification with concentrated HCl to pH ˜1, the mixture was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried (MgSO4), the solids were filtered and the filtrate was concentrated to give N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid and the starting material in about a 2:1 ratio (8.5 g combined weight).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[CH2:13]1[CH2:18][O:17][CH:16]=[CH:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:16]2[CH2:15][CH2:14][CH2:13][CH2:18][O:17]2)[N:3]=1
Reactant: N#Cc1cccc2[nH]nc(I)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
A mixture of 3-iodo-1H-indazole-4-carbonitrile (3.0 g, 11.1 mmol), DHP (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) in THF (40 mL) under nitrogen was heated at 85° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using petroleum ether/EtOAc (5:1) to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (3.31 g, 84.0%). MS (ESI): m/z=354 [M+1]+.
Reaction SMILES: N1C=CC(C2C=[N:10][NH:9][C:8]=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([C:49](=O)[CH2:50][C:51]2[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:49]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[CH:8][NH:9][N:10]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Product: Clc1cc(-c2n[nH]cc2-c2ccncc2)ccc1OCc1ccc2ccccc2n1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting 1-[3-Chloro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CD3OD) δ 8.37 (m, 4 H), 8.02 (d, J=8.7 Hz, 2 H), 7.93 (d, J=8.3 Hz, 2H), 7.78 (m, 2 H), 7.61 (t, J=7.1 Hz, 1 H), 7.31 (m, 2H), 7.21 (m, 1 H), 5.44 (s, 2H); MS: (M+H m/z=413.0).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].O1CCOCC1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=S1(=O)N=C(Cl)c2ccccc21

Procedure:
Saccharin (10 g) was treated sequentially with dioxane (40 mL), thionyl chloride (15 mL) and DMF (0.4 mL). The resulting suspension was heated to reflux for 24 hours. The reaction mixture was concentrated to dryness and recrystallized from 60 mL toluene to give 5.7 g of the sub-title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:42])=[O:26]
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2ccccc2)c1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of alcohol 3 (342 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipecolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-(3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (470 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.50-6.90 (m, 9H), 5.93 (t, J=6.0 Hz, 1H), 5.46 (d, J=3.4 Hz, 0.83 H, pipercolate a-H of rotamer A), 4.67 (s, 2H), 3.50 (d, J=12.9 Hz, 1H), 3.32 (td, J=12.5, 3.0 Hz, 1H), 2.75 (m, 2H), 2.53 (d, J=13.6 Hz, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 2.97-2.71 (m, 6H), 1.62 (s, 9H), 138 (s, 3H), 1.35 (s, 3H), 1.03 (t, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.3, 175.0, 170.0, 168.0, 167.5, 158.5, 141.7, 141.2, 130.2, 128.9, 128.7, 126.5, 120.2, 114.7, 113.6, 82.8, 66.1, 51.6, 47.1, 44.5, 38.2, 32.9, 32.0, 28.4, 26.8, 25.3, 24.0, 23.4, 21.6, 9.2. HRMS(FAB): (M+Na)+ calcd: 602.3094. found: 602.3090.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=3)[CH:20]([C:31]3[CH:36]=[CH:35][C:34]4[O:37][CH2:38][O:39][C:33]=4[CH:32]=3)[CH:19]2[C:40]([O:42]C)=[O:41])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=3)[CH:20]([C:31]3[CH:36]=[CH:35][C:34]4[O:37][CH2:38][O:39][C:33]=4[CH:32]=3)[CH:19]2[C:40]([OH:42])=[O:41])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 25.6 %

Procedure:
Methyl (1RS,2SR,3RS)-3-[2-(3Carboxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (I ml) and aqueous sodium hydroxide (1M, 1 ml ,l mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5% AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:15]1[CH2:23][CH2:24][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Product: N#CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1

Procedure:
Prepare by the method of example 76.1 using 4-chlorophenyl-acetonitrile (1.0 g, 6.6 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (1.5 g, 6.6 mmol) to give the title compound.
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.C([O:34][C:35](=[O:47])[C:36]([CH3:46])([CH3:45])[CH2:37]SC1SC(N)=NC=1)C>>[CH3:37][C:36]([CH3:46])([CH2:45][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])=[N:10][CH:9]=1)[C:35]([OH:47])=[O:34]
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Product: CC(C)(CSc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Reactant: [H][H]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: COc1ccc([C@@H](C)C(=O)O)cc1
Yield: 88.8 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.36 g (2 mmoles) of p-methoxyatropic acid and 20 ml of methanol. Then, 7.5 mg (0.009 mmole) of Ru((+)-BINAP)-(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 12 hours at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 19° C. Thereafter, the solvent was distilled off to provide 0.32 g of (2R)-(-)-2-(p-methoxyphenyl)propionic acid. The yield was 89%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][CH2:29][O:28][CH3:27])[CH:7]=1
Reactant: COCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: COCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.19 mmol), intermediate 42.1, and 2-methoxyethanol (42 μl; 0.515 mmol), example 50 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:12]
Reactant: OCc1ccncc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.2 %

Procedure:
To a solution of 3-bromo-4-(hydroxymethyl)pyridine (1.6 g, 8.4 mmol) in methylene chloride (90 mL) was added thionyl dichloride (1.6 mL, 22.0 mmol) dropwise over at 0° C. The reaction was stirred at room temperature for 2 h and then concentrated. The yellow solid was dried in a vacuum to afford the compound 5 (2.05 g, 100%).