Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[C:46]([O:50][C:51](=[O:54])[CH2:52][NH2:53])([CH3:49])([CH3:48])[CH3:47]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:53][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (60 mg) and glycine tert-butyl ester hydrochloride (33 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118, the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 616.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH2:29][CH3:30])=[C:27]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:46]=[CH:45][C:44]4[CH2:43][CH2:42][CH2:41][NH:40][C:39]=4[N:38]=3)[CH2:33][CH2:32]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:29]([C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:46]=[CH:45][C:44]3[CH2:43][CH2:42][CH2:41][NH:40][C:39]=3[N:38]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1c(NCC(C(=O)OC(C)(C)C)C(=O)c2ccc(OC)cc2)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 112.5 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane (50-50), ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:17][NH2:18]>N1C=CC=CC=1>[F:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:18][N:17]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(F)ccc1F
Reactant: NN
Solvent: c1ccncc1
Product: Fc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 40 %

Procedure:
A solution of 2,5-difluorobenzophenone (0.655 g, 3.0 mmol) and hydrazine (1.0 mL) in dried pyridine (10 mL) was heated at 130° C. for 5 hours and then concentrated and purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.254 g, 40% yield): mp 124-125° C.; 1H NMR (CDCl3) δ 10.89 (br s, 1H), 7.94 (d, 2H), 7.65 (dd, 1H), 7.42-7.54 (m, 3H), 7.33 (dd, 1H), 7.21 (dt, 1H); EL-MS (m/z) 212 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:26])([CH3:25])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](O)=[O:23])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH2:28]>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:25])([CH3:26])[CH2:10][C:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:21][C:22](=[O:23])[NH:28][CH3:27])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)COc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of [3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]acetic acid (480 mg, 1.32 mmol) in dimethylformamide (5.0 mL) is added methyl amine (1.52 mL, 1.0 M in tetrahydrofuran, 1.52 mmol) and Bop reagents (670 mg, 1.52 mmol). The reaction mixture is stirred at room temperature for 3 hours before evaporation to dryness. The resulting residue is chromatographed (30% ethyl acetate/hexane) to give 500 mg of [1,1-dimethyl-2-(7-methylcarbamoylmethoxy-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (75%). FDMS m/e=375.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[C:19]=2[C:20](=[O:22])[CH3:21])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccn2cc(-c3ccc(F)cc3)nc12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(-c2ccc(F)cc2)nc2c([N+](=O)[O-])cccn12
Yield: 55 %

Procedure:
2-(4-Fluorophenyl)-8-nitroimidazo[1,2-α]pyridine (2 g, 7.8 mmol) was added to acetic anhydride (15 mL). To this mixture was added a catalytic amount of concentrated sulfuric acid and the reaction mixture was heated to reflux for 1 hour. The resulting mixture was concentrated to a slurry, neutralized by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 1.3 g (55%) of 1-[2-(4-fluorophenyl)-8-nitroimidazo[1,2-α]pyridin-3-yl]ethanone as a brown solid. 1H NMR (DMSO-d6): δ 9.93 (d, 1H), 8.62 (d, 1H), 7.78 (q, 2H), 7.46 (m, 3H), 2.20 (s, 3H); MS m/z 300 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(OC)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
107 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-methoxyphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])(=[O:14])=[O:13].Cl.N1C=CC=CC=1>C(#N)C>[CH3:11][S:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[CH:1]1)(=[O:14])=[O:13]
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)CCOCCn1cnc2cnc3ccccc3c21
Reaction time: 0.33 h
Yield: 67.9 %

Procedure:
Triethyl orthoformate (2 mL, 12 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.1 g, 10 mmol) in acetonitrile (50 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 20 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide a viscous oil. The oil was triturated with ethyl acetate. The resulting solid was isolated by filtration and washed with ethyl acetate to provide 2.17 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinoline as an off-white powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[NH2:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1>N1C=CC=CC=1>[O:37]1[CH:38]=[CH:39][C:35]([NH:34][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)=[N:36]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: Nc1ccon1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O

Procedure:
Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), 3-aminoisoxazole (0.12 ml) and pyridine (5 ml) and the resultant suspension was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate), evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.14 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H), 3.29 (m, 4H), 7.06 (d, 1H), 7.50 (d, 1H), 7.63 (m, 3H), 8.09 (m, 2H), 8.13 (s, 1H), 8.85 (d, 1H), 11.46 (s, 1H); Mass Spectrum: M+H+ 445.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.C1(N2C3N=C(S(C)=[O:36])N=CC=3C(C)=C(I)C2=O)CCCC1>>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:36])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CSc1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Product: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1

Procedure:
Prepared from 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one following the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS (APCI) Calc'd for C13H14BrN3O2S: 357, 355.0. Found: 358 (M+1), 356. 1H NMR δ (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.63 (s, 1H), 5.91-5.86 (m, 1H), 2.89 (s, 3H), 2.15 (br s, 2H), 2.04 (br s, 2H), 1.87-1.79 (m, 2H), 1.61-1.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH2:14]([NH2:16])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([NH:16][C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10])[CH3:15]
Reactant: CCN
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNC(=O)c1sc(C)nc1C
Temperature: 140 °C
Reaction time: 25 h
Yield: 50.3 %

Procedure:
3.0 g of ethyl 2,4-dimethylthiazole-5-carboxylate, 7.0 g of ethylamine hydrochloride, 6.0 g of triethylamine, and 100 mL of ethanol were added into a 250 mL of high-pressure reactor. And the reaction mixture was heated to 120-160° C. and stirred for 20 to 30 hours, and then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.5 g N-ethyl-2,4-dimethylthiazole-5-carboxamide which was used in the next step directly without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[Cl:1][C:2]1[C:3]([C:8]2([O:18][CH3:21])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of the product of Example 1A (2.16 g, 8.00 mmol) in tetrahydrofuran (70 mL) was added 60% sodium hydride (0.96 g, 24.0 mmol) in portions, followed by addition of methyl iodide (1.6 mL, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 5 hours, quenched with saturated ammonium chloride (300 mL), extracted with ethyl acetate (300 mL), washed with water (300 mL), brine, dried with anhydrous sodium sulfate, filtered, and concentrated to a yellow oil. The residue was chromatographed on silica gel, eluting with 0-to-30% ethyl acetate in hexanes to provide 2.147 g (94% yield) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (d, J=12.55 Hz, 2H), 1.80 (td, J=12.88, 3.73 Hz, 2H), 2.04 (td, J=13.57, 3.73 Hz, 2H), 2.23-2.32 (m, 2H), 2.92 (s, 3H), 3.87 (s, 4H), 7.37 (dd, J=7.97, 4.58 Hz, 1H), 7.88 (dd, J=7.97, 1.53 Hz, 1H), 8.51 (dd, J=4.58, 1.53 Hz, 1H). MS (DCI) m/z 284.13 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)[CH:38]=[CH:37][C:36]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O[CH:58]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[CH3:74])[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>O1CCCC1>[C:49]([C:36]1[CH:37]=[CH:38][C:39]([O:41][CH2:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[CH:40][C:35]=1[O:34][CH:58]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[CH3:74])[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])(=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(c1ccccc1)c1ccc(OCc2cccnc2)cc1O
Reactant: Cc1ccccc1C(O)CCC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl azodicarboxylate (6.45 mL) is added dropwise to a stirred, cooled (0° C.) solution of triphenylphosphine (8.6 g) in dry tetrahydrofuran (60 mL). After a further 30 minutes, a solution of 2′-hydroxy-4′-(pyridin-3-ylmethoxy)benzophenone (5 g) and tert-butyl 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (S)-enantiomer, (5.13 g) in dry tetrahydrofuran (60 mL) is added dropwise over 25 minutes and stirring continued for a further 3 hours at °C. The reaction is allowed to warm to ambient temperature overnight before being concentrated under vacuo. The resultant oil is purified by flash chromatography on silica eluting with a mixture of dichloromethane and ethyl acetate (9:1 v/v). Fractions homogeneous in the required product are combined and concentrated under reduced pressure to give t-butyl 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, as a colourless oil (8.66 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:7][CH:8]=1)(=[O:25])=[O:24]
Reactant: CC(C)CC(=O)c1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Dissolve 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (210 mg, 1.086 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.167 mL, 1.195 mmol) and methanesulfonyl chloride (0.093 mL, 1.195 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound (256 mg, 87%). GC-MS m/z: 271
Reaction SMILES: N[C@H](C(O)=O)CCSC.COC1C=C(OC)C=CC=1C[N:15]1[CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH2:18][C@@H:17]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:39]>FC(F)(F)C(O)=O.ClCCl>[O:39]=[C:16]1[C@H:17]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:18][CH:19]=[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][NH:15]1
Reactant: COc1ccc(CN2CC(c3ccccc3)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Agent: CSCC[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CC=C(c2ccccc2)CNC1=O)OCc1ccccc1
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of L-methionine (2.56 g, 17.2 mmol) in trifluoroacetic acid (15 mL) was added to a solution of benzyl (3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (0.84 g, 1.72 mmol) in dichloromethane (20 mL). After 18 h, the mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, washed with water (2×), saturated aqueous sodium bicarbonate (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (0.44 g). MS 337 (M+1).
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].BrC[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:3]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]([O:15][CH3:16])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(OC)cccc1SC(=O)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)cccc1SCc1ccccc1

Procedure:
A solution of S-2-carbomethoxy-3-methoxyphenyl dimethylthiocarbamate (1.2 g, 4.5 mmol) and sodium methoxide (0.24 g, 4.5 mmol) in methanol (10 ml) was stirred at reflux temperature under a nitrogen atmosphere for 4 hours. α-Bromotoluene (0.60 ml, 4.9 mmol) was then added, and heating was maintained for an additional hour. The cooled mixture was evaporated, and the residue partitioned between diethyl ether and water. The organic layer was separated and washed with 1% aqueous sodium hydroxide solution, water, saturated aqueous sodium chloride solution, dried (sodium sulfate), and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734), eluting successively with 10:1 and 5:1 hexane-ether. Evaporation of the appropriate fractions gave methyl 2-benzylthio-6-methoxybenzoate as a colorless syrup; yield (0.70 g, 54%); NMR (CDCl3, 60 MHz): δ4.06 (s, SCH2Ph) p.p.m.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C.CCOC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: ClCCCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCCCCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL) was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and warmed up to room temperature. To the reaction mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×10 mL), brine (10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane:EtOAc (97.5:2.5) to give the desired product (0.900 g, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H) 1.54-1.17 (m, 4H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1ccc(F)cc1)c1ccccc1-c1ccccc1
Yield: 84.6 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with 5.6 g of p-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g (84.6% of theory) of ethyl 4-[p-fluoro-N-(biphenyl-2-yl)-benzamido]butyrate, MP 83° to 84°.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.C[Si](C)(C)[O:32][C:33]1([C:39]([O:41]C)=[O:40])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1>CO>[OH:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][CH2:36][N:35]([CH2:3][CH:2]([OH:1])[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[CH2:34]1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: COC(=O)C1(O[Si](C)(C)C)CCCNC1
Solvent: CO
Product: O=C(O)C1(O)CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in MeOH (3 mL) was added methyl 3-(trimethylsilyloxy)piperidine-3-carboxylate (100 mg, 0.432 mmol). The reaction mixture was heated at 80° C. for 2 days. The reaction mixture was concentrated in vacuo. The residue was treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 14 mg of 3-hydroxy-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.69 (4H, t, J=7.91 Hz), 7.54-7.65 (3H, m), 5.21-5.32 (1H, m), 3.69-4.01 (1H, m), 3.51 (2H, d, J=12.30 Hz), 3.33-3.43 (1H, m), 3.07-3.27 (2H, m), 2.32 (1H, br. s.), 1.78-2.08 (3H, m). MS (m+1)=545. HPLC Peak RT=3.24 minutes (Analytical Method A). Purity=95%.