Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:50]([F:53])([F:52])[F:51])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([NH:16][CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH2:13]3)[NH:7][C:6]=2[CH:49]=1.[C:54]([BH3-])#N.[Na+].C(O)(=O)C.C=O>CO>[Cl:1][C:2]1[C:3]([C:50]([F:51])([F:52])[F:53])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:13][CH:14]([N:16]([CH2:17][C@@H:18]4[C@H:22]5[O:23][C:24]([CH3:26])([CH3:27])[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH2:38][C:39]7[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=7[O:47][CH3:48])[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:54])[CH2:15]3)[NH:7][C:6]=2[CH:49]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.10 mmol) in methanol (2.5 mL) was treated with sodium cyanoborohydride (84 mg, 1.3 mmol). The pH of the solution was adjusted to ˜6 by the dropwise addition of a 10% (v/v) solution of glacial acetic acid in methanol. The mixture was treated with 37% aqueous formaldehyde (0.12 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature till complete by LCMS. After 2 h, the reaction was complete and the reaction mixture was concentrated to remove the methanol. The aqueous solution that remained was diluted with 7 mL NaHCO3 and the aqueous phase was extracted with three 10 mL portions of CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated to yield a colorless stiff foam/glass. The crude material was purified by flash chromatography (20 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (62 mg, 80%) as a colorless glass: MS (ESI+) for C39H45ClF3N7O4 m/z 768.0 (M+H)+; MS (ESI−) for C39H45ClF3N7O4 m/z 766.3 (M−H)−; HPLC purity 92.1% (ret. time, 3.29 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH:62]2[CH:57]([CH2:58][CH2:59][CH2:60][CH2:61]2)[CH2:56][CH2:55][CH2:54]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:53]3[C@@H:62]4[C@@H:57]([CH2:58][CH2:59][CH2:60][CH2:61]4)[CH2:56][CH2:55][CH2:54]3)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Reactant: C1CCC2NCCCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), HATU (0.35 mmol) and decahydroquinoline (3:2 mixture of cis/trans-isomers; 2.5 mmol) were added and the reaction stirred at room temperature for 3 hours. The solvent was evaporated and the residue product was purified by flash chromatography on silica, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.85 (s, 1H), 4.7 (m, 1H), 4.2 (m, 2H), 3.7 (m, 1H), 3.1-2.7 (m, 4H), 2.0-1.4 (m, 26H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]2([CH2:40][OH:41])[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[OH:41][CH2:40][C:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:23])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2(CO)CCCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-(1-hydroxymethyl-cyclopentyl)-benzenesulfonamide (example B.13) according to general procedure II. Yellow solid. MS (ISP) 594.0 [(M+H)+]; mp 253-255° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCN(CC)CCCN
Product: CCOC(=O)C(=O)NCCCN(CC)CC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
13.0 g of N,N-diethyl-1,3-diaminopropane were added to 70 ml of diethyl oxalate with stirring at room temperature over a period of 20 minutes. After stirring at room temperature for 2 hours, excess diethyl oxalate was distilled off under reduced pressure to obtain 21.7 g of N,N-diethyl-N'-ethoxalyl-1,3-diaminopropane as an oily product. 6.90 g of this oily product and 3.99 g of 3-(2-methoxyethoxy)propylamine were dissolved in 30 ml of methanol and the solution was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain 9.51 g of Compound B-1 as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([CH3:25])([OH:24])[CH3:23]>CN(C=O)C>[OH:24][C:22]([CH3:25])([CH3:23])[CH2:21][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[Br:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(C)(C)O)c1
Temperature: 80 °C
Yield: 25.8 %

Procedure:
Ethyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.12 mmol), potassium carbonate (5.07 g, 36.72 mmol) and 1-chloro-2-methylpropan-2-ol (0.75 mL, 7.34 mmol) were placed in 50 mL DMF and the reaction was heated at 80° C. for 18 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under vacuum to an oil. Purification by column chromatography on silica gel using EtOAc/hexane (0-50%) gave the product (0.5 g, 26%) as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:21])[CH2:7][NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:10]([O:12][CH3:13])=[O:11].[CH2:22]=O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:21][CH2:22][N:8]([CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:7]=1
Reactant: C=O
Reactant: COC(=O)C(NCC(O)c1cccs1)c1ccccc1Cl
Solvent: CCO
Product: COC(=O)C(c1ccccc1Cl)N1C=C(c2cccs2)OC1
Temperature: 40 °C
Yield: 90.1 %

Procedure:
Methyl N-(2-(2-thienyl)-2-hydoxyethyl)-2-o-chlorophenylglycinate (21) (2.5 g, 7.6 mmol) was dissolved in ethanol and treated with 37% formaline (1.85 g, 22.8 mmol), then heated at 40° C. over the night under nitrogen. The ethanol is evaporated under vacuum and the residual water was removed by azeotropic distillation with toluene to provide 2.3 g of desired product as a mixture of diastereoisomers. 1H-NMR (CDCl3, ppm) 7.72 (1H, m), 7.43 (1H, m), 7.2-7.3 (2H, m), 7.15 (1H, m), 6.95 (2H, m), 5.35 (1H, q), 5.15 and 5.05 (2H, 2s), 4.55 (2H, q), 4.40 (2H, q), 3.75 and 3.70 (3H, 2s), 3.3-3.5 (1H, m), 2.9-3.1 (1H, m).
Reaction SMILES: [F-].[K+].FC([P:10](=[O:25])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(F)C(F)(F)F.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[P:10]([O:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:18]([C:19]([F:22])([F:21])[F:20])([F:23])[F:24])([C:11]([C:12]([F:13])([F:15])[F:14])([F:17])[F:16])=[O:25]
Reactant: Oc1ccccc1
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Product: O=P(Oc1ccccc1)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Potassium fluoride (0.122 g; 2.1 mmol) is suspended in cooled (0° C.) tris(pentafluoroethyl)phosphine oxide (7.378 g; 18.3 mmol) in a 100 ml glass flask, and phenol (1.797 g; 19.1 mmol) is added. The reaction suspension is warmed and stirred at 80° C. for 4.5 h. A pale-brown reaction suspension is then observed. After recondensation in vacuo (10−3 mbar) at 40° C., phenyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OC6H5, is isolated as clear and colourless liquid (3.127 g; 8.3 mmol) in a yield of 45% and a purity of 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:30]1C2C(=CC=CC=2)CCC1O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:30][CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: OC1CCc2ccccc2C1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2CC[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting cis-(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.18-1.31, 2.09, 2.54, 2.64, 2.95, 2.99, 4.33, 4.69, 5.43, 7.22-7.35, 7.51; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1454.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:24][C:12]([F:11])([F:23])[C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (0.208 g, 1.463 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.358 g, 1.463 mmol) in dichloromethane (3 mL) was added triethylamine (303 mg, 3 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/CH3OH=10:1) to give the title compound (0.4 g, 78% yield). MS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:25])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (5.0 g, 10.8 mmol) in tetrahydrofuran/methanol (50 mL, 1:1) containing 3 Å molecular sieves at 0° C. was added tetra n-butylammonium fluoride (22 mL, 22 mmol, 1 M in tetrahydrofuran). After stirring at room temperature for 24 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was partitioned between diethyl ether and saturated sodium hydrogen carbonate solution. The aqueous layer was extracted with diethyl ether. The organic extracts were combined and the solution was filtered through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with iso-hexanes/ethyl acetate 20:1 to 3:2 to afford (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 82%) as a colorless oil and as a mixture of rotamers. LCMS (m/z) 345.1 [M+H], Tr=2.78 min. A solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 8.72 mmol) in tetrahydrofuran (20 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (13 mL, 13.0 mmol, 1 M in tetrahydrofuran). After stirring at −78° C. for 1 h, the mixture was treated with iodomethane (1.4 mL, 22.5 mmol). The reaction mixture was stirred at −78° C. for 1 h, then at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with water. The aqueous phase was extracted with dichloromethane (2×) and the organic solution was passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 4:1 to 0:1 to afford the title compound (1.62 g, 52%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.41-1.52 (m, 18H), 1.53-1.67 (m, 4H), 1.71-1.99 (m, 3H), 3.17-3.51 (m, 1H), 3.70-3.81 (m, 3H), 3.90-4.21 (m, 1H). LCMS (m/z) 359.0 [M+H], Tr=2.90 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH:25]([C:32](=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[NH4+:44].C(O)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:44]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Yield: 82.8 %

Procedure:
A mixture of methyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.34 g), ammonium acetate (685 mg) and acetic acid (5 ml) was refluxed for 3 hrs. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionate (1.07 g, yield 83%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:5, volume ratio).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Prepared analogously to example 303a from 3,4-dinitro-benzoyl chloride and 2-amino-4-trifluoromethyl-pyridine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]([CH3:14])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccc(C(=O)NN)cc1I
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccc(C)c(I)c2)o1
Temperature: 150 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A stirred mixture of 3-iodo-4-methylbenzohydrazide (preparation 55b, 5.00 g, 18.1 mmol) and triethyl orthoacetate (11.00 mL, 58.2 mmol) in acetic acid (30 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled and concentrated in vacuo. Aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with dichloromethane. The organic solution was dried (MgSO4) and the solvent was removed in vacuo. The crude material was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (4.26 g, 78%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[N:16][OH:15]
Reactant: [NH3+]O
Reactant: Cc1ccc(C(=O)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
49.5 g (0.263 mol) of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone are dissolved in 250 ml of ethanol at 80° C. To the solution are added dropwise 19.2 g (0.276 mol) of hydroxylammonium chloride and 36.7 g (0.447 mol) of sodium acetate dissolved in 125 ml of water. The reaction mixture is refluxed for 3.5 hours. The mixture is poured into ice water, affording a white solid. The filtration yields 39.2 g of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone oxime as a white solid, mp. 54-68° C. The crude product is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC1(c2cccnc2)CCCC1
Product: Cc1cccc(C(=O)NCC2(c3cccnc3)CCCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=309.1, tR (minutes, Method A)=1.11
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:13](OC(=O)C)(=[O:15])[CH3:14]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(F)(F)F)c(F)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a mixture of 3-fluoro-4-trifluoromethyl-phenylamine (16.9 g, 92.6 mmol), N,N-dimethyl-4-aminopyridine (1.13 g, 9.26 mmol), and toluene (230 mL) was added acetic anhydride (13.1 mL, 0.139 mol). The reaction mixture was heated at reflux for 3 h, and stirred at 23° C. for 16 h. The reaction mixture was concentrated and the crude product was dissolved in EtOAc (100 mL). The organic layer was washed with water (40 mL) and brine (40 mL), dried, filtered, and concentrated under reduced pressure. The crude solid was triturated from DCM/hexanes to yield the titled compound (16.5 g, 81% yield). MS (ESI/CI): mass calcd. for C9H7F4NO, 221.1; m/z found, 222.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.68 (d, J=12.5 Hz, 1H), 7.52 (t, J=8.3 Hz, 1H), 7.45 (br s, 1H), 7.19 (d, J=8.5 Hz, 1H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:22]([C@@H:24]1[CH2:26][C@H:25]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:41]1([CH2:45]Br)[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:45][CH:41]2[CH2:44][CH2:43][CH2:42]2)=[CH:19][CH:20]=1)[C:22]([C@@H:24]1[CH2:26][C@H:25]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)=[O:23])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: BrCC1CCC1
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(OCC2CCC2)cc1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 89.3 %

Procedure:
A mixture of ((1S,2S)-1-{[[(1R,2R)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4-hydroxy-phenyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (51 mg, 0.11 mmol), K2CO3 (69 mg, 0.5 mmol) and cyclobutylmethyl bromide (22 mg, 0.15 mmol) in DMF was stirred at 55° C. for over night. After cool to rt, the mixture was filtered through a silica pad (EtOAc). The filtrate was concentrated and the residue was subjected to ISCO (12 g column, 0-40% EtOAc in hexane over 25 min) to give the titled compound (53 mg). MS (MH+ 540).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(S)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.74 g) in dry acetonitrile (10 ml) was added to a solution of 4-fluorothiophenol (5.00 g) in acetonitrile (40 ml). The mixture was cooled to 5° C. by immersion in an ice-water bath and pyridine (3.15 ml) added dropwise to the stirred solution. The mixture was stirred at 5° C. for 1 hour, allowed to reach room temperature and stirred for a further 2 hours, and then the solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water, dilute hydrochloric acid, and water again. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester as a pale yellow solid (10.81 g).