Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:4]2[C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]2
Reactant: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCOCC2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=c1ccc2c(OCCN3CCOCC3)ccc(Cl)c2[nH]1
Temperature: 125 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
N-(2-chloro-5-(2-morpholinoethoxy)phenyl)cinnamamide (800 mg, 2.1 mmol, 1 eq.) was placed in chlorobenzene (1.9 mL), in the presence of aluminium trichloride (1.6 g, 12.4 mmol, 6 eq.). The reaction mixture was heated at 125° C. and stirred for 2 hours. After cooling down to room temperature, it was diluted with a water and ice mixture and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-5-(2-morpholinoethoxy)quinolin-2(1H)-one (220 mg, 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:6]1[CH:7]=[CH:2][CH:3]=[C:4]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)[CH:5]=1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (272 mg, 1.0 mmol) in toluene (10.0 mL) was added 3-pyridinyltributyltin (442 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (127 mg, 48%). MS (CI/NH3) m/z 270 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.70-1.93 (m, 3H), 2.00-2.12 (m, 1H), 2.28-2.39 (m, 1H), 2.52 (s, 3H), 2.67-2.76 (m, 1H, 3.11-3.18 (m, 1H), 3.98-4.13 (m, 2H), 7.38-7.44 (m, 2H), 7.86-7.92 (m, 1HO, 8.37 (d, J=3.0 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.67 (dd, J=6.0 Hz, J=1.8 Hz, 1H), 8.84 (d, J=2.1 Hz, 1H).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CO)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccccc2)cc1

Procedure:
(-)-2-Phenoxypropanol [α]D25 = -38.95° (c. 0.9, CHCl3) was treated with tosylchloride in pyridine to give the corresponding (-)-2-phenoxypropyl tosylate of which 1.10 g. was reacted with LiPPh2 following Example 28 to give 0.87 g. of (+)-2-phenoxypropyl diphenylphosphine having [α]D25 = +27.90° (c. 3.03, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:13].[Br:14]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[Br:14][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:12])[C:3]=2[O:2][CH3:1])[C:7]1=[O:13]
Reactant: BrBr
Reactant: COc1c(C)ccc2c1CCC2=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(C)ccc2c1CC(Br)C2=O
Temperature: 22.5 °C
Yield: 44.2 %

Procedure:
To a stirred solution of 4-Methoxy-5-methyl-indan-1-one (5.0 gm, 0.0284 mole) in Acetic acid (65 ml) and Hydrobromic acid (1 ml), a solution of Bromine (1.47 ml, 0.0284 mole) in 5 ml Acetic acid was added at 10-20° C. The reaction mixture was stirred at 20-25° C. for an hour. Then it was poured into saturated solution of Sodium bicarbonate and extracted with Diethyl ether (3×100 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give crude product which was purified over column chromatography using Ethyl acetate:Hexane (5:95) as a mobile phase. The collected fractions were distilled to give 3.2 gm of desired product as a viscous oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH3:13])[NH:9][C:8]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH3:13])[N:9]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:8]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1[nH]c(=O)n(-c2ccccc2)c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)n(-c2ccccc2)c(=O)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 38.2g (0.2 mole) 4-phenyl-1-methyl urazole in 200 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 20 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 25 ml water was then added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake washed with water. After drying and recrystallizing from benzene-cyclohexane (1:1, by volume) there was obtained 65g (91%) 4-phenyl-1-methyl-2-(trichloromethylthio) urazole having a melting point of 154° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH3:23])[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][S:28]([CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[CH:17]1([NH:16][C:14]2[N:13]([CH3:23])[C:12]3[CH:24]=[CH:25][C:9]([N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:35]5[CH:37]=[CH:38][C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=5)[N:7]=4)[CH3:26])=[CH:10][C:11]=3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-N2-cyclohexyl-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (92 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (31 mg, 24%). 1H NMR (300 MHz, D6-DMSO) δ 9.20 (s, 1H), 7.77-7.80 (M, 3H), 7.10 (s, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.70 (br s, 1H), 3.51 (s, 3H), 3.44 (s, 3H), 2.85 (s, 3H), 2.01 (br s, 2H), 1.74 (br s, 2H), 1.62 (d, J=11.1 Hz, 1H), 1.16-1.32 (m, 5H) ppm. MS (ESI) m/z=520 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.00 g, 7.69 mmol), benzyl alcohol (796 mL, 832 mg, 7.69 mmol) and 4-dimethylaminopyridine (9.4 mg, 77 μmol) in dichloromethane (5 mL) was added DCC (1.59 g, 7.71 mmol) and the mixture was stirred at ambient temperature for 3 h. The mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography using a 0-30% gradient of heptane/ethyl acetate gave benzyl 4-bromomethyl-3-nitrobenzoate as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])=[O:2].[C:23]([Mg]Br)(=O)[CH:24]([CH3:26])[CH3:25].Cl>O1CCCC1.C(Cl)Cl>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COc1c(C=O)ccc2c1C(=O)OCc1cc(C)ccc1S2
Reactant: CC(C)C(=O)[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)ccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (2.1 mmol) of the compound from Example I in 10 ml of absolute tetrahydrofuran are treated under argon at 0° C. with 1.2 ml (2.3 mmol) of a 2M isobutyryl-magnesium bromide solution in tetrahydrofuran and the mixture is stirred at 25° C. for 1 h. After addition of 2 ml of 1N hydrochloric acid, the mixture is diluted with methylene chloride, washed with water, dried and evaporated. After chromatographic purification on silica gel Si60 (petroleum ether/ethyl acetate 5:1), 121 mg (15% of theory) of the main product are obtained as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless oil.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]1([CH2:35][CH2:36][CH2:37]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:37][CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCc1ccccc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCCc2ccccc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m.p. 164° C. and MS: m/e=488.4 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-phenyl-1-propylbromide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: O=C(O)c1ccncc1
Product: O=C(NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1)c1ccncc1

Procedure:
The N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and isonicotinic acid as described above in EXAMPLE 1, Step 2.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[C:12]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([F:11])[CH:5]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1F
Reaction time: 48 h

Procedure:
Methyl iodide (182.1 mL, 1.319 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2-fluorophenol (210 g, 1.099 mol; see step (i) above) and K2CO3 (303.92 g, 2.19 mol) in dry acetone (1.7 L). Stirring was continued at 60° C. for two days under a nitrogen atmosphere before the reaction mixture was filtered and the solvent was concentrated under reduced pressure. This provided 4-bromo-2-fluoro-1-methoxybenzene (225 g) as a liquid, which was employed directly in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>CS(C)=O.O>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:15][CH2:16]1
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 80 °C
Reaction time: 3.75 h
Yield: 9.3 %

Procedure:
10% sodium hydroxide aqueous solution (6.70 g) was added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (2.07 g) obtained in Example 3(1) in dimethylsulfoxide (21 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.78 g) was added thereto. After being stirred for 3.75 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1 to 10:1), thereby yielding the entitled compound (0.39 g) as white solid.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:5][CH2:4]1)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:23]1([O:22][C:20]([N:3]2[CH2:8][CH2:7][CH:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[CH:10]=3)[CH2:5][CH2:4]2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1CCC(c2cccc(OC(C)C)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Temperature: 45 °C
Yield: 61.8 %

Procedure:
To N-ethyl-4-(3-(1-methylethoxy)phenyl)piperidine (Preparation 45, 2.0 g, 8.10 mmol) in toluene (20 ml) at 85° C. was added phenyl chloroformate (1.0 ml, 9.70 mmol) and the mixture was heated at reflux for 4 h. The solution was cooled to 45° C. and aqueous sodium hydroxide solution (1 ml of 50% aqueous sodium hydroxide solution in 8 ml of water) was added. The reaction mixture was cooled to room temperature and the organic layer was separated and washed with methanol: 1N aqueous hydrochloric acid (1:1, 2×20 ml), methanol: 1N aqueous sodium hydroxide solution (1:1, 25 ml) and water (20 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. This was purified by silica column chromatography eluting with ethyl acetate:hexane (1:5) to give the title compound as an oil (1.7 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(-c2cc3ccccc3o2)c2c1C(=O)NC2=O
Yield: 32.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 3-amino-6-bromophthalimide (80.0 mg, 0.332 mmol) was dissolved in acetonitrile (4.0 mL), and, the solution was treated with 2-benzofuraneboronic acid (161 mg, 0.996 mmol), palladium acetate (9.0 mg, 0.040 mmol), tri(o-tolyl)phosphine (24.3 mg, 0.080 mmol) and triethylamine (0.463 mL, 3.32 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=15/1) to obtain Compound 171 (30.1 mg, yield 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[F:23][C:24]1[CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH:26][N:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[CH2:5][C:6]2[CH:19]=[C:9]3[NH:10][C:11](=[O:18])[C:12]4[C:17]([N:8]3[N:7]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:27]=[CH:26][N:25]=1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(F)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Cc3cccc(-c4ccnc(F)c4)c3)nn2c2ccccc12

Procedure:
A mixture of Example 61B (0.1 g, 0.282 mmol), 2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol) triethylamine (0.11 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.039 g, 0.01 mmol) and tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL) was heated at 100° C. for 6 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and brine, then evaporated. The residue was purified by chromatography on silica gel with 20% to 80% ethylacetate in hexane to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 5.75 (s, 1 H) 7.44-7.53 (m, 4 H) 7.68-7.74 (m, 2 H) 7.83-7.88 (m, 2 H) 8.04 (d, J=8.24 Hz, 1 H) 8.11 (d, J=6.71 Hz, 1 H) 8.30 (d, J=5.49 Hz, 1 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)c3cccs3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, thiophene-2-carbonyl chloride (29 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 28% of theory).
Reaction SMILES: C(C1C=C(C(C)(C)C)C=CC=1O[C@H](C)C([N:19]1[C@H:23]([CH:24]=[CH2:25])[CH2:22][CH2:21][C:20]1=[O:26])=O)(C)(C)C.[OH-:28].[K+].Cl>O>[NH2:19][C@H:23]([CH:24]=[CH2:25])[CH2:22][CH2:21][C:20]([OH:26])=[O:28]
Reactant: [OH-]
Reactant: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: C=C[C@@H](N)CCC(=O)O
Temperature: 25 °C

Procedure:
A solution of (5S)-N-((2R)-2-(2,4-di-t-butylphenyloxy)-propanoyl)-5-ethenylpyrrolidin-2-one (19a, 1.0 g, 2.5 mmol) and 87% potassium hydroxide (317 mg, 5.7 mmol) in water (2 mL) is refluxed for 1.5 hours. The solution is allowed to cool to room temperature. Water is added (15 mL) and the solution is acidified to pH 7 with concentrated hydrochloric acid and extracted with diethyl ether (3×10 mL) to remove the chiral auxiliary. The aqueous solution is then acidified to pH 5.5 with concentrated hydrochloric acid and extracted with diethyl ether (3×15 mL). The second series of organic extracts are combined and dried (MgSO4). Concentration by rotary evaporation affords (4S)-4-amino-5-hexenoic acid (B).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.C=O.[C:37]([BH3-])#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH3:37])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: [BH3-]C#N
Reactant: Cn1nnnc1-c1cccc(NC(=O)NC[C@@H]2CCCC[C@H]2NCCCc2ccc(F)cc2)c1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CCCc1ccc(F)cc1)[C@@H]1CCCC[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea (98 mg), the product of Step g of Example 31, in 4 mL of CH2Cl2 was added a solution of formaldehyde in THF (excess), and the mixture was stirred for 15 minutes. Then excess amount of sodium cyanoborohydride was added, and the mixture was continued to stir for 5 hrs at room temperature. After quenching the reaction with saturated Na2CO3, it was extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated to give an oily residue. It was purified by column chromatography (silica gel, 0.6:5.494 cNH4OH/CH3OH/CH2Cl2) to give pure N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[N-methyl-3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea.