Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[C:30](=[O:36])[CH2:29]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:25][C:26]4[CH:27]=[C:28]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH2:29]5)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1C(=O)Cc2cc(N)ccc21
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1C(=O)Cc2cc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)ccc21

Procedure:
N-Methyl-N-(3-{[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 5-amino-1-methyl-1,3-dihydro-indol-2-one (37.0 mg, 0.228 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a green-brown foam (0.017 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.81 (d, J=6.6 Hz, 1H), 7.65 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30-7.25 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.66 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 6.31 (d, J=7.8 Hz, 1H), 5.31 (t, J=6.2 Hz, 1H), 4.76 (d, J=6.2 Hz, 2H), 3.57 (s, 2H), 3.32 (s, 3H), 3.21 (s, 3H), 3.09 (s, 3H). MS=493 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[NH2:16]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[C:3]3[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Cn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of diisopropyl ether and chloroform, collected by filtration and dried under reduced pressure to give the title compound (121 mg) as a pale-purple powder crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:44](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:44][C:39]1[CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:36]=[C:37]([CH3:41])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCOCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M286) (377 mg, 0.615 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (211 mg, 69%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: CC(=O)c1csc2ccc(C#N)cc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc2scc(C(=O)CBr)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of phenyltrimethylammonium tribromide (2.8 g) in tetrahydrofuran (5 ml) was added dropwise under nitrogen over 30 minutes to a stirred solution of 3-acetylbenzo[b]thiophen-5-carbonitrile (1.5 g) in tetrahydrofuran (50 ml), then the mixture was stirred at ambient temperature for 2 hours. The resulting solid was collected by filtration and triturated with a hot mixture of ethanol (21 ml) and acetic acid (14 ml). The product was collected by filtration and dried in vacuo to give 3-(bromoacetyl)benzo[b]thiophen-5-carbonitrile as a white solid (1.05 g).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:26](C#N)#[N:27].N1C=CC=CC=1.CN1CCCC1=O>Cl>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][C:19]=3[F:25])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(Br)cc3F)cc2)CC1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H](CCc2ccc(-c3ccc(C#N)cc3F)cc2)CC1

Procedure:
A mixture of 38.4 g of 1-(trans-4-n-propylcyclohexyl)-2-(4'-bromo-2'-fluorobiphenyl-4-yl)-ethane (M.p. 61.1°, C.p. 114.7°), 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid is added and the mixture is warmed at 70° for 1.5 hours, with stirring, and worked up in the customary manner to give 1-(trans-4-n-propylcyclohexyl)-2-(4'-cyano-2'-fluorobiphenyl-4-yl)-ethane, M.p. 89.4°, C.p. 168.4°.
Reaction SMILES: [CH2:1]([C:8]1([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][C:12](=[CH:14]O)[C:11](=[O:16])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24]O>C(O)C.O>[CH2:1]([C:8]1([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][C:12]2[CH:14]=[N:24][O:16][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)C(=CO)C1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)C=Cc2oncc2C1
Temperature: 120 °C
Yield: 22.4 %

Procedure:
Under a nitrogen atmosphere a solution of 4-benzyl-6-hydroxymethylene-4-((trimethylsilyl)ethynyl)cyclohex-2-enone (76 mg, 0.245 mmol) in ethanol (6.13 mL) was added to a stirred solution of hydroxylamine hydrochloride (177.6 mg, 2.53 mmol, 10.3 eq) in water (256 μL) at room temperature. The mixture was heated to 120° C. and stirred at reflux for 1 hour. After heating, the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with dichloromethane/ethyl ether (1:2, 3×10 mL). The organic layers were then combined and washed with saturated aqueous sodium bicarbonate solution (1×10 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow-brown oil (76.4 mg). The crude was purified first by dissolving the product in petroleum ether/ethyl ether (5:1) and decanting the soluble portion from the insoluble solid. The insoluble material was washed with petroleum ether/ethyl ether (5:1) several times and the resulting mother liquor was found by thin layer chromatography (TLC) to contain the desired compound. The mother liquor was purified by flash column chromatography [petroleum ether-ethyl ether (5:1)] to give 32 (17.1 mg, 0.055 mmol, 22%) as a colorless oil: 1H NMR (CDCl3) δ 8.09 (1H, s), 7.32-7.22 (5H, m), 6.56 (1H, dd, J=1, 10 Hz), 6.0 (1H, d, J=10 Hz), 2.96 (1H, d? J=16 Hz), 2.94 (1H, d, J=13 Hz), 2.83 (1H, d, J=16 Hz), 2.73 (1H, d, J=13 Hz), 0.16 (9H, s); 13C NMR (CDCl3) δ 164.4, 148.7, 139.3, 135.0, 131.0, 128.0, 127.1, 114.4, 109.1, 88.4, 44.2, 39.2, 30.3, 0.13. MS (ESI+) m/z 308.1 [M+H]+, HRMS (ESI+) calcd for C19H21NOSi+H 308.1471. found 308.1467.
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.[NH2:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28]O>>[NH2:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 30 °C

Procedure:
Seed culture (4 ml) of each of Corynebacterium glutamicum ATCC 21854 and Corynebacterium glutamicum SA95 was inoculated into 40 ml of SSM medium containing 100 μg/ml of each of phenylalanine, tyrosine, and serine, and cultured with shaking at 30° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([OH:24])=[N:26][CH:27]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)[C@@H](C)c2ccccn2)c(C)c1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=O)c2ccc(O)nc2)[C@@H](C)c2ccccn2)c(C)c1
Yield: 29.7 %

Procedure:
Using General Procedure G: To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine (0.11 g, 0.35 mmol) in dry DMF (7 mL) was added 6-hydroxy-nicotinic acid (79 mg, 0.57 mmol) followed by EDCI (115 mg, 0.59 mmol), HOBT (86 mg, 0.63 mmol), and DIPEA (0.20 mL, 1.15 mmol). Purification of the crude material by radial chromatography on silica gel (1 mm plate, 10:1:1 CH2Cl2-MeOH—NH4OH) provided 45 mg (29%) of the free base of the title compound as a colorless oil. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 147 (49 mg, 62%) as a white solid. 1H NMR (D2O) δ 1.19-1.57 (m, 4H), 1.58 (d, 3H, J=6.9 Hz), 2.35 (s, 3H), 2.39 (s, 3H), 2.51-2.71 (m, 2H), 3.20 (t, 2H, J=6.3 Hz), 4.22 (s, 2H), 4.55 (q, 1H, J=6.9 Hz), 6.64 (d, 1H, J=9.6 Hz), 7.82 (dd, 1H, J=2.7, 9.6 Hz), 7.94-7.99 (m, 2H), 8.05-8.12 (m, 2H), 8.35 (s, 1H), 8.55 (dt, 1H, J=1.5, 8.1 Hz), 8.75 (dd, 1H, J=1.2, 5.7 Hz); 13C NMR (D2O) δ 14.53, 16.73, 17.45, 24.48, 26.53, 39.24, 51.26, 53.06, 60.39, 115.68, 119.28, 126.70, 135.93, 137.14, 137.29, 137.42, 140.95, 141.95, 148.01, 148.77, 149.56, 156.29, 165.39, 166.54; ES-MS m/z 434 (M+H). Anal. Calcd. For C25H31N5O2.3.5HBr.3.0H2O: C, 38.96; H, 5.30; N, 9.09; Br, 36.28. Found: C, 38.99; H, 5.29; N, 8.95; Br, 36.24.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O>C1COCC1>[C:26]1([CH2:25][C@H:16]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of dimethyl methylphosphonate (3.10 mL, 28.60 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.70 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 6 (1.00 g, 3.58 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded the compound dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]-phosphonate 7 as a clear oil (0.797 g, 59%), which crystallizes in hexane as a white solid; mp 78-81° C. (lit.1 mp 76-78° C.); Rf 0.38 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 1.38 (9H, s, (CH3)3), 2.84-3.32 (4H, m), 3.74 and 3.78 (6H, 2xs, 2xOMe), 4.55 (1H, q, J=8.4 Hz, —CH—), 5.28 (1H, d, J=8.4 Hz, —NH—), and 7.16-7.32 (5H, m, Ar—H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C@:11]([CH3:18])([CH2:16][CH3:17])[C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1O)[O:28][C:27]([CH3:34])([CH3:33])[CH2:26][CH2:25]2>>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C@:11]([CH3:18])([CH2:16][CH3:17])[C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[O:28][C:27]([CH3:34])([CH3:33])[CH2:26][CH2:25]2
Reactant: CC[C@@](C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Reactant: CC1(C)CCc2cc(Cl)c(O)cc2O1
Product: CC[C@@](C)(Oc1ccc(OCCCOc2cc3c(cc2Cl)CCC(C)(C)O3)cc1)C(=O)O

Procedure:
The title compound was prepared following the procedure described in Example 1, Steps F-G employing (2R)-methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate and 6-Chloro-2,2-dimethylchroman-7-ol.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[NH:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:28]([C:37](O)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C@@H:28]([NH:27][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:37](=[O:38])[N:13]2[CH2:12][CH2:11][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([F:2])([F:16])[F:17])[CH2:15][CH2:14]2)=[CH:31][CH:32]=1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 69.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) from 4-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Step c) (0.792 g, 3.0 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (5 mL). Purification by silica gel chromatography (5:2 hexane:EtOAc) provided the title compound as a white foam (1.06 g). MS (ESI, pos. ion) m/z: 511 (M+1); MS (ESI, neg. ion) m/z: 509 (M−1). Calc'd for C26H30ClF3N2O3: 510.98.
Reaction SMILES: CC([O:4][C@:5]12[C@@H:33]3[CH:34]4[N:35]([CH3:37])[CH2:36][C@@:30]5([CH2:40][O:41][CH3:42])[C@@H:31]([C@H:32]3[O:38][CH3:39])[C@@:26]4([C@@H:27]([O:44][CH3:45])[CH2:28][C@H:29]5[OH:43])[C@@H:7]3[CH2:8][C@:9]([OH:25])([C@@H:20]([O:23][CH3:24])[C@@H:21]1[OH:22])[C@H:10]([O:11]C(C1C=CC=CC=1)=O)[C@H:6]23)=O.[H-].[K+]>CO>[CH3:37][N:35]1[C@H:34]2[C@:26]34[C@@H:7]5[CH2:8][C@:9]6([OH:25])[C@@H:20]([O:23][CH3:24])[C@H:21]([OH:22])[C@@:5]([OH:4])([C@H:6]5[C@H:10]6[OH:11])[C@H:33]2[C@H:32]([O:38][CH3:39])[C@@H:31]3[C@@:30]([CH2:40][O:41][CH3:42])([C@H:29]([OH:43])[CH2:28][C@@H:27]4[O:44][CH3:45])[CH2:36]1
Reactant: COC[C@]12CN(C)C3[C@@H]4[C@H](OC)[C@H]1[C@@]3([C@@H](OC)C[C@H]2O)[C@@H]1C[C@@]2(O)[C@H](OC(=O)c3ccccc3)[C@@H]1[C@]4(OC(C)=O)[C@@H](O)[C@@H]2OC
Agent: [H-]
Agent: [K+]
Solvent: CO
Product: COC[C@]12CN(C)[C@@H]3[C@@H]4[C@H](OC)[C@H]1[C@@]3([C@@H](OC)C[C@H]2O)[C@@H]1C[C@@]2(O)[C@H](O)[C@@H]1[C@]4(O)[C@@H](O)[C@@H]2OC
Yield: 55.8 %

Procedure:
Mesaconitine 70 mg was dissolved in 5 ml of methanol. To this solution, 1 ml of 5% potassium hydride was added, and the mixture was heated under reflux for 3 hours. After methanol in the reaction mixture was distilled off, 5 ml of water was added to the residue and the mixture was extracted three times with 10 ml. of methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to thin-layer chromatography for separation and purification (eluting solvent: 10% methanol/ammonia-saturated chloroform) to give mesaconine (30 mg). 14-O-p-Chlorobenzoylmesaconine 20 mg was obtained in the same manner as in Example 90, except for the use of 30 mg of mesaconine and 30 mg of p-chlorobenzoyl chloride as each substitute for 30 mg of aconine and 30 mg of m-chlorobenzoyl chloride in Example 90.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.O=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: O=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](C(=O)O)c1ccc(F)cc1

Procedure:
1.0 g (5.15 mmol) of 2-(p-fluorophenyl)-3-methylcrotonic acid and 0.52 g (5.15 mmol) of triethylamine were suspended in 6 ml of methanol in a glove box (O2 content <1 ppm) in a 30 ml autoclave at RT and a solution of 4.1 mg (0.0051 mmol) of Ru(OAc)2 ((R)-MeOPIPHEP) in 5 ml of methanol was added as the catalyst. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under an initial pressure of 200 bar. The pressure decreased to about 190 bar during the reaction. After a reaction period of 21 hours a sample of the hydrogenation solution was evaporated at 50°/20 mbar and analyzed. There was obtained (S)-2-(p-fluorophenyl)-3-methylbutanoic acid with an ee of 93%.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: COC(=O)c1ccc(Cn2c(-c3ccc(C=O)cc3)nc3cc(Cl)c(Cl)cc32)cc1

Procedure:
Methyl 4-[5,6-dichloro2-(4-formylphenyl)benzimidazol-1-ylmethyl]benzoate was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and methyl 4-bromomethylbenzoate by following General Procedure 3.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]([CH2:27][C@H:28]([O:32][CH:33]([CH3:35])[CH3:34])[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][O:16][C:17]([NH:19][CH2:20][C:21]2[CH:22]=[C:23]([CH2:27][C@H:28]([O:32][CH:33]([CH3:35])[CH3:34])[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)O[C@@H](Cc1cccc(CNC(=O)OCc2ccc(NC(=O)OC(C)(C)C)nc2)c1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)O[C@@H](Cc1cccc(CNC(=O)OCc2ccc(N)nc2)c1)C(=O)O

Procedure:
3-{3-[(6-t-Butoxycarbonylaminopyridin-3-ylmethoxycarbonylamino)methyl]phenyl}-2(S)-isopropoxypropanoic acid was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][C:21]=1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
5-Bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5 g, 1.23 mol, 1 eq) was dissolved in anhydrous THF (3 L) and cooled to 78° C. To this solution was added a solution of LDA (2M in heptane/THF/ethyl benzene, 2.25 L, 4.5 mol, 3.65 eq) maintaining the temperature below 70° C. After the addition was complete, the solution was stirred for additional 30 min at 78° C. The acetone-dry ice bath was removed and the reaction was quenched with a saturated aqueous solution of NH4Cl (1 L), maintaining the temperature below 10° C. Another batch of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5 g) was processed using the same protocol. The crude reaction mixtures from both reactions were combined and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×5 L). The combined organic layers were dried and passed through a pad of silica gel. The filtrate was evaporated, and the residue was triturated with DCM to give 70 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. The mother liquor was evaporated and the solid thus obtained was purified by recrystallization using DCM/hexanes to give 180 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.
Reaction SMILES: [C:1]([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][Mg]Cl.O>O1CCCC1>[CH3:2][C:1]([CH3:16])([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)[OH:3]
Reactant: CC(=O)C1=CCCCCCCCCCC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C1=CCCCCCCCCCC1
Yield: 96 %

Procedure:
52 g (0.25 mole) of 1-acetyl-1-cyclododecene, prepared as described in Example 2, are added over 30 minutes to 200 ml of a 1.5-molar solution of methyl-magnesium chloride in tetrahydrofuran at from 0° to +10° C. After completion of the addition, the reaction mixture is hydrolyzed with 20 ml of water and the tetrahydrofuran solution is filtered to remove the salt which has precipitated. After destilling off the tetrahydrofuran under reduced pressure (50° C./20 mbars) the product which remains is fractionated. 52 g of dimethyl-cyclododecenyl-carbinol (96% yield) of boiling point=108°-112° C./0.01 mm Hg and refractive index nD25 =1.5000 are obtained.