Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[O:32][C:31]1=O.COC(OC)OC.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:33](=[O:32])[C:34]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:30]=[CH:31]5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])O[La](O[N+](=O)[O-])O[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 95 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (330 mg, 0.845 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (345 mg, 2.113 mmol), trimethoxymethane (0.926 mL, 8.45 mmol), and tris(nitrooxy)lanthanum, 6H2O (110 mg, 0.254 mmol) in tetrahydrofuran (Volume: 2 mL) was heated at 95° C. in a sealed vial for 20 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), 1 N NaOH solution (30 mL), and brine (30 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was subjected to prep. reverse phase HPLC purification. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (188 mg, 0.362 mmol, 42.8% yield) as a yellow solid. The product is mixture of two atropisomers at rt. LCMS (M+H)+=520.29. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.9 Hz), 4.17 (m, 2H), 3.73 (m, 2H), 3.35 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([OH:10])[CH:12]=2)[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2cccc(O)c2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccc(O)c2)[nH]n1
Reaction time: 8 h
Yield: 51.7 %

Procedure:
DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.294 mmol) (prepared from 5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (99 mg, 0.294 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. Washing with ethyl acetate afforded 74 mg (51.7% Yield) of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 489, 96%. 1H NMR (300 MHz, DMSO-d6): δ13.6 (s, 1H), 9.6 (s, 1H), 8.0 (t, 1H), 7.5 (t, 1H), 7.1 (m, 7H), 6.9 (d, 1H), 6.8 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C(N(CC)[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])C>C1COCC1>[F:28][C:27]([F:30])([F:29])[C:26]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1)=[O:31]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CCN(CC)C(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
tert-Butyl 1-(4-bromophenyl)ethylcarbamate (6.35 g, 21.2 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. under an atmosphere of nitrogen. n-Butyllithium (21 ml, 52.9 mmol, 2.5M in hexanes) was added dropwise under 10 minutes and the reaction was stirred at −78° C. for 3 hours. A solution of diethyl trifluoroacetamide (5.0 g, 29.6 mmol) in 10 ml dry THF was added dropwise and the reaction was stirred 1.5 hours at −78° C. Reaction was quenched with NH4Cl (sat) (50 ml) and H2O (50 ml) and allowed to reach room temperature. The aqueous phase was separated and extracted with EtOAc (100 ml). The combined organics were washed with NH4Cl (sat) (2*100 ml), H2O (100 ml), dried over MgSO4, filtered and evaporated. Unreacted starting material was removed by precipitation from MeOH/H2O (9/1). The mother liquor was evaporated and the residue purified by flash chromatography using Pet. Ether/EtOAc (7:1→5:1) as eluent to give 3.09 g (46%) of the title compound as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[S:11].[I:20][CH3:21]>CO>[I-:20].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH+:9]=[C:10]([NH:12][C:13](=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[S:11][CH3:21]
Reactant: CCN(CC)C(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CI
Solvent: CO
Product: CCN(CC)C(=O)NC(=[NH+]c1c(Cl)cccc1Cl)SC
Product: [I-]

Procedure:
(0.1 mole) of 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl) thiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain 1-(2,6-dichlorophenyl)-3-(N,N-diethylcarbamyl)-2-methylthiouronium iodide.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][C:14](=O)[CH2:13][CH2:12]2.[NH2:18][CH2:19][CH2:20][N:21](CC)[C:22](=[O:24])[O-:23].[C:27](O)(=O)[CH3:28]>>[CH2:27]([O:23][C:22]([NH:21][CH2:20][CH2:19][NH:18][CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)=[O:24])[CH3:28]
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: CC(=O)O
Reactant: CCN(CCN)C(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)NCCNC1CCc2cccc(OC)c2C1
Reaction time: 15 h
Yield: 46.2 %

Procedure:
10.0 g (159 mmol) of sodium cyanoborohydride were added to the solution of 7.00 g (40 mmol) of 8-methoxy-2-tetralone, 8.00 g (61 mmol) of N-(2-aminoethyl)ethylcarbamate and 9.60 g (160 mmol) of glacial acetic acid at 0° C. After 15 hours at room temperature, the mixture was concentrated, taken up in tert.-butyl methyl ether, and treated with water. The pH of the aqueous phase was adjusted to 10 using sodium hydroxide solution. The mixture was stirred vigorously for 30 minutes. The organic phase was separated off, and the aqueous phase was extracted thoroughly with the last-mentioned solvent. Drying the organic phase and concentrating supplied an oil, which was purified by chromatography on silica gel (toluene/ethanol gradients with addition of 0.3% triethylamine). 5.40 g (46%) of the pure title compound were obtained as a brownish oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[OH:1])([O-:15])=[O:14]
Reactant: O=C(O)C=Cc1cccc(O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 26.1 %

Procedure:
3-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (1.70 g, 26.1 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (1.0 g, 26%). 1H NMR (CD3COCD3): δ8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,1H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:5][CH:4]=1)=[O:2].O.O.P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:13]([O:12][C:11]([NH:10][CH:8]([C:6]1[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C=O)s1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A mixture of tert-butyl 1-(5-formylthiazol-2-yl)ethylcarbamate (3.5 g, 0.014 mol), sodium dihydrogen phosphate dihydrate (2.9 g, 0.019 mol) and 2-methyl-2-butene (3.85 g, 0.055 mol) in tert-butyl alcohol (70 ml) and water (40 mL) was stirred at room temperature for 30 minutes. Sodium chlorite (3.22 g, 0.035 mol) was added and the reaction maintained at room temperature for an additional 2 hours. The reaction was concentrated, diluted with water (50 mL) and acidified (pH=4) with the addition of 3N H3PO4. The mixture was extracted with DCM, the organic layer dried over anhydrous Na2SO4 and evaporated to dryness to afford 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (2.35 g, 60%). LC-MS: (FA) ES+ 273.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[CH:5]=[N:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].[BH4-].[Na+].COC1C=C(C=CC=1OC)CNCC(OC)OC>C(O)C>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: COc1ccc(C=NCC(OC)OC)c(OC)c1OC
Agent: COc1ccc(CNCC(OC)OC)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CNCC(OC)OC)c(OC)c1OC
Yield: 100 %

Procedure:
Imine 11e (14.28 g, 0.05040 mol) was dissolved in ethanol (100 mL) and reacted with NaBH4 (3.00 g, 0.0793 mol) as described previously for compound 12a. A colorless oil (14.38 g, 100%) was obtained. 1H NMR (300 MHz, CDCl3) δ 6.89 (d, J=8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.45 (t, J=5.4 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.80 (s, 2H), 3.70 (s, 3H), 3.31 (s, 6H), 2.68 (d, J=5.4 Hz, 2H); low resolution ESIMS m/z (rel intensity) 286 (MH+, 100), 181 (69). Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12; N, 4.91. Found: C, 59.16; H, 8.24; N, 4.64.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].C(O)(=O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CCOCC.O>[CH:13]1([NH:16][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: c1cc(CCNC2CC2)ccn1

Procedure:
4-Vinyl pyridine (50 mmol), glacial acetic acid (3 ml), cyclopropylamine (4.28 g, 75 mmol) and water (12.8 ml) were heated at 50° C. for 22 hours. The crude reaction products were added to a vigorously stirred mixture of ether and saturated aqueous NaHCO3. After partitioning, the organic phase was washed with water, brine and dried. Filtered and solvents removed under vacuum. The residue was further distilled under vacuum (Kugelrohr) and the product amine collected. NMR (CDCl3) 8.45 (m, 2H), 7.05 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.07 (m, 1H), 1.37 (m, 2H), 1.25 (m, 2H); m/z 163.17.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]#[N:33])[CH:28]=[CH:29][CH:30]=1.[H-].[Na+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=1)[C:32]#[N:33])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CC#N)c1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(C#N)c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 3-benzyl-4-bromo-8-(trifluoromethyl)quinoline (10.0 g, 27.31 mmol) and (3-methoxyphenyl)acetonitrile (5.57 mL, 40.96 mmol) in THF (100 mL) is treated with NaH (1.64 g, 41.0 mmol, 60% dispersion in oil). After 0.5 h at ambient temperature, the reaction is heated at 50° C. for 2 h. The cooled reaction is diluted with water, extracted with ethyl acetate, and the combined extracts are dried (MgSO4) and concentrated. The residue is purified via column chromatography using 10:90 ethyl acetate:hexane as the eluent. The purified product is dissolved in a mixture of methylene chloride and hexane and concentrated until precipitation commences. After precipitation is complete, [3-benzyl-8-(trifluoromethyl)quinolin-4-yl](3-methoxyphenyl)acetonitrile is isolated as an off-white crystalline solid (5.18 g, 44%). HRMS: calcd for C26H19F3N2O+H+, 433.15222; found (ESI, [M+H]+), 433.1528.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([O:23][CH3:24])[C:12]=1[C:13]#[N:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)C>[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[C:15]([O:23][CH3:24])[C:12]=1[C:13]([NH2:14])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(N)=O
Temperature: 90 °C

Procedure:
To a solution of 254 mg (6.350 mmol) sodium hydroxide in 2 ml water and 2 ml ethanol at room temperature under nitrogen, was added 195 mg (0.635 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzonitrile. The reaction mixture was heated in a 90° C. oil bath overnight. The reaction mixture was cooled to room temperature and 7 ml water was added. The product was collect by filtration and dried to provide 192 mg (y: 93%) of the title compound as a white solid. MS (m/e): 326.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:20][OH:21])[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[O:21][N:20]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccc(-c3ccc(Cl)cc3)cc2)=NO1
Yield: 31.5 %

Procedure:
A stirred suspension of 4-(4′-chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid (2.126 g, 0.00700 mol) and 4-methylphenyl)sulfonic acid monohydrate (0.067 g, 0.00035 mol) in toluene (22 mL) was heated under nitrogen at reflux over a Dean-Stark trap for 7 hours, and allowed to cool. The volatiles were rotary evaporated. The residue was dissolved/suspended in dichloromethane and chromatographed on silica gel (221 g, 230-400 mesh), eluting with dichloromethane (20×200 mL) to give 0.63 g of 3-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-6-oxo-6H-1,2-oxazine as a light purple solid; mp 190-192° C.
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1>O1CCCC1.COCCOC>[Cl:5][C:6]1[NH:7][CH:8]([CH2:3][CH3:4])[C:9]([F:13])=[C:10]([Cl:12])[N:11]=1
Reactant: CCBr
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCC1NC(Cl)=NC(Cl)=C1F

Procedure:
To magnesium turnings (4.27 g) in tetrahydrofuran (56 ml) was added a solution of bromoethane (19 g) in THF (19 ml) over 5 hours. To this slurry at 0° C. was added a solution of the product of part (i) (24 g) in 1,2-dimethoxyethane (70 ml) over 1 hour. The reaction was quenched at 10° C. using glacial acetic acid (10 g) to give a solution of the title compound which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:38]=[CH:37][N:36]=1
Reactant: Nc1ccnc(O)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccnc(O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.49 g, 1.1 mmol) was reacted with 4-amino-pyridin-2-ol (Molbridge) (0.14 g, 1.3 mmol), HATU (0.72 g, 1.9 mmol) and iPr2NEt (0.46 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-yl)-amide as a off white solid (20 mg, 3.4%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:3]1=[O:27].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:3](=[O:27])[CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:37])[N:8]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2cccnc2)C1=O
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(Cc3cccnc3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(pyridin-3-yl)methyl-1H-1,4-benzodiazepin-2-one (0.48 g) in dry methylene chloride (30 ml) was added dropwise a solution of 3-methylphenyl isocyanate (0.195 g) in dry methylene chloride (5 ml) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same temperature for 1 hour and at ambient temperature overnight. The resultant precipitates were collected by filtration and washed with isopropyl ether to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1-(pyridin-3-yl)methyl-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:4][C:5]([C:15](=[O:26])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH3:17])=[C:6]([CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:39](O)[CH3:40]>O=S(Cl)Cl>[CH2:39]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:14]=[C:2]([Cl:1])[C:3]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:4][C:5]=1[C:15](=[O:26])[N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH3:17])[CH3:40]
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid in ethanol (1 mL), 10 drops of SOCl2 were added. The mixture was stirred at rt for 24 hrs. The crude was purified via reverse phase preparative LCMS to afford 4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid ethyl ester 43-1 (12.2 mg). MS: [M+H]+576.3; tR=6.33 min (method 3).
Reaction SMILES: [CH2:1]([N:5]([CH3:22])[C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:11]([OH:13])=O)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH3:22])[C:6](=[O:7])[C:8]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][N:21]=2)[CH:14]=[C:10]([C:11]([NH:58][C@@H:59]([CH2:73][C:74]2[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=2)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=2)=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[Butyl(methyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (237 mg, 0.78 mmol) is dissolved in DMF (5 mL), and diisopropylethylamine (546 μL, 3.1 mmol), HATU (358 mg, 0.94 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (319 mg, 0.78 mmol) are added. The reaction stirred at room temperature 5 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound. ESI MS m/z 619.3 [M+H]+.