Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:27][CH2:28][N:29]2[C:30](=[O:39])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]2=[O:38])[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Br)C2(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN3C(=O)c4ccccc4C3=O)c(=O)c1Br)C2(C)C

Procedure:
4-Bromo-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (100 mg, 0.306 mmol) and potassium carbonate (51 mg, 0.0369 mmol) in N,N-dimethylformamide (3 mL) were stirred with 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (93 mg, 0.366 mmol) at 80° C. for 7 hours. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was used for the next reaction without purification.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.C[Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(I)C.Cl>C1COCC1.CCCCCC>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([CH2:1][CH3:2])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccccc1O[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C(=O)OC)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.46 mL) in THF (3 mL) at 0° C. was added 1.6M BuLi in hexane (2.01 mL). After stirring for 30 minutes at 0° C., 2.74 mL of this solution was added to a solution of methyl (2-trimethylsilyloxyphenyl)acetate from Step 1, (357 mg) in THF (5 mL) at 0° C. After 20 minutes, ethyl iodide (0.144 mL) was added and the mixture was stirred for 18 hours at r.t. Then, 2 mL of 1N HCl was added and the resulting mixture was stirred for 30 minutes, extracted with EtOAc, washed twice with brine, dried over MgSO4, filtered, and evaporated to dryness, giving the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13]Cl)[CH:7]=1)[C:3]([OH:5])=[O:4].[S-:15][C:16]#[N:17].[K+]>CO>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:15][C:16]#[N:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Product: N#CSCc1cc(C(N)C(=O)O)ccc1O
Yield: 78 %

Procedure:
A solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid (0.5 g, 1.98 mmole) and potassium thiocyanate (0.4 g, 4.12 mmole) in 10 ml of methanol is stirred at room temperature for 16 hours. The reaction mixture is filtered to remove the potassium chloride, the filtrate is evaporated and to the residue is added saturated aqueous sodium bicarbonate until the pH is 7. The title compound precipitates as a white powder which is filtered and dried. (1.83 g, 78% yield), NMR (TFA-D+D2O) ppm (δ) 4.1 (s,2), 5.08 (s,1), 6.9-7.3 (m,3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH2:28]C)=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:32])[CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCOCC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-ylamino)quinoxaline-6-carboxylate (180.0 mg, 0.47 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (22.7 mg, 0.95 mmol) at 0° C. and stirred for 1 h at room temperature. Then CH3I (134.0 mg, 0.94 mmol) was added at 0° C. and stirred overnight at room temperature. The reaction mixture was quenched by the addition of NH4Cl solution (100 ml) and adjusted to pH 6 with hydrochloric acid (1N), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylate as yellow oil (100 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:17]2[N:13]([CH3:12])[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][C:16]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: N#CC(=O)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 28 %

Procedure:
A 1.50 g (0.0090 mole) sample of 4-chlorobenzoylcyanide was added over a one-hour period to 1.50 g (0.0082 mole) of ethyl 1,4-dimethylpyrrole-2-acetate at 120°-130° through which nitrogen was slowly bubbled. The mixture was heated for 27 hours. The resulting oil was chromatographed on silica gel with successive elution with hexane and 1,1,1-trichloroethane. The solvent was evaporated in vacuo from compound-bearing fractions. The residue was chromatographed through a Waters Associates, Prep LC, System 500 with elution with a 2:3 mixture of hexane:1,1,1-trichloroethane. Evaporation of solvent from the second compound-bearing fraction afforded solid which was recrystallized from methanol to give 0.74 g (28 percent yield) of ethyl 5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate, mp 108°-109°, undepressed by admixture with authentic material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][C:12]#[N:13].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:11]([C:12]#[N:13])[C:10]1=[O:14]
Reactant: N#CCC(=O)Nc1ccc(F)cc1Cl
Reactant: CO/C=C/C(C)=O
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of N-(2-chloro-4-fluorophenyl)-2-cyanoacetamide (2.00 g, 9.40 mmol), (3E)-4-methoxybut-3-en-2-one (1.13 g, 11.2 mmol), 1,4-diazabicyclo[2.2.2]octane (1.05 g, 9.40 mmol) and 2-(2-methoxyethoxy)ethanol (20 mL) was stirred at 130° C. for 3 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50). The obtained residue was washed with ethyl acetate/hexane and collected by filtration to give the title compound (0.75 g, 30%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=1)#[CH:2].FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[F:9][C:7]1[CH:8]=[C:3]2[CH:1]=[CH:2][NH:10][C:4]2=[N:5][CH:6]=1
Reactant: C#Cc1cc(F)cnc1N
Agent: Fc1ccc(P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2[nH]ccc2c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of 3-ethynyl-5-fluoro-pyridin-2-ylamine (1.25 g, 9.2 mmol) in DMF (20 mL) is treated with (Rh(cod)2Cl)2 (23 mg, 0.023 mmol) and tris-(4-fluoro-phenyl)-phosphane (115 mg, 0.368 mmol) and stirred at 85° C. for 0.5 h. The mixture is then poured over brine (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 35%-75% EtOAc in heptane to afford 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.05 g, 84%). MS: 137 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.15 (s, NH, 1H), 7.99 (s, 1H), 7.44 (d, 1H), 7.18 (s, 1H), 6.28 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:3]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CSc1nc(Cl)c2c(n1)CCN(C(=O)OC(C)(C)C)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc2c(c(Nc3ccc(Cl)cc3Cl)n1)CN(C(=O)OC(C)(C)C)CC2
Yield: 60.8 %

Procedure:
A mixture of tert-butyl 4-chloro-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate (100 mg, 0.317 mmol), 2,4-dichloroaniline (56 mg, 0.348 mmol) and sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 412 □l, 0.412 mmol) in tetrahydrofuran (2 ml) was heated at reflux over night. The mixture was partitioned between ethyl acetate and water. Organic layer was separated and washed with brine, dried (MgSO4) and filtered. Concentration of filtrate afforded crude product, which was purified by flash chromatography (0.5% methanol in dichloromethane as eluent) to give tert-butyl 4-[(2,4-dichlorophenyl)amino]-2-methylthio-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate as a light yellow oil (85 mg, yield 61%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)[CH3:5].C(O)(=O)C.Cl>ClCCl>[CH3:1][O:2][NH:3][CH:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[CH:14]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)[CH3:5]
Reactant: CON=C(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CONC(C)c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-[1-(3-pyridin-3-yl-phenyl)-1H-benzoimidazol-5-yl]-ethanone O-methyl-oxime (prepared as described in WO 96/33191) (0.88 g, 2.57 mmol) in dichloromethane (10 ml) was added pyridine-borane complex (0.87 ml, 8.57 mmol) and glacial acetic acid (2.5 ml), successively. The resultant solution was stirred at reflux in a nitrogen atmosphere for 4 days. Hydrochloric acid (5 ml, 1M) was added to the cooled solution and stirring was continued for 30 min and the resultant mixture was concentrated in vacuo. The concentrate was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1 v/v). This afforded 27 mg of the desired product. LC-ESI-HRMS of [M+H]+ shows 345.1717 Da. Calc. 345.171536 Da. dev. 0.5 ppm.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:11][C:12]([CH3:17])([CH2:15][Cl:16])[CH2:13][OH:14]>C1CCCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:14][CH2:13][C:12]([CH3:17])([CH3:11])[CH2:15][Cl:16]
Reactant: CC(C)(CO)CCl
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCCCC1
Product: CC(C)(CCl)CO[Si](C)(C)C

Procedure:
The initiator of structure (3), designated PFI10, was prepared using the procedures broadly described in WO 91 112277. The hydroxyl functionality in 2,2-dimethyl-3-chloropropanol was protected by reaction with trimethylsilyl chloride. A solution of trimethylsilyl chloride (27.16 g, 0.25 mol) in dry cyclohexane (150 g) was treated with 20.4 g of imidazole (0.30 mol) under an argon atmosphere. The resulting slurry was stirred vigorously at room temperature as 2,2-dimethyl-3-chloropropanol (30.93 g, 0.25 mol) was added slowly to the mixture. The rate of addition was controlled to keep the reaction temperature below 40° C. The resulting slurry was filtered affording a clear solution of the desired 1-trimethylsilyloxy-2,2-dimethyl-3-chloropropane. Analysis using a Gas Chromatography-Mass Spectroscopy (GC-MS) technique found essentially no side products. The trimethylsilyl protected adduct was obtained in quantitative yield. A repeat of this experiment gave similar results.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][NH:15][CH3:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:3]([CH2:14][NH:15][CH3:16])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: CNCc1c(C)ccc2[nH]c(=O)c(=O)[nH]c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CNCc1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 8 h

Procedure:
To a cooled (10° C.) solution of 6-methyl-5-methylaminomethyl-1,4-dihydro-quinoxaline-2,3-dione (10° C.) of (1.23 g, 5.6 mmol) in concentrate H2SO4 (5 mL), KNO3 (0.606 g, 6 mmol) was added. Reaction mixture stirred overnight and quenched with ice. Green ppt filtered and washed with ice-cold water and dried (0.77 g, 42%); mp 260-261° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:21])[C:8]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:9]=2[NH:10][C:11](=[O:15])[C:12]=1[O:13]C>Cl.C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:8]2[C:7](=[O:21])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[C:12]([OH:13])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: COc1c(-c2cccs2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2cccs2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
A solution of 4-(2-thienyl)-8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.20 g) in 2.4N HCl/THF (1:1, 200 mL) was allowed to stir at room temperature for 1 hour followed by heating to 50 C. for 1 hour. The reaction mixture was partitioned between ether and water. The organic portion was dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized twice from ethyl acetate/hexanes to afford the title compound (0.048 g); mp 231-233 C. (dec.); NMR: 11.70 (bs, 1), 7.72 (d, 1, J=8.6), 7.62-7.60 (m,2), 7.40 (d, 1, J=1.9), 7.32 (dd, 1, J=8.6, 2.0), 7.10 (m, 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.[NH3:36].C1(C)C(C)=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:36][C:11]([C@@H:13]3[CH2:17][C:16]([F:19])([F:18])[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: N
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
In a 50 mL seal tube, (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-4,4-difluoropyrrolidine-1-carboxylate (1.8 g, 4.02 mmol) and acetic acid, ammonia acetate salt (1.55 g, 20.1 mmol) were combined with xylene (16 ml). The reaction mixture was heated to 140° C. and stirred for 4 hr. The reaction mixture was cooled and diluted with EtOAc (50 ml). It was washed with water and brine, dried with MgSO4, concentrated and purified on a silica gel column (CH2Cl2, 30%, 50%, 80% EtOAc/CH2Cl2) to afford (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidine-1-carboxylate as a yellow solid (1.77 g, 74%): ESI-LRMS m/e calcd for C18H22BrF2N3O2 [M+] 428. found 429 [M+H+].
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(C4C=CC(C([C@@H]5CCC[C@H]5C(O)=O)=O)=CC=4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.NC1C=CC(C2C=CC(C([C@@H]3CCCC[C@H]3C(O)=O)=O)=CC=2)=CC=1>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:80])([F:81])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:66]=[CH:65][C:64]([C:67]([C@@H:69]5[CH2:74][CH2:73][CH2:72][CH2:71][C@H:70]5[C:75]([OH:77])=[O:76])=[O:68])=[CH:63][CH:62]=4)=[CH:59][CH:60]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(-c2ccc(C(=O)C3CCCCC3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCCC[C@H]3C(=O)O)cc2)cc1
Agent: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid above, racemic 2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid. The racemic product obtained was separated by chiral SFC to afford (1R,2R)-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclohexanecarboxylic acid (or enantiomer). [α]D: +25.4° in DMSO. LCMS calcd for C31H25F3N2O5 (m/e) 562, obsd 563 (M+H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][OH:42]>>[OH:42][CH2:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][N:36]1[C:30](=[O:31])[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:35])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:24][CH:25]=1)[CH3:33]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)N1CCC[C@H]1CO)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (2S)-pyrrolidin-2-ylmethanol. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
1,3-Di-(4-nitrophenyl)urea was prepared by the dropwise addition of a solution of p-nitrophenylisocyanate (16.4 g, 0.1 mole) in dimethyl formamide (150 ml) to a solution of p-nitroaniline (13.8 g, 0.1 mole) in dimethylformamide (130 ml) at 4° C. 1,3-Di-(4-nitrophenyl)urea precipitated slowly as a yellow solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:4].[OH-].[Na+].O.CCCCCC>C(Cl)(Cl)Cl>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCCCCC
Product: O=C(O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To 1-(4-methoxy carbonyl butyl)5-nitroindole (0.5 g) was added molar sodium hydroxide (10 ml) and the solution stirred in an oil bath at 120° C. for 90 minutes. It was then cooled, water (10 ml) added and the solution extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (2×10 ml) and the combined aqueous extracts were acidified with molar HCl and extracted with ethyl acetate. (3×15 ml). The organic extracts were dried over anhydrous sodium sulphate, filtered and rotary evaporated to give a yellow gum. The gum was dissolved in hot chloroform, then hexane (2 ml) added and the solution cooled on ice when yellow crystals separated. These were filtered off and washed with chloroform:hexane (50:50) followed by hexane. The crystals were dried in vacuo (0.423 g, 1.61 mmol, 81%), MP 141-2° C. TLC on silica in toluene:methanol:acetic acid (90:16:8) gave one yellow spot and when viewed under UV. Mass spec and NMR analysis were as expected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].C(=O)([O-])[O-].[Ca+2].[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25][C:26]#[N:27])=[C:20]([CH3:28])[CH:19]=1.Cl>C1COCC1.O>[CH3:24][C:22]1[CH:23]=[C:18]([NH:17][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=[C:20]([CH3:28])[C:21]=1[S:25][C:26]#[N:27]
Reactant: Cc1cc(N)cc(C)c1SC#N
Reactant: Cc1ccccc1CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1CC(=O)Nc1cc(C)c(SC#N)c(C)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
2-(2-Methylphenyl)acetyl chloride (9.9 g, 58.8 mM) was added to a stirred suspension of calcium carbonate (7.87 g, 78.7 mM) and 4-amino-2,6-dimethylphenyl thiocyanate (7 g, 39.3 mM) in dry THF (150 mL). The mixture was stirred for 1 hour. Water (1000 mL) was added. The mixture was acidified to pH4 with 2M HCl and extracted with ethyl acetate. The combined extracts were washed with water, then with saturated sodium chloride solution and dried (MgSO4). The solvent was removed by evaporation. The pale green solid obtained was triturated with ether to give 2,6-dimethyl-4-[2-(2-methylphenyl)acetamido]phenyl thiocyanate (B), as a cream coloured solid in 83% yield; NMR (CDCl3, 200 MHz): 2.47(s, 3H), 2.49(s, 6H), 3.69(s, 2H), 7.14-7.17(m, 4H), 7.55(s, 2H), 10.27(s, 1H).