Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCO.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:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccn2)c1
Temperature: 100 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (208 mg, 0.180 mmol) was added to a solution of 3-ethoxycarbonylphenyl boronic acid (350 mg, 1.80 mmol), 2 -bromopyridine (189 μL, 1.99 mmol) and potassium carbonate (499 mg, 3.61 mmol) in EtOH:toluene (4.00 mL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 100° C. in a sealed microwave vial for a total of 15 min. After cooling to rt, the reaction mixture was filtered through a short column of Celite®, eluting with EtOAc. The filtrate was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (isocratic elution; 10% EtOAc/hexanes as eluent) to afford the title compound i-2a. m/z (ES) 228 (MH)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]([CH3:19])=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C.N1CCCCC1>[CH3:19][C:12]1[NH:11][CH:9]=[CH:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C/C=C/c1ccccc1
Reactant: CCOC(=O)C=C(C)N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC=CC1c1ccccc1
Yield: 72.3 %

Procedure:
(E)-3-Phenyl-2-propenal (13.8 ml, 0.11 mol) and ethyl 3-amino-2-butenoate (12.9 g, 0.1 mol) were dissolved in 150 ml of absolute ethanol containing 0.5 ml of piperidine. The mixture was heated under reflux for 18 hours followed by removal of the solvent under vacuum to yield 17.6 g of ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate as a brown viscous oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(NCCCCS(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
m-Chloroperbenzoic acid (487 rag) was added in small portions to a solution of tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (1.20 g) in dichloromethane (10 ml) with ice-cooling, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed successively with aqueous sodium bisulfite, saturated aqueous sodium bicarbonate, and water and then dried (MgSO4), and concentrated. The residue was chromatographed on silica gel. Tetraethyl 4-(phenylsulfinyl)butylaminomethylenebisphosphonate was obtained as a colorless oil (1.05 g, 85%) from the fraction eluted with chloroformmethanol (50:1, v/v).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:4]1[CH:3]=[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: CC1(C)OBOC1(C)C
Reactant: Nc1ccc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Temperature: 80 °C

Procedure:
Dissolve 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol) in dioxane (80 mL) in a RBF under nitrogen. Add triethylamine (10 mL, 3.6 equiv.) then sparge with nitrogen to de-gas. Add 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 2.9 equiv.) dropwise via syringe over approximately 5 minutes. Sparge an additional 5 minutes with nitrogen then add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.603 g, 3.7 mol %, 1:1 complex with dichloromethane). Place under nitrogen and heat at 80° C. overnight. After the reaction cools, filter via Celite® washing with hexanes. Concentrate filtrate to dryness and use crude.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH3:49])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and isopropylamine (0.032 mL, 0.37 mmol). The mixture was stirred at r.t. overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (22 mg, 51%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:19]O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2cccnc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2cccnc2c1

Procedure:
To a solution of example 11A (1.98 g, 10.59 mmol) in 40 mL of anhydrous methanol was slowly added SOCl2 (1.5 mL, 31.7 mmol), and a drop of dimethylformamide as catalyst. The mixture was refluxed for 5 hrs and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and neutralized with aqueous sodium bicarbonate to pH 8. The product was extracted with methylene chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford 2.13 g of the title compound. MS (ESI+) m/z 202 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]([CH3:18])[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]C)[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3].Br>C(O)(=O)C.C(O)C>[CH3:1][S:2]([C:5]1[N:6]([CH3:18])[C:7]([C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: COc1cc(-c2nnc(S(C)(=O)=O)n2C)ccn1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(-c2cc[nH]c(=O)c2)nnc1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 111.4 %

Procedure:
The title compound of example 26.1 (6.4 g, 23.9 mmol) was dissolved in acetic acid (190 mL) and 20-30% hydrogen bromide in ethanol (190 mL) was added to the reaction. It was allowed to stir at 80° C. for 3.5 hours. The reaction was concentrated once, diluted with ethanol and concentrated again. Ethanol was added once more and the mixture was sonicated until a precipitate formed. The solid was filtered and dried under vacuum to afford the title compound (6.77 g, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]2)[CH2:27][NH:26]1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]2[CH2:27][C@H:28]3[C@H:33]([CH2:32][CH:31]=[CH:30][CH2:29]3)[CH2:25]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1C[C@H]2CC=CC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1.13 g of 3,4-dichlorophenylacetic acid in 6 mL of THF was added 0.90 g of 1,1'-carbonyldiimidazole. After 30 minutes a solution of 0.61 g of cis-3a,4,7,7a-tetrahydroisoindoline in 2 mL of THF was added and the mixture was stirred at room temperature overnight. Toluene (50 mL) was added, and the solution was washed successively with 5% hydrochloric acid, water, and 10% aqueous sodium carbonate solution, dried, and concentrated to give 1.50 g of cis-2-(3,4-dichlorophenylacetyl)-3a,4,7,7a-tetrahydroisoindole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2cncn2C)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 33.6 %

Procedure:
5-(4-Bromo-3-methylphenyl)-1-methylimidazole (D92, 1.52 g, 6.1 mmol) was dissolved in DME (50 ml) and water (50 ml), then treated with 4-boronobenzoic acid (1.0 g, 6.1 mmol), sodium carbonate (2.57 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (O) (100 mg). The mixture was heated at reflux (48 hours), cooled and the DME removed in vacuo. The aqueous residue was treated with 10% Na2CO3 (approx 30 ml), then washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that precipitated was collected by filtration. This solid was dried in vacuo to yield the title compound as a white solid (600 mg, 34%).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11](=[O:27])[N:12]([C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH2:40])[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH:40][C:17](=[O:18])[C@@H:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]1=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(O)CF
Temperature: 0 °C
Yield: 36.7 %

Procedure:
A stirred mixture of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid (2.20 g, 6.07 mmol), 3(R,S)-Amino-5-fluoro-4(R,S)-hydroxy-pentanoic acid tert-butyl ester (1.39 g, 6.68 mmol), HOBt (902 mg, 6.68 mmol), DMAP (853 mg, 6.98 mmol) and THF (20 mL) was cooled to 0° C. then EDC (1.28 mg, 6.68 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (30-70 to 55-45% ethyl acetate/hexane) to afford the title compound as a white foam (1.23 g, 32%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.35-1.42 (9H, 2s), 2.50-2.65 (2H, m), 3.20-3.35 (2H, m), 3.60 (1H, m), 3.98 (1H, m), 4.10-4.32 (3H, m), 5.62-5.70 (1H, m), 6.44 (1H, m), 6.80-6.98 (1H, m), 7.21-7.41 (5H, m), 7.55-7.62 (3H, m), 7.95 (2H, m), 8.58 (1H, t), 9.18 (1H, br s).
Reaction SMILES: C([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)[C:6]1=[O:23])C=C.BrCC1C=CC=CC=1[Cl:32]>>[Cl:32][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:7]1[C:8]2[CH:14]=[CH:13][S:12][C:9]=2[C:10](=[O:11])[N:5]([OH:4])[C:6]1=[O:23]
Reactant: Clc1ccccc1CBr
Reactant: C=CCOn1c(=O)c2sccc2n(Cc2cccc(Br)c2)c1=O
Product: O=c1c2sccc2n(Cc2ccccc2Cl)c(=O)n1O

Procedure:
3-Allyloxy-1-(3-bromo-benzyl)-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) was alkylated with 1-bromomethyl-2-chloro-benzene via general procedure B2. The crude intermediate was deprotected via general procedure D2. The final product was purified by mass triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.65 (bs, 1H), 8.10 (d, 1H, J=5.1 Hz), 7.52 (dd, 1H, J=1.5, 7.8 Hz), 7.32 (dt, 1H, J=1.5, 7.5 Hz), 7.25 (dt, 1H, J=1.5, 7.5 Hz), 7.13 (d, 1H, J=5.4 Hz), 6.96 (dd, 1H, J=1.5, 7.5 Hz), 5.31 (s, 2H); Electrospray MS: 309 (M+H); retention time: 2.31 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-di hydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:14]([O:16]C)Cl.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[F:8])[CH:14]=[O:16]
Reactant: Fc1ccccc1F
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
57 g (0.5 mol) of ortho-difluorobenzene in 250 ml of methylene chloride is added to 100 g (0.75 mol) of anhydrous aluminum chloride. The mixture is stirred mechanically at 0° C. (ice bath) while 85.5 g (0.75 mol) of dichloromethyl methylether is added dropwise. Vigorous HCl evolution takes place, and the reaction mixture turns orange-red. After the addition, the mixture is stirred at room temperature for 15 minutes, and the liquid phase is decanted into 500 ml of ice and water. The residue in the reaction flask is washed with methylene chloride until colorless, and the washings are added to the water. The mixture is shaken well in a separatory funnel until the methylene chloride layer is green. The organic layer is washed with saturated potassium carbonate solution until neutral, is dried MgSO4) and is distilled to give 3,4-difluorobenzaldehyde, B.P. 70-74° C/20 mm. The dark residue in the distillation pot solidifies on cooling to give tris-(3,4-difluorophenyl)methane, M.P. 95-96° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.CO>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([F:15])[F:14])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)c1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2cccc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Reaction time: 0.42 h
Yield: 18.8 %

Procedure:
n-Butyllithium (0.254 mL, 0.63 mmol) was dropwise added to 4-bromo-2-(difluoromethyl)pyridine (120 mg, 0.58 mmol) in anhydrous THF (5.00 mL) at −78° C. under argon atmosphere. The reaction mixture was stirred for 25 min. N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (235 mg, 0.58 mmol) in anhydrous THF (5.00 mL) was dropwise added. The reaction mixture was stirred for 2 h, then methanol (5 mL) was added and the temperature was allowed to reach room temperature. The reaction mixture was partitioned between aqueous ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by prep. HPLC to afford the title compound (47.1 mg, 18%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:47])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=1[Cl:46]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:47])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=3[Cl:46])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(COC(=O)Cl)c(Cl)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c(Cl)c1

Procedure:
2-Chloro-4-methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 2-chloro-4-methylbenzyl carbonochloridate (59.3 mg, 0.18 mmol) according to General Procedure H to give 20 mg (24.8%) of white solid. Anal. Calcd. for C27H33ClN4O2 m/z 480.2, found: 481.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.43 (d, J=8.8 Hz, 2H), 7.27 (d, J=7.72 Hz, 2H), 7.19 (bs, 1H), 7.06 (m, 1H), 6.97 (m, 2H), 5.06 (m, 2H), 3.67 (m, 1H), 3.56 (m, 1H), 3.00 (m, 1H), 2.78 (m, 2H), 2.52 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.93 (m, 2H), 1.79 (m, 3H), 1.64 (m, 1H), 1.34 (m, 8H).
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH2:20][CH3:21]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH2:20][CH3:21])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.00 g of trans-β-benzoylacrylic acid, 1.67 ml of n-propanol and 1.05 g of sulfuric acid was stirred at 100° C. for 1.5 hours. A pressure was gradually reduced with the aspirator and n-propanol was distilled away for 15 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 100° C. for 10 minutes and then cooled, followed by the procedure as in Example 1 to give 5.78 g of n-propyl trans-β-benzoylacrylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([O:17]CC)=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[OH-].[Li+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([C:15]([OH:17])=[O:16])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 4-(4-nitrophenyl)thiazole-2-carboxylate (Intermediate 3, step A, 7.0 g) in THF (70 ml) was added (1 ml) 1N lithium hydroxide monohydrate solution and reaction mixture was stirred for 4 hours at RT. Organic solvent was concentrated, water was added, and the reaction mixture was made acidic by dilute HCl solution. This resulted in precipitation of white solid, which was filtered and washed with water. The solid was dried to obtain the title compound. Yield: 6.2 gm (98%). 1H NMR (DMSO-d6, 300 MHz): δ 8.78 (s, 1H), 8.32 (d, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1F)[C:11](OCC)=[O:12]>>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]([OH:12])[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Product: Cc1nccn1C(O)c1cccc(F)c1

Procedure:
Prepared from 2-methylimidazole and ethyl 3,4-difluorobenzoate.
Reaction SMILES: Cl.Cl.[N:3]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1([O:24][C:25](=O)[N:26]([C:36]2[CH:41]=[C:40]([O:42][C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]4([C:55](=[O:64])[NH:56][C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=5)[CH2:54][CH2:53]4)=[O:51])=[C:45]([F:65])[CH:44]=3)[CH:39]=[CH:38][N:37]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:3]1([CH:7]2[CH2:10][N:9]([C:25]([NH:26][C:36]3[CH:41]=[C:40]([O:42][C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]5([C:55]([NH:56][C:57]6[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=6)=[O:64])[CH2:54][CH2:53]5)=[O:51])=[C:45]([F:65])[CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:24])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: C1CN(C2CNC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CC(N2CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a suspension of 3-(azetidin-1-yl)azetidine dihydrochloride (111 mg) in N,N-dimethylformamide (1.5 ml) was added triethylamine (0.167 ml), followed by stirring at room temperature for 15 min. A crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) was added thereto, followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated and the residue was purified by LC-MS. Fractions containing the target compound were concentrated, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and to the resultant solid (31.5 mg) was added diethyl ether (2 ml) to suspend. This was collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as colorless powder (5.0 mg).