Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=C([C:15]2[C:20]([C:21](N)=[O:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)C(C2C=CC(N)=CC=2)=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([NH2:42])[C:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)([O-:26])=[O:25].C(Cl)(=O)C1C=CC=CC=1>CN(C1C=CN=CC=1)C.CN1CCCC1=O>[C:21]([N:42]=[C:29]1[CH2:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=[C:30]1[C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)(=[O:22])[C:20]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC(=O)c1ccccc1-c1cc(N)ccc1-c1ccc(N)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(N=C1CC([N+](=O)[O-])=CC=C1c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
A method for preparing 4,4'-diaminobiphenyl-2-benzamide which consists essentially of the steps of reacting 4,4'-dinitro-2-biphenylamine with benzoyl chloride in the presence of 4-dimethylamine pyridine in N-methyl-2-pyrrolidinone (NMP) to give 2-(N-benzoylimino)-4,4'-dinitrobiphenyl, and hydrogenating said 2-(N-benzoylimino)-4,4:dinitrobiphenyl.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccncc1C(O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (97 mg, ol) in THF (5 mL) at −78° C. was added 1.0M phenylmagnesium bromide in THF (0.46 mL) and the reaction mixture stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by preparation TLC of silica gel with 10% methanol in dichloromethane to yield [3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-phenyl-methanone as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[OH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH2:34][CH2:35]O>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][N:33]([CH2:32][CH2:31][OH:30])[CH:37]([CH3:39])[CH3:38])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC(C)N(CCO)CCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)N(CCO)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)(1-methylethyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N,N-bis(2-hydroxyethyl)isopropyl amine following General Procedure J.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][O:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.Cl[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>>[C:8]1([CH:5]2[O:4][CH2:3][CH:2]([O:1][CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:7][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1cccs1
Reactant: O[C@H]1CO[C@@H](c2ccccc2)OC1
Product: c1ccc(C2OCC(OCc3cccs3)CO2)cc1

Procedure:
Using the procedure of Example 56, cis-5-hydroxy-2-phenyl-1,3-dioxane was reacted with 2-chloromethylthiophene to give, after repeated recrystallization from petroleum ether, cis-2-phenyl-5-(2-thienyl)methoxy-1,3-dioxane m.p. 68.5°-69°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c(OC)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,4-Dimethoxy-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:21][CH2:20][N:10]3[C:11]4[N:19]=[CH:18][CH:17]=[CH:16][C:12]=4[NH:13][CH2:14][CH2:15][CH:9]3[CH2:8]2)=[CH:4][CH:3]=1.[CH:24]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:28]([N:13]2[CH2:14][CH2:15][CH:9]3[CH2:8][N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:21][CH2:20][N:10]3[C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]2=3)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Product: O=C(C1CCC1)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the product of Example 64C (97 mg, 0.31 mmol) in dichloromethane (2 mL) was added to cyclobutanecarbonyl chloride (0.048 mL, 0.42 mmol). The resulting, turbid solution was stirred at room temperature for 12 hours, and then the reaction was quenched by the addition of 20% Na2CO3 (1 mL). After 30 minutes, the mixture was made basic (pH˜9) by addition of 1 M NaOH (˜0.2 mL), diluted with water (3 mL) and extracted with CHCl3 (3×2 mL). The combined organic phases were dried over K2CO3 and concentrated: 1H NMR (300 MHz, CD3OD) δ ppm 1.58-2.02 (m, 5H), 2.06-2.44 (m, 4H), 2.68-3.26 (m, 6H), 3.42-3.65 (m, 3H), 3.96-4.47 (m, 2H), 6.82-7.11 (m, 3H), 7.17-7.58 (m, 3H), 8.08-8.32 (m, 1H); MS (DCI) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH:11]([CH2:14][O:15][CH3:16])[CH2:12][CH3:13])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(COC)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC(COC)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 18.5 mmol, 1.0 eq.) and MeI (6.9 mL, 111 mmol, 6 eq.) in THF/DMF (4:1, 50 mL) at 0° C. was slowly added NaH (1.35 g, 55.5 mmol, 3 eq.). The resulting mixture was warmed to room temperature and stirred over night. The reaction was quenched carefully by slow addition of water until no bubbling (H2) was observed. The reaction mixture was poured over ice water and extracted with 3×EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (30% to 50% EtOAc-hexanes) to give (1-methoxymethyl-propyl)-methyl-carbamic acid benzyl ester (4.4 g, 94%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:24]([O:26][C@H:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1)[CH3:25].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[C:35](=[O:36])[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:27]([O:26][CH2:24][CH3:25])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:39][CH:38]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: FC(F)(F)c1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine (0.733 g, 2.20 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting solution was diluted with methylene chloride (130 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.91 g (74%) of a whitish oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[F:21]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>O1CCCC1>[F:21][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)c1ccccn1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(F)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a stirred, cooled (−78° C.) solution of 5.00 mL (10.0 mmol) of a 2.0 M solution of lithium diisopropylamine in tetrahydrofuran under an atmosphere of nitrogen was added a solution of 1.5 g (9.1 mmol) of methyl 2-pyridin-2-yl-propanoate in 4.0 mL of anhydrous THF. The reaction mixture was allowed to stir for 10 min then warmed to 0° C. over 30 min. The mixture was then re-cooled to −78° C. and a solution of 3.70 g (11.8 mmol) of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide in 4.0 mL THF was added. The resulting mixture was allowed to warm to ambient temperature and stir for 2 h. The reaction was quenched with 50 mL of a saturated ammonium chloride solution and then extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 0-40% ethyl acetate in hexanes gradient to afford the title compound as a dark oil (1.3 g, 78%). LC-MS: m/z (E/S) 184 (MH)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]1([CH3:9])[CH3:8].N1C=CC=CC=1.CO[C@](C1C=CC=CC=1)(C(F)(F)F)C(Cl)=O>ClC(Cl)C>[CH3:8][C:3]1([CH3:9])[C:2](=[O:1])[CH2:6][CH2:5][C:4]1=[O:7]
Reactant: CC1(C)C(=O)CC[C@@H]1O
Agent: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)C(=O)CCC1=O
Reaction time: 8 h

Procedure:
The enantiomeric excess of 3 was assayed by 1H NMR of the corresponding Mosher's ester which was prepared by treatment of alcohol 3 (11 mg, 0.09 mmol) in dichloroethane (0.3 mL, Aldrich) with pyridine (27 μL, 0.33 mmol, Aldrich) and (R)-α-methoxy-α-trifluoromethyphenylacetic acid chloride (58 μL, 0.31 mmol, Fluka). The mixture was stirred overnight and then partitioned between water (10 mL) and ether (10 mL). The ether layer was washed with 1 M HCl (10 mL) and saturated NaHCO3 solution and then was dried (MgSO4), filtered and evaporated. 1H NMR analysis was done on the crude ester.
Reaction SMILES: [CH3:1][N:2]1C(=O)CCC1.Cl[C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([C:22]#[C:23][CH3:24])[C:10]=1[C:25]([F:28])([F:27])[F:26].C([Cu])#N.[OH-].[NH4+]>CCOCC>[CH3:24][C:23]1[NH:15][C:12]2[C:11]([CH:22]=1)=[C:10]([C:25]([F:26])([F:27])[F:28])[C:9]([C:1]#[N:2])=[CH:14][CH:13]=2
Reactant: CN1CCCC1=O
Reactant: CC#Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Temperature: 195 °C
Yield: 64 %

Procedure:
An NMP solution (150 mL) of N-[4-chloro-2-(1-propyn-1-yl)-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (10 g, 31.5 mmol) was treated with CuCN (11.3 g, 126 mmol) and the resulting mixture was heated at 195° C. for 90 h. Two reactions were carried out simultaneously. The combined dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (100 mL). The resulting slurry was stirred with the addition of Et2O and filtered through celite. The filtrate was diluted with Et2O and partitioned. The aqueous portion was extracted with Et2O four times. The combined organic portions were washed with brine and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-60% EtOAc-hexanes gradient) afforded the title compound as a solid (9 g, 64%):
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C=O)C>[Si:20]([O:12][C@H:11]1[CH2:10][C@H:9]2[N:13]([CH3:14])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[C:1]([O:3][CH3:4])=[O:2])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2CC[C@H]1N2C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
2β-Carbomethoxy-3β-hydroxytropane (304 mg, 1.43 mmol) was dissolved in 4 mL of dry DMF. Imidazole (208 mg, 3.01 mmol) and tert-butyldimethylsilyl chloride (345 mg, 2.29 mmol) were added, and the reaction mixture was stirred overnight. Water was then added, and the mixture was extracted with ether. The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel half-saturated with ammonia using ethyl acetate as eluent to give 265 mg of the title compound (55% yield): IR (thin film) 2951, 2897, 2857, 1790, 1716, 1497, 1271, 1144, 1107, 837 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 3.91 (dt, 1H, J=11.1, 6.1 Hz), 3.67 (s, 3H), 3.45-3.35 (m, 1H), 3.25-3.17 (m,1H), 2.75-2.68 (m,1H), 2.18 (s, 3H), 2.35- 1.42 (m, 6H), 0.84 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75.46 MHz) δ 171.4, 64.6, 64.4, 61.6, 54.0, 51.1, 41.2, 39.5, 28.2, 25.8, 25.2, 18.1, 6.6, 6.3; mass spectrum m/z 313 (M+), 256, 242, 182, 97, 82; HRMS (FAB) calcd for C16H32NO3Si (MH ) 314.2143, found 314.2145.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2cc(Cl)nnc2-c2ccccc2Cl)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (4.1 g, 12.9 mmol) in phosphorus oxychloride (15 mL) was stirred at 95° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The separated aqueous layer was extracted with EtOAc (40 mL×2). The combined organic was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure to afford 4.2 g (97%) of the title compound as a pink foam. HPLC/MS (method A): retention time=3.50 min, (M+H)+=335.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=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.[CH3:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:63]3[CH2:64][CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CC1CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 3-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (186 mg). LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)O1.[F:27][C:28]1[C:29](I)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1>O1CCOCC1.O.[Pd]>[F:27][C:28]1[C:29]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)=[CH:30][C:31](=[O:52])[N:32]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:48])=[O:49])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[CH:33]=1
Reactant: CC1(C)OB(c2ccc(-n3ncnn3)cc2)OC1(C)C
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3ncnn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Pd EnCat™ (317 mg, 0.10 mmol) was added to a mixture of potassium carbonate (393 mg, 2.84 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-tetrazole (258.4 mg, 0.95 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (490 mg, 0.95 mmol), T3, in 1,4-dioxane:water (4:1, 10 mL). The reaction was heated to 80° C. and stirred at this temperature overnight. The reaction was filtered through celite, and the filter pad was washed with methanol (250 mL). The combined filtrates were concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in n-heptane (20-100%) and methanol in EtOAc (0-10%) to afford the title compound as a light tan solid (500 mg, 98%). MS (LCMS) m/z 534.4 (M−1). 0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[C:35](=[O:36])[N:34]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:26]2[N:27]=[C:28](S(C)=O)[N:29]=[CH:30][C:25]=2[C:24]=1[CH3:42].C1(=O)OC(=O)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:28]3[N:29]=[CH:30][C:25]4[C:24]([CH3:42])=[C:23]([Br:22])[C:35](=[O:36])[N:34]([CH:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Agent: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(C4CCCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of 4-(6-amino-pyridin-3-yl)-azepane-1-carboxylic acid tert-butyl ester (614 mg, 2.10 mmol) in toluene (10 mL) was refluxed in a Dean-Stark apparatus for 3 h. The heat was removed and when the reflux subsided 6-bromo-8-cyclopentyl-2-methansulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (700 mg, 1.89 mmol) was added. This mixture was refluxed for 12 h under N2. Succinic anhydride (500 mg) was added and the reflux continued for 3 h. The reaction mixture was cooled and dissolved in ethyl acetate (100 ml) and the organic layer was washed with water (100 mL total). The organic layer was dried over magnesium sulfate and the solvents evaporated. The crude product was subjected to chromatography on silica gel and eluted with a chloroform/2-propanol gradient to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-azepane-1-carboxylic acid tert-butyl ester as a yellow powder (414 mg, 0.82 mmol). MS (APCI+) 500, 600 (M+1,100).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])[CH3:3].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH:25]=[O:26])([CH3:1])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 76.65 g of 2-(1,1-dimethylethyl)-6-methylphenol (Aldrich), 65.42 g of hexamethylenetetramine and 700 ml of trifluoroacetic acid were stirred at reflux temperature for about 24 hours, then allowed to cool and evaporated. The residue from the evaporation was taken up in 1500 ml of water and 1000 ml of chloroform and neutralized to pH 7 with solid sodium carbonate. The resultant layers were separated and the aqueous layer was washed with chloroform. The organic layer was dried over sodium sulfate overnight, after which it was again washed with a volume of chloroform and evaporated. The resultant residue was then taken up in 375 ml of toluene, heated on a steam bath and then allowed to cool to room temperature overnight. Subsequent workup gave 28.3 g of the desired subtitled intermediate.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH:8]([CH3:9])[C:4]=2[C:3]=1[C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:21]=1[C:22]([NH:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH:8]([CH3:9])[C:4]=2[C:3]=1[C:11]([CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: CC1OCc2sc(N)c(C(=O)C3CCOCC3)c21
Product: CC1OCc2sc(NC(=O)c3c(F)cccc3C(F)(F)F)c(C(=O)C3CCOCC3)c21

Procedure:
The title compound was prepared from the product of Example 52A and 2-fluoro-6-trifluoromethylbenzoyl chloride by the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.33 (d, J=6.1 Hz, 3H), 1.64-1.71 (m, 4H), 3.01-3.10 (m, 2H), 3.34-3.43 (m, 1H), 3.82-3.93 (m, 2H), 4.89-5.04 (m, 2H), 5.36-5.45 (m, 1H), 7.75-7.85 (m, 3H), 12.08 (br s, 1H). MS (ESI+) m/z 493 (M+H)+.