Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:26]([F:29])([F:28])[F:27])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:4]=[N:3]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:26]([F:29])([F:28])[F:27])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][N:17]([CH3:30])[CH2:18][CH2:19]2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-methyl-7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (65 mg, 0.161 mmol) and sodium cyanoborohydride (20 mg, 0.322 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 19 mg (28%). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 7.23 (m, 4H), 7.17 (m, 1H), 4.66 (s, 2H), 3.90 (s, 3H), 3.47 (s, 2H), 2.51 (m, 2H), 2.18 (s, 3H), 2.05-2.25 (m, 4H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.7, 139.5, 135.1, 133.8, 128.3, 127.2, 126.2, 124.74, 124.67 (q, J=272 Hz), 124.6, 122.6 (q, J=33 Hz), 121.3, 119.6 (q, J=3.8 Hz), 79.2, 70.6, 51.9, 46.2, 40.6, 38.2, 32.5. Mass spec.: 418.15 (MH)+. Accurate mass spec.: m/z 418.2119 [MH]+, Δ=3.1 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(O)c2ncccc21
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCCC(O)c3ncccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.5 g of 5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine, O-acetate in 10 ml of methanol-water (8:2) is added KHCO3 and the mixture stirred at room temperature overnight. The mixture is concentrated under vacuum, diluted with 10 ml of water and extracted with ethyl acetate. The extract is dried (Na2SO4) and the solvent removed to give the product as a solid. Chromatography on silica gel with ethyl acetate as solvent gives crystals, m.p. 182°-185° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.O>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Cc1ccc(N)nc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)nc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 2.33 g (10.0 mM) of the phenyl carbamate 8 and 1.08 g (10.0 mM) of 2-amino-5-methylpyridine in 9 ml of anhydrous DMF was stirred at 70° C. for 2 hrs., cooled and poured into water with stirriang. The resulting precipitate was collected, washed with water and then acetone to give 1.9 g of the above urea as a pale yellow solid, m.p. 227° C. (dec.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[F:12].I[CH3:14]>C1COCC1>[Cl:3][C:4]1[C:5]([F:12])=[CH:6][CH:7]=[C:8]([CH2:10][O:11][CH3:14])[N:9]=1
Reactant: CI
Reactant: OCc1ccc(F)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a suspension of sodium hydride (0.48 g, 12 mmol, 60% dispersion in mineral oil) in THF (15 mL) at 5° C. under nitrogen was added (6-chloro-5-fluoropyridin-2-yl)methanol (1.57 g, 9.28 mmol) suspended in THF (20 mL). The resulting suspension was stirred at this temperature for 30 minutes and then iodomethane (0.75 mL, 12 mmol) was added slowly. The reaction was warmed to room temperature over 48 hours. Further iodomethane was added (173 μL, 2.8 mmol) and stirring at room temperature was continued for 4 hours followed by the addition of further sodium hydride (110 mg, 2.75 mmol) at 5° C. The reaction was continued stirring for 24 hours before quenching with water (10 mL) and saturated aqueous ammonium chloride solution (20 mL) until pH=7. The solution was extracted with diethyl ether (3×50 mL). The organic layers were dried over sodium sulphate, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-50% DCM in pentane to afford the title compound (600 mg, 37% yield).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=O)[NH2:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(COC)OC.O>[NH2:17][CH2:16][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: COCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COCCNc1ccc2ncc(-c3ccc(CN)cc3)n2n1
Temperature: 160 °C
Yield: 14.4 %

Procedure:
To a mixture of 3-bromo-N-(2-methoxyethyl)imidazo[1,2-b]pyridazin-6-amine (57.6 mg, 0.21 mmol), (4-carbamoylphenyl)boronic acid (87.4 mg, 0.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.7 mg, 0.011 mmol) and potassium phosphate (134 mg, 0.63 mmol) was added 1:1 Dimethoxyethane/water (0.75 mL). The resulting mixture was heated at 160° C. (microwave) for 6 min. The reaction was then filtered and diluted with a mixture of 1:1:1 methanol/water/acetonitrile, and then filtered again. The filtration was finally purified by preparative HPLC (neutral) to afford 3-(4-(aminomethyl)phenyl)-N-(2-methoxyethyl)imidazo[1,2-b]pyridazin-6-amine (9 mg, 14% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.29 (d, J=8.6 Hz, 2H), 7.98 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.66 (d, J=9.6 Hz, 1H), 6.79 (d, J=9.9 Hz, 1H), 3.69 (t, J=5.6 Hz, 2H), 3.59 (t, J=5.4 Hz, 2H), 3.42 (s, 3H); LRMS (ESI) m/e 312.2 [(M+H)+, calcd for C16H18N5O2 312.2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:29]([O-])([O-])=O.[K+].[K+].CI.[Na+].[Cl-]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:29])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)sc2c1CCCC2
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: CN(c1sc2c(c1C(=O)OC(C)(C)C)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
tert-Butyl 2-(3,4-dichlorophenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (21.64 g, 46.8 mmol) was dissolved in acetone (200 ml), and K2CO3 (12.9 g, 93.6 mmol) was added thereto. Methyl iodide (5.83 ml, 93.6 mmol) was then added, and the suspension was heated overnight at 40° C. After cooling to room temperature, water and saturated NaCl solution were added and the product was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the product was purified by crystallization from methanol.
Reaction SMILES: C([Li])(CC)C.C1CCCCC1.[C:12](=[O:14])=O.CC(C)=O.CN(CCN(C)C)C.[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH3:35].CN(C=O)C>C1COCC1.CCOCC>[F:34][C:32]1[CH:31]=[CH:30][C:29]([CH3:35])=[C:28]([Cl:27])[C:33]=1[CH:12]=[O:14]
Reactant: Cc1ccc(F)cc1Cl
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(C=O)c1Cl
Temperature: -30 °C

Procedure:
A solution of 1.3M s-butyl lithium in cyclohexane (75 mL, 98 mmol) is added to a dry-ice/acetone cooled solution of TMEDA (9.67 g, 83 mmol) in THF (90 mL), maintaining the internal reaction temperature <-70° C. The reaction mixture is cooled and maintained at ≤-80° C. with an ether/liquid nitrogen bath while a solution of 2-chloro-4-fluorotoluene (10 g, 69 mmol) in THF (10 mL) is added dropwise. The resulting reaction mixture is stirred with dry-ice/acetone cooling for 1h, then is cannulated into an ether/liquid nitrogen cooled and mechanically stirred solution of DMF (25.1 g, 345 mmol) in THF (50 mL). The resulting mixture is warmed to -30° C. and partitioned between dilute aqueous HCl and ether. The organic solution is washed with aqueous NaHCO3, dried (MgSO4), and concentrated and triturated with hexanes to afford 2-fluoro-5-methyl-6-chlorobenzaldehyde as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]([C:41](Cl)=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>C(Cl)Cl.O>[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]([C:41]([N:1]2[C:2]3[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=3[CH2:4][N:5]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]2)=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)c2ccccc2-c2ccccc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.65 ml of triethylamine in 12 ml of CH2Cl2 chilled at 0° C. was added a solution of [1,1'-biphenyl]-2-carbonyl chloride in 6 ml of CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2 and H2O. The organic layer was separated and washed with 2 N citric acid, brine and dried-with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C31H28N2O6S: Calc'd: C,66.9; H,5.1; N,5.0; Found: C,67.3; H,5.2; N,4.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(#N)C>[S:25]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(COS(C)(=O)=O)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 3,4,5-trimethoxybenzyl alcohol (9.0 g, 45.4 mmol), N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 g, 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and them a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(-c3cccs3)ccc21
Temperature: 115 °C
Yield: 93.3 %

Procedure:
To a solution of 5-bromo-1-indanone (0.52g, 2.5 mmol) in toluene (5 mL) were added tetrakis(triphenylphosphine)-palladium(0) (29 mg, 0.03 mmol), thiophene-2-boronic acid (0.48 g, 3.7 mmol), ethanol (5 mL), and 2.0 N sodium carbonate (3 mL). The solution was flushed with nitrogen for 3 minutes. The reaction was heated at 110-120° C. for 4 h. Reaction cooled to room temperature and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2×50 mL), water (40 mL), saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated to afford 5-(2-thienyl)-2,3-dihydro-1H-inden-1-one (0.50g, 94% yield) as pure solid product. 1H NMR (400 MHz, CDCl3) 7.80 (d, 1H), 7.70 (s, 1H), 7.62 (d, 1H), 7.43 (dd, 1H), 7.38 (dd, 1H), 7.12 (m, 1H), 3.20 (m, 2H), 2.66 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:29])[C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([NH:24][C:23]1[CH:22]=[C:21]([F:20])[C:27]([F:28])=[C:26]([F:29])[CH:25]=1)=[O:18]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2cc(F)c(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 25.9 %

Procedure:
The product is prepared according to the procedure described in example 68, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 214 mg of 3,4,5-trifluoroaniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 72 mg of 2-(1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)-N-(3,4,5-trifluorophenyl)acetamide are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[NH2:11].O.[OH-].[Na+]>O1CCCC1>[NH2:11][C@@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH2:9][OH:8]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@H](N)CO)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a suspension of lithium aluminum hydride (7.75 g) in tetrahydrofuran (200 ml) is gradually added dropwise a solution of 3-(3,4-dimethoxyphenyl)-L-alanine methyl ester (12.2 g) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes, and then thereto are added dropwise water (7.7 ml), 10% aqueous sodium hydroxide solution (7.7 ml) and water (23.1 ml). The reaction mixture is stirred at room temperature overnight, and filtered through a cerite pad. The filtrate is concentrated to give (2S)-2-amino-3-(3,4-dimethoxyphenyl)-1-propanol (10.8 g) as an brown oily product.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)C>C1COCC1.C(OCC)(=O)C>[CH3:21][N:19]([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:22])[CH2:2][C:1]#[N:3])=[CH:18][CH:17]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.9 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 14.3 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of 4-dimethylamino-benzoic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is diluted with ethyl acetate and then extracted with 10% NaOH(aq). The aqueous layer is acidified (pH 6-7) with a 1 M HCl(aq) solution affording a white precipitate. The precipitate is filtered and washed with water. The filtrate is then extracted ethyl acetate. The organic layer is concentrated in vacuo. The organic extraction yields very little of the expected 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile, however, the precipitate isolated from the acidification of the original aqueous layer is indeed the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile. Upon drying the precipitate in vacuo, the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile is isolated as a light brown solid in the amount of 3.295 gms. (68% yield).
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH:13]([F:15])[F:14])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:28]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[C:11]=2[O:12][CH:13]([F:14])[F:15])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]1)[CH3:29]
Reactant: CCOC(=O)c1cnc2c(OC(F)F)c(F)ccc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(OC(F)F)c(F)ccc2c1=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 33.4 %

Procedure:
In 96 ml of N,N-dimethylformamide was dissolved 3.0 g (0.01 mole) of ethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate obtained as described above, and 6.9 g (0.05 mole) of potassium carbonate and 12.5 g (0.08 mole) of ethyl iodide were added thereto. The mixture was stirred at 100° C. for 14 hours. After completion of the reaction, the solvent was removed under reduced pressure, and water was added to the residue. Crystals precipitated were collected by filtration and applied to silica gel column chromatography (the eluent used was a mixture of chloroform: methanol = 95 : 5) to obtain 1.1 g of ethyl 1-ethyl-7-fluoro-8-difluoromethoxy-1.4-dihydro-4-oxoquinoline-3-carboxylate as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37].CN1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC(=O)n1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21

Procedure:
6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50 mg, 0.108 mmol), isobutyl chloroformate (42 ml, 0.325 mmol), N-methylmorpholine (119 ml, 1.08 mmol), potassium carbonate (74.9 mg, 0.542 mmol), and DMF (4 mL) were warmed at 80° C. for 16 h. After cooling to 23 C, the reaction was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (142). Compound (104) was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (143) in the manner of example 6: Mass Spectrum (CI) 462 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]1[CH2:9][CH:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC(O)CN1S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a cold solution of 11.85 g (38 mmoles) 1-(4-toluenesulfonyl)-4-hydroxy-D-proline ethyl ester in 37 mL pyridine at 0° C. was added 8.0 g (41 mmoles) of 4-toluenesulfonyl chloride portionwise in 15 minutes. The cold solution was stirred one hour at 0° C. and then 48 h at room temperature. Water (100 mL) was added dropwise in the solution cooled at 0° C. which was stirred 30 minutes at 0° C. The precipitate was filtered and washed with cold water and ether to give 15.55 g of titled compound. MP 122° C. [α]20 =+26.36° (c=2, chloroform)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:37])[N:21]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:23](Br)[N:24]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+].ClCCl.O>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:37])[N:21]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:29]([O:31][CH3:32])=[O:30])[CH:22]=[CH:23][N:24]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Temperature: 75 °C

Procedure:
To Methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167b, 543 mg) in ethanol (15 mL) was added ammonium formate (855 mg) and 10% Pd/C (103 mg) and the reaction was heated at 75° C. for 1 h. The mixture was filtered through celite and the solids washed with ethanol. The filtrate was collected and the volatiles removed in vacuo to give a pale yellow solid. Dichloromethane and water were added and the organic layer separated. The aqueous layer was further extracted with dichloromethane and ethyl acetate. The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo to give the subtitle product an off white foam (331 mg).