Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].CCN(C(C)C)C(C)C.[CH3:38][C:39]([CH3:56])([CH3:55])[CH2:40][C:41]([O:43][C@@H:44]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:45](O)=[O:46])=[O:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:38][C:39]([CH3:56])([CH3:55])[CH2:40][C:41]([O:43][C@H:44]([C:45](=[O:46])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:13])[CH3:14])[CH:10]=[CH2:11])[CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:42]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CC(C)(C)CC(=O)O[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)OC(=O)CC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
90 mg (0.23 mmol) of (S)-α-amino-N- [(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 0.047 ml of Hunig base in 2ml of acetonitrile were treated dropwise at room temperature with a solution of 60.7 mg of (S)-α-[(3,3-dimethylbutyryl)oxy]hydrocinnamic acid and 101 mg of BOP in 5 ml of acetonitrile. The mixture was stirred at room temperature for 4 hours, subsequently poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The organic phase was washed with ammonium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. After elution with a 20:1 mixture of methylene chloride and methanol, there were obtained 50 mg (34%) of (S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl 5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl 3,3-dimethylbutyrate as a yellow oil. MS: 637 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O[CH2:24][C@@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl.[Cl:46][C:47]1[CH:48]=[C:49]([NH:54][C:55]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[O:56])[CH:50]=[CH:51][C:52]=1[Cl:53].C(N(CC)C(C)C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:46][C:47]1[CH:48]=[C:49]([NH:54][C:55]([N:57]2[CH2:62][CH2:61][N:60]([CH2:24][C@@H:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:26]3)[CH2:59][CH2:58]2)=[O:56])[CH:50]=[CH:51][C:52]=1[Cl:53]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
Dess-Martin periodinane (8.60 g) was added to tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate (4.00 g) in dry DCM at 0° C. The reaction was warmed to RT and stirred for a further 2 h. Aqueous sodium thiosulfate (10% w/v, 50 ml) was added and the DCM layer was removed then dried (MgSO4), filtered and evaporated to form the crude aldehyde. The residue was then dissolved in dry dichloromethane (100 ml) followed by addition of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (5.72 g), N, N-diisopropylethylamine (3.17 mL) and NaBH(OAc)3 (9.76 g) and the reaction was stirred under argon for 18 h. 1M NaOH (50 mL) was added followed by vigorous stirring and the dichloromethane layer was extracted. The organic layer was dried (MgSO4), filtered and evaporated. Purification by chromatography (EtOAc neat) afforded the title compound (2.10 g) as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([F:18])=[CH:5][C:4]=1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:34]#[N:35])=[N:24][N:25]2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:21][CH:20]=1)[CH3:2].[CH3:36][O-:37].[Na+]>CO>[CH3:36][O:37][C:34]([C:23]1[C:22]2[C:26](=[CH:27][C:19]([C:4]3[CH:5]=[C:6]([F:18])[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:15])[CH3:16])=[CH:8][C:3]=3[CH2:1][CH3:2])=[CH:20][CH:21]=2)[N:25]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[N:24]=1)=[NH:35]
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C#N)nn(C3CCCCO3)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carbonitrile (Preparation 6, 37.42 g, 75.6 mmol) in methanol (700 mL) was added sodium methoxide (12.21 g, 226.8 mmol) and the reaction mixture was then stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (1 L) and water (500 mL). The organic layer was washed with water (500 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a gum (37.26 g) in a 94% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16][OH:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.Cl.[CH3:19]O>>[CH3:19][O:17][CH2:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: OCc1cnn2c(-c3cccnc3)ccnc12
Reactant: CO
Agent: Cl
Product: COCc1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-methanol in 50 ml. of methanol is added anhydrous hydrochloric acid in 10 ml. of methanol. The mixture is heated on a steam bath for 3 hours and the solvent removed. The residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The dichloromethane solution is dried over magnesium sulfate, concentrated and diluted with hexane to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:6]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[S:3][C:2]([NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:6][N:5]=2)[CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1nnc(-c2cccnc2)s1
Product: CCOC(=O)C(=CNc1nnc(-c2cccnc2)s1)C(=O)OCC
Temperature: 120 °C
Reaction time: 9 h

Procedure:
2-amino-5-(3-pyridyl)-1,3,4-thiadiazole (10 g) was reacted with diethyl ethoxymethylene-malonate (18 g) under stirring at 120° C. for 9 hours. After cooling the reaction mixture was crystallized from CH2Cl2 -isopropyl ether to give diethyl N-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]-aminomethylene-malonate, m.p. 144°-145° C. (15.8 g) which was treated with polyphosphoric acid (6.6 g: 3.5 g of 99% H3PO4 and 3.1 g of P2O5) and POCl3 (27.8 g) under stirring at 120° C. for 40 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1.[CH3:35][NH2:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=2[CH:11]=[C:10]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:9]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccccc4C)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 232-235° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([C:11]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=O)[CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].C1N2CN3CN(C2)C[N:28]1C3.[Br-].[NH4+]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:11]2[N:5]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](=[O:4])[CH2:2][N:28]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:12]=2[CH:22]=1
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1N(CC(F)(F)F)C(=O)CBr
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Br-]
Agent: [NH4+]
Solvent: O
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(F)(F)F

Procedure:
Reflux 1.13 g. (0.0025 moles) of 2-[2-bromo-N-(2,2,2-trifluoroethyl)-acetamido]-5-chloro-2'-fluorobenzophenone, 1.4 g. (0.01 mole) of hexamethylenetetramine, and 0.98 g. (0.01 moles) of ammonium bromide together for 43/4 hours. Pour the reaction mixture into water and extract with dichloromethane. Dry the dichloromethane solution over anhydrous sodium sulfate, filter and evaporate. After recrystallization, the so-obtained 7-chloro-1,3-dihydro-1-(2,2,2-trifluoroethyl)-5-(2'fluorophenyl)-2H-1,4-benzodiazepin-2-one melts at 123°-125° C. Thin layer chromatography shows the product to be pure single spot material.
Reaction SMILES: BrC1CCCC=1C=O.C([O:11][C:12](=[O:34])/[CH:13]=[C:14](\[CH3:33])/[CH:15]=[CH:16][C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[CH:22]=[CH:23][C:24]1[C:29]([CH3:31])([CH3:30])[CH2:28][CH2:27][CH2:26][C:25]=1[CH3:32])C>>[CH3:33]/[C:14](/[CH:15]=[CH:16][C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[CH:22]=[CH:23][C:24]1[C:29]([CH3:31])([CH3:30])[CH2:28][CH2:27][CH2:26][C:25]=1[CH3:32])=[CH:13]\[C:12]([OH:34])=[O:11]
Reactant: CCOC(=O)/C=C(\C)C=CC1=C(C=CC2=C(C)CCCC2(C)C)CCC1
Agent: CC1=C(/C=C/C2=C(/C=C/C(C)=C/C(=O)O)CCC2)C(C)(C)CCC1
Agent: CCOC(=O)/C=C(C)/C=C/C1=C(/C=C/C2=C(C)CCCC2(C)C)CCC1
Agent: O=CC1=C(Br)CCC1
Product: CC1=C(C=CC2=C(C=C/C(C)=C/C(=O)O)CCC2)C(C)(C)CCC1

Procedure:
As in Example 4, 2-bromocyclopentene-1-carboxaldehyde was converted to (2E,4E)-3 Methyl-5-(2-((E)-2(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-1-cyclopenten-1-yl)-2,4-pentadienoic acid ethyl ester which on hydrolysis with base gave (2E,4E)-3-Methyl-5-(2-((E)-2 (2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-1-cyclopenten-1-yl)-2,4-pentadienoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(C)cc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
Into a 150-mL 3-necked round-bottom flask, was placed a solution of ethyl 2-(4-methylphenyl)quinazoline-4-carboxylate (2.64 g, 9.03 mmol, 1.00 equiv) in ethanol (50 mL). This was followed by the addition of sodium hydroxide (1.8 g, 45.00 mmol, 5.00 equiv, 20%) dropwise with stirring at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of water. Hydrogen chloride (5%) was employed to adjust the pH to 3-4. The solids were collected by filtration. This resulted in 2.30 g (96%) of 2-(4-methylphenyl)quinazoline-4-carboxylic acid as a light green solid. MS (ESI) m/z 265 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][N:15]3[C@@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[C:5]([F:18])=[C:4]([NH:19][NH2:20])[N:3]=1.[CH:21]1([CH2:26][C@H:27]([CH2:31][N:32]([CH:41]=[O:42])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][NH:20][C:28](=[O:29])[C@H:27]([CH2:26][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:31][N:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:41]=[O:42])[C:5]([F:18])=[C:6]([N:8]2[CH2:17][CH2:16][N:15]3[C@@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)[N:7]=1
Reactant: NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCN3CCOC[C@H]3C2)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of (9aR)-8-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (1.41 g, 4.66 mmol) in DMF (45 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (1.36 g, 4.45 mmol), N-methylmorpholine (2.45 mL, 22.3 mmol), 1-hydroxy-7-azabenzotriazole (0.730 g, 5.364 mmol), and EDC (1.02 g, 5.32 mmol). The solution was stirred overnight and was then diluted with Et2O (200 mL). The mixture was washed with water (2×100 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (100 mL). This Et2O layer was washed with a fresh portion of water (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DCM (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was azeotroped with MeOH (50 mL) to give [(2R)-3-(2-{2-chloro-5-fluoro-6-[(9aR)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (2.4027 g, 91% crude yield) as a red/orange oil. LCMS: (M+H)+: 590.2.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][S:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:14]([O:13][C:11]([N:7]1[C@H:6]([CH:4]=[O:5])[CH2:10][S:9][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CON(C)C(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.2 %

Procedure:
To a −78° C. solution in THF (6 mL) of N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid-N-methoxy-N-methyl amide (550 mg, 2.0 mmol) was added lithium aluminum hydride (1.0 M in THF, 3.0 mL, 3.0 mmol) and the reaction mixture was stirred for 2.5 hours. The reaction was quenched with 10% aqueous citric acid (30 mL) and warmed to ambient temperature. The mixture was warmed to ambient temperature and extracted with ether (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxaldehyde (440 mg) which was used without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2[C:15](=[O:17])[CH3:16])=[CH:8][C:7]=1Br)(=[O:5])=[O:4].C(N(CC)CC)C>CO.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2[C:15](=[O:17])[CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cc2c(cc1Br)C(C)(C)CN2C(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNS(=O)(=O)c1ccc2c(c1)N(C(C)=O)CC2(C)C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
1-Acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonic acid methylamide (270 mg, 0.75 mmol), Pd/C (10%, 79 mg) and triethylamine (209 μL, 1.5 mmol) were suspended in MeOH (10 mL). The reaction was stirred under a hydrogen atmosphere for 1 h, then the mixture was filtered through Celite and filtrate was evaporated in vacuo to give the title compound (160 mg) as a white solid. 1H NMR (CDCl3): 8.65 (1H, s), 7.62 (1H, d), 7.26 (1H, d), 4.52 (1H, s), 3.88 (2H, s), 2.70 (3H, d), 2.26 (3H, s), 1.40 (6H, s). MS: [M+H]+=283.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Al](C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:26]2[CH2:27][O:28][C:29](=[O:39])[N:30]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:25]=2[CH:24]=[C:23]([C:40](OC)=[O:41])[CH:22]=1.[Al]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:26]2[CH2:27][O:28][C:29](=[O:39])[N:30]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:25]=2[CH:24]=[C:23]([C:40]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:41])[CH:22]=1
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)OC2
Agent: C[Al](C)C
Agent: [Al]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)OC3)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a dry flask charged with anhydrous CH2Cl2 (1 mL) was added 1-isopropylpiperazine (0.057 mL, 0.434 mmol, 2 eq). The mixture was cooled to 0° C. under nitrogen. To this cooled mixture was added Al(CH3)3 (0.217 mL of a 2M toluene solution, 0.434 mmol, 2 eq). After 15 min, methyl 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-7-carboxylate (100 mg, 0.217 mmol, 1 eq) was dissolved in CH2Cl2 (1 mL) and added to the aluminum reagent at 0° C. under nitrogen. After 2 min the cooling bath was removed. Let stir at rt for 5d. The reaction was diluted with CH2Cl2, and washed with water. The aqueous layer was back extracted 2× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 2:1 hexanes/acetone giving 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(4-isopropylpiperazin-1-yl)carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one. Mass spectrum (ESI) 458.0 (M+1); 460 (M+3).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O>>[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: COc1cccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c1
Product: COc1cccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.40 (t, J=7.8 Hz, 1H), 7.24-7.31 (m, 2H), 7.06-7.11 (m, 1H), 6.82 (d, J=13.5 Hz, 2H), 5.23 (s, 2H), 3.84 (s, 3H), 2.87 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H16F5NO4S, 474.1 (M+H). found 474.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34](OCC)=[O:35])[C:16]1=[O:39].[CH2:40]([O:42][CH2:43][CH2:44][NH2:45])[CH3:41]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:23]=2)[C:18]([OH:33])=[C:17]([C:34]([NH:45][CH2:44][CH2:43][O:42][CH2:40][CH3:41])=[O:35])[C:16]1=[O:39]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)c3ccccc3C2=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine employing methods similar to those described in Example 370 and was obtained as a white solid: ES+ MS: 573 (M+H+).
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C(#N)C>[CH3:9][C:2]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[N:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccccn1
Reactant: COC(=O)C(=O)C(C)Br
Solvent: CC#N
Product: COC(=O)c1nc2ccccn2c1C
Yield: 30.7 %

Procedure:
Methyl 3-bromo-2-oxobutanoate (6.5 g, 34.3 mmol) was added to a stirred solution of 2-aminopyridine (4.0 g, 42.5 mmol) in acetonitrile (100 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The mixture was concentrated in vacuo and the residue was diluted with water and the pH was to 7.5 using sodium bicarbonate solution. The mixture was extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 8% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 25.1%) as a pale yellow solid. 1H NMR: 200 MHz, CDCl3: δ 7.95 (d, 1H), 7.7 (d, 1H), 7.25 (t, 1H), 6.8 (t, 1H), 4.0 (s, 3H), 2.8 (s, 3H). MS: [M+H]+: m/z=191.1.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38]>>[C:37]([CH2:39][C:40]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)=[O:41])#[N:38]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and cyanoacetic acid, (Aldrich, Cat. No. C88505), LCMS (M+H)+: m/z=551.2.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N.C([Li])CCC.C[O:24][B:25](OC)[O:26]C>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([B:25]([OH:26])[OH:24])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(C#Cc2ccccc2)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C#Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
In a flame-dried flask, 4-(phenylethynyl)-1-bromobenzene (15.0 g, 58.4 mmol) was dissolved in dry THF (225 mL). The solution was treated with 3 cycles of evacuation and refilling with N2, then chilled to −78° C. in a dry ice/acetone bath. To the stirred solution was added a solution of n-butyllithium in hexanes (1.6 M, 40 mL, 1.1 eq) by syringe over the course of 10 minutes. The resulting solution was stirred for an additional 30 minutes before trimethylborate (9.77 mL, 9.1 g, 1.5 eq) was added slowly over 15 minutes. After stirring for an additional 15 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature and stir for 16 h. At this time, 2 M HCl (aqueous) (375 mL) was added, and the biphasic system was stirred vigorously for 2 hours. Ethyl acetate was added, and the organic layer was separated, dried (MgSO4), filtered and evaporated. Methylene chloride (100 mL) was added to the solid residue, which was crushed and mixed into a paste, then filtered and washed with additional portions of methylene chloride to give 8.5 g of the title compound as a white powder.