Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].ClC1C=C(C=CC=1)CCl.CS(C)=O.[C:21](=O)([O-:23])[O-:22].[Na+].[Na+]>O>[CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[C:5]([OH:7])(=[O:6])/[CH:2]=[CH:4]/[C:21]([OH:23])=[O:22]
Reactant: O=C([O-])[O-]
Agent: CC(C)(N)C(=O)O
Agent: ClCc1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 500 mg. (5.0 mmole) of 2-methylalanine and 800 mg. (5.0 mmole) of m-chlorobenzyl chloride in 10 ml. of dimethylsulfoxide is stirred at 60° C. for 6 hours and then allowed to cool to 20°-25° C. over 12 hours. Water, 150 ml., is added followed by a saturated sodium carbonate solution until a basic pH of 8 is obtained. The product is extracted into 50 ml. of ethyl ether which is then washed with four 25 ml. portions of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (15-20 mm.) at 35°-40° C. The residue is converted into the hydrogen fumarate salt with 0.40 g. fumaric acid in 25 ml. 80% ethanol-20% ethyl acetate solution followed by precipitation with hexane. After filtering and drying, the m-chlorobenzyl ester of 2-methylalanine as the hydrogen fumarate salt containing one equivalent of fumaric acid as a co-precipitant, m.p. 144.0°-149.0° C., is obtained. Further recrystallization from the aforementioned ethanol-ethyl acetate-hexane system gives an analytical sample.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=3)[NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:17][C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:9]=[CH:10]3)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2c(c1)CN(CCN1CCCC1)N2
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (0.100 g, 0.434 mmol) and 4-phenoxyphenyl isocyanate (0.0917 g, 0.434 mmol) in 6 mL of THF was stirred at 50° C. for 1 hour, cooled to room temperature and concentrated under reduced pressure. The residue was triturated in diethyl ether and collected by filtration to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.63 (m, 4 H), 2.44 (m, J=6.44 Hz, 4 H), 2.86 (t, J=6.61 Hz, 2 H), 4.46 (t, J=6.78 Hz, 2 H), 6.97 (m, 4 H), 7.09 (m, 1 H), 7.35 (m, 3 H), 7.49 (m, 2 H), 7.59 (m, 1 H), 7.88 (m, 1 H), 7.96 (s, 1 H), 8.65 (m, 2 H); MS (ESI) m/z 442 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH2:28])[CH2:12][CH2:11]2)=[N:2]1.[CH3:29][C:30]([CH3:35])=[CH:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH:28][C:32](=[O:33])[CH:31]=[C:30]([CH3:35])[CH3:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: COc1cc(N)c(CCN2CCN(c3nsc4ccccc34)CC2)cc1OC
Reactant: CC(C)=CC(=O)Cl
Product: COc1cc(CCN2CCN(c3nsc4ccccc34)CC2)c(NC(=O)C=C(C)C)cc1OC
Yield: 68.2 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy phenylamine (300 mg, 0.75 mmol) and 3,3 dimethyl acryloyl chloride (87.7 μL, 0.79 mmol) and following the procedure as outlined in Example 1, 246 mg of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenyl}-amide was isolated as a white foam in 100% purity @ 254 nm; LCMS (APCI): 481 [M+H]+; mp 58° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cn2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Yield: 94.1 %

Procedure:
5.08 g of 4-[5-(4-(benzyloxycarbonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in 240 ml of ethanol in a Parr bottle. 2 g of 10% Pd/C (50% in water) are added. The reaction medium is stirred at 35° C. under 45 psi hydrogen for 3.5 h. It is filtered on a Whatman filter under an inert atmosphere and then the filter residue is washed many times with methanol. The methanol is evaporated under reduced pressure. 3.57 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:9]=2[S:8][C:7]1=[O:24].[OH:26]O>O1CCOCC1.O.CO.CN1C(=O)CCC1>[F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:26])=[CH:14][C:9]=2[S:8][C:7]1=[O:24]
Reactant: CC1(C)OB(c2ccc3c(c2)sc(=O)n3CC2CC2(F)F)OC1(C)C
Reactant: OO
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1sc2cc(O)ccc2n1CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[(2,2-difluorocyclopropyl)methyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2(3H)-one (18-1) (0.483 g, 1.32 mmol) in anhydrous 1,4-dioxane (5 mL) was added a 30% by weight solution of hydrogen peroxide in water (0.537 mL, 5.26 mmol. The reaction mixture was then stirred at room temperature for 0.5 hours. The crude reaction mixture was diluted with methanol and NMP, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 5% acetonitrile/0.1% trifluoroacetic acid/water→95% acetonitrile/0.1% trifluoroacetic acid/water) gave 3-[2,2-difluorocyclopropyl)methyl]-6-hydroxy-1,3-benzothiazol-2(3H)-one (18-2) as a tan solid. HRMS (M+H)+: observed=258.0396, calculated=258.0395.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:9]2[C:18]3[O:17][CH2:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc2c1OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1

Procedure:
A toluene solution (10 ml) of 5-bromo-2,3-dihydrobenzo[1,4]dioxin (10 mmol) was stirred under argon at 0° C. and was treated with the dropwise addition of n-butyllithium (10 mmol) over ten minutes. After stirring for a further twenty minutes a solution of 1-benzyl-4-piperidone in toluene (10 mmol in 10 ml) was added dropwise over five minutes. Stirring was continued for two hours, at which point water (100 ml) was added and the product extracted into ethyl acetate (4×50 ml). The combined organics were washed with water (2×50 ml), brine (75 ml) and dried (MgSO4). Filtration and concentration in vacuo gave an oil.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5](=[O:36])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.[OH-].[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5](=[O:36])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([OH:1])[CH:22]=[CH:23][C:24]=4[F:26])[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Temperature: 25 °C

Procedure:
Aqueous hydrogen peroxide solution (35%, 3.7 mL) is added dropwise to a solution of {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (5.0 g) in acetic acid (30 mL) chilled in an ice bath. The solution is stirred with cooling for 0.5 h and at room temperature for another 2 h. Ice-cold water (50 mL) and 2 N aqueous NaOH solution (20 mL) are added, and the mixture is stirred at room temperature overnight. The mixture is extracted with ethyl acetate, and the combined extracts are washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 2): tR=1.01 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)N(CCO)CCO)c1
Reaction time: 72 h
Yield: 30.7 %

Procedure:
A solution of diethanolamine (2.1 g, 20 mmol) in tetrahydrofuran (20 ml) was added slowly to a stirred solution of 3-nitrobenzenesulfonyl chloride (2.2 g, 10 mmol) in tetrahydrofuran (80 ml) at 20°-25°. After stirring at this temperature for 3 days, solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. After drying the ethyl acetate extract (Na2SO4), filtering and concentrating, the residue was recrystallized from ethyl acetate-hexane to give 0.89 g of the sulfonamide, m.p. 100°-102° C.
Reaction SMILES: C[O:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][NH:10][C:9]2=[S:13])=[CH:5][C:4]=1[F:17].B(Br)(Br)Br.[CH3:22]O>C(Cl)Cl>[OH:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH3:22])=[CH:5][C:4]=1[F:17]
Reactant: CO
Reactant: COc1c(F)cc(Cn2cc[nH]c2=S)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1nccn1Cc1cc(F)c(O)c(F)c1

Procedure:
A solution of 1-(4'-methoxy-3',5'-difluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione (0.0046 mol) in 40 ml methylene chloride is treated with a solution of BBr3 (0.014 mol) in 10 ml methylene chloride. After four hours methanol is cautiously added, the mixture is stirred for an additional eighteen hours and the solvents are evaporated. The residue is dissolved in water, washed with ethyl acetate, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extracts are dried (MgSO4) and filtered and the solvent evaporated to yield 1-(4'-hydroxy-3'5'-difluorobenzyl)-2-(methylthio)imidazole. This compound then is substituted for 1-(4'-hydroxy-3',5'-difluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione in the process of Example 1 to yield 1-(4'-acetoxy-3',5'-difluorobenzyl)-2-(methylthio)imidazole.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)=O.Cl>C(O)(=O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([NH2:5])=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=2)[CH:8]=1
Reactant: CSc1nccc(-c2cc(C)ccc2NC(=O)C(C)(C)C)n1
Agent: Cl
Solvent: CC(=O)O
Product: CSc1nccc(-c2cc(C)ccc2N)n1
Yield: 35.2 %

Procedure:
24 g 2,2-dimethyl-N-[4-methyl-2-[2-(methylthio)-4-pyrimidinyl]phenyl]propanamide was dissolved in 120 mL glacial acetic acid and the mixture warmed to reflux when 60 mL 15% hydrochloric acid solution was gradually added. After the addition was completed, the reaction mixture was heated at reflux for 4 h. After cooling, volatiles were removed in vacuo, the residue was taken up in 200 mL water and ice was added. The resulting mixture was neutralized to pH 10 with 5% sodium hydroxide solution and extracted with ether. Organic extracts were washed with brine, dried, evaporated to dryness and then dried in a vacuum oven to yield 6.2 g of the title compound as a tan solid melting at 120°-123° C. 1H NMR (CDCl3): δ 2.30 (s,3H), 2.60 (s,3H), 5.8 (s,2H,NH2), 6.60-8.6 (5H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[C:14]([C:21]2([CH3:26])[O:25][CH2:24][CH2:23][O:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19].[CH3:27]I>CN(C)C=O>[CH3:27][N:11]([C:12]1[CH:13]=[C:14]([C:21]2([CH3:26])[O:22][CH2:23][CH2:24][O:25]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[F:3]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Nc3ccc(F)cc3F)c2)OCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1F)c1cc(C2(C)OCCO2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium hydride (60%; 0.14 g) was added portionwise to an ice-cooled solution of 2-[3-(2,4-difluorophenylamino)-4-nitrophenyl]-2-methyl-1,3-dioxolane (1 g) in N,N-dimethylformamide. To the resulting mixture as added methyl iodide (1.7 g). The mixture was stirred at 0° C. for 30 minutes, poured into ice-water (50 ml) and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The oily residue was purified by column chromatography on silica gel (30 g) eluting with toluene to give an oil of 2-{3-[N-methyl-N-(2,4-difluorophenyl)amino]-4-nitrophenyl}-2-methyl-1,3-dioxolane (0.88 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 92.2 %

Procedure:
To a solution of 100 mg (0.32 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 150 mg (0.96 mmoles) of piperidin-4-one in 5 ml of DMF, 88 mg (0.64 mmoles) of K2CO3 is added at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with H2O and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 96 mg of disired 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S-:11].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (Aldrich) (2.000 g, 12.27 mmol) in THF (25 mL) was added sodium thiomethoxide (Aldrich) (0.903 g, 12.88 mmol). The reaction mixture was stirred at rt under N2 for 3 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 5% to 10% acetone in hexanes) to afford the product as white solid (1.3 g). MS (ESI pos. ion) m/z: 174.9. 1H NMR (300 MHz, CDCl3) δ ppm 2.57 (s, 3H) 2.65 (s, 3H) 7.02 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2)=[N+]=[N-].O.[OH-].[Na+]>O1CCCC1>[NH2:7][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2
Reactant: [N-]=[N+]=NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a suspension of lithium aluminum hydride (1.9 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise with stirring a solution of 6-(3-azidopropoxy)carbostyril (10 g) in anhydrous tetrahydrofuran (200 ml) under ice-cooling. The mixture is stirred at room temperature for one hour, and thereto are added dropwise water (2 ml), a 15% aqueous sodium hydroxide solution (2 ml) and water (6 ml). The insoluble materials are collected by filtration, and added to a mixture of chloroform-methanol (8: 1). The mixture is heated, and then cooled. The insoluble material are removed by filtration. The filtrate is concentrated under reduced pressure to remove the solvent, and thereto is added diethyl ether. The precipitated crystals are collected by filtration to give 6-(3-aminopropoxy)carbostyril (6.2 g) as a white powder.
Reaction SMILES: C(C([CH2:7][CH2:8][NH:9][C:10]1[CH:32]=[N:31][C:13]2[N:14](COCC[Si](C)(C)C)[C:15]3[CH:20]=[N:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=3[C:12]=2[CH:11]=1)=O)(C)(C)C.Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:8]([NH:9][C:10]1[CH:32]=[N:31][C:13]2[NH:14][C:15]3[CH:20]=[N:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=3[C:12]=2[CH:11]=1)[CH3:7]
Reactant: CC(C)(C)C(=O)CCNc1cnc2c(c1)c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNc1cnc2[nH]c3cnc(C#N)cc3c2c1
Temperature: 75 °C
Yield: 26.9 %

Procedure:
A solution of 3-(tert-butylcarbonyl)ethylamino-9-(2-trimethylsilanyl-ethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (161 mg, 0.345 mmol) in 1,4-dioxane (500 μL) was treated with 48% aqueous hydrobromic acid (500 μL) and heated at 75° C. for 10 min. The cooled reaction mixture was basified to pH 12 with 6N aqueous sodium hydroxide solution and then adjusted to pH 7-9 with dropwise addition of 1N hydrochloric acid. The solid was collected via centrifugation, the aqueous supernate discarded, and the solid dissolved in 1-2 mL of DMSO and purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as a yellow solid (22 mg, 26%). 1H NMR (DMSO-D6, 500 MHz): 8.89 (d, J=1.0 Hz, 1H), 8.78 (d, J=0.9 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.78 (d, J=2.7 Hz, 1H), 5.76 (t, J=5.5 Hz, 1H), 3.20-3.07 (m, 2H), 1.25 (t, J=7.1 Hz, 3H). LCMS (Method E): RT=2.69 min, M+H+=238.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].N#N.[H][H].[H][H]>[Ni]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N#N
Product: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a reactor was added 10 g of 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine, 1.4 g of Ra-Nickel (type A-5001 from Johnson Matthay) and 100 mL of Me-THF. The reactor was inerted by three nitrogen/hydrogen swings, then pressurized to 25 psig with hydrogen. The reaction mixture was stirred under 25 psig of hydrogen at 25° C. until the hydrogen uptake ceased (1.6 L consumed) and the reaction was judged complete by HPLC. BuOAc (50 mL) was added to the reaction mixture and MeTHF was distilled off under atmospheric pressure until <1% of Me-THF were detected by GC. Maintaining a batch temperature of 90° C., heptane (50 mL) was added over 20 min. The solution was then allowed to cool to room temperature over 8 hrs. The solids were filtered off and the cake was washed with 50 mL heptane. The solid was dried in a vacuum oven at 60° C. for 12 hr to afford 4-(4-Amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (8.88 g; 95% yield) as a light yellow crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:6]([C:15]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)[C@@H]1COCC(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a solution of (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (4.611 g, 19.60 mmol) in DCM (65 mL) was added benzylamine (2.6 mL, 23.80 mmol), N-methylmorpholine (11 mL, 100.0 mmol), 1-hydroxy-7-azabenzotriazole (3.20 g, 23.51 mmol), and EDC (4.51 g, 23.53 mmol). The solution was stirred overnight and then diluted with DCM (100 mL). The solution was washed with 6 N aq. HCl (2×100 mL), and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide crude (3S)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (6.454 g, >100% crude yield) as a pale yellow foam. LCMS: (M+H)+: 325.2.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.Cl.[F:9][CH2:10][CH2:11][NH2:12]>N1C=CC=CC=1>[F:9][CH2:10][CH2:11][N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: O=c1ccocc1
Reactant: NCCF
Agent: Cl
Solvent: c1ccncc1
Product: O=c1ccn(CCF)cc1
Yield: 88.6 %

Procedure:
500 mg (5.2 mmol) of 4H-pyran-4-on was dissolved in 5 ml of pyridine, 1.54 g (15.5 mmol) of 2-fluoroethylamine hydrochloride was added, and reacted at 70° C. for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chlroform-methanol (10:1)) to obtain 650 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccc(F)cc2F)cc1
Yield: 31 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (710 mg, 1.81 mmol, prepared in example 17) and 2,4-difluorophenylboronic acid (285 mg, 1.81 mmol) was accomplished in a manner analogous to that described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride. Further purification was achieved by reverse phase C18 chromatography to afford 213 mg (31%) of the title compound as a white solid.