Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][C:4]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCCC1(O)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 1-(2-hydroxyethyl)cyclohexanol (11.2 g) and pyridine (17 ml) in dichloromethane (100 ml) was added p-toluenesulphonyl chloride (19.5 g). The mixture was then stirred at room temperature under an atomosphere of nitrogen for 3 hours before being partitioned between ether (300 ml) and water. The organic layer was washed consecutively with 4N hydrochloric acid, water, 5% sodium hydrogen carbonate solution, and brine, and dried. Concentration in vacuo gave a residue which was purified by chromatography (500 g silica gel; 20% ethyl acetate in petroleum ether as eluant) to give 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol [E; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: [NH2-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([N:23]1[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[O:9]([CH:25]1[CH2:26][N:23]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 8.6 g (0.22 mole) of sodium amide in 100 mL of dry toluene was added 18.8 g (0.2 mole) of phenol in 50 mL of dry toluene. The mixture was stirred at 60° C. for 2 hr. and the reaction temperature raised to 80° C. A solution of 63.4 g (0.2 mole) of 1-benzhydryl-3-methanesulfonyloxyazetidine (J. Org. Chem. 37, 3954 (1972)) in 200 ml of dry toluene was added dropwise. After stirring 2 hr at 80° C. the mixture was cooled and water added. The toluene was extracted with dilute NaOH solution, dried (Na2SO4) and concentrated. About one-third of the residue was removed. The rest of the residue was crystallized twice from water-isopropyl alcohol. Yield 9.3 g (15%); m.p. 83°-85° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CC(O)(C)C.O>[C:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:10])([CH3:17])([CH3:16])[CH3:15]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of γ-aminobutyric acid (1 equivalent) in t-BuOH (4 ml/gram) and H2O (3 ml/gram) was added NaOH (1 equivalent), BOC2O (1 equivalent), and the mixture was stirred at room temperature for 24 hours. The solvent was thereafter evaporated and the residue was partitioned between hexane and water. The aqueous layer was acidified with KHSO41N to reach pH=2, and was thereafter extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was evaporated to give the desired product as a white solid (85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][OH:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:14][C:3]1[C:2]([Cl:1])=[C:12]([Cl:13])[C:6]2[S:7][C:8]([CH2:10][OH:11])=[CH:9][C:5]=2[CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: OCc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Yield: 107.9 %

Procedure:
A solution of 1.24 g of 6,7-dichloro-5-hydroxy-2-hydroxymethylbenzo[b]thiophene, 0.9 g of ethyl bromoacetate, 0.6 g of potassium carbonate, 25 ml of 2-butanone and 0.5 ml of dimethylformamide is stirred under reflux for 2 hrs. The aqueous layer is extracted twice with 50 ml portions of dichloromethane. The combined organic extracts, are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a clear oil which crystallizes on standing. Recrystallization of the crude product from acetone-hexane gives 1.8 g of ethyl[(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetate mp 117°-118.5°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1

Procedure:
Prepared analogously to Example Id by catalytic hydrogenation of 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raney nickel in ethyl acetate/methanol (1:1).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)C)n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate (2.47 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.36 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.72 g) was added to the reaction mixture and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 2-isopropyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow oil (1.59 g, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1([F:35])[CH2:34][O:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2([F:35])[CH2:34][O:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: FC1(CBr)COC1
Product: O=C1OC2(CCN(C(=O)c3cn(CC4(F)COC4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 3-bromomethyl-3-fluoro-oxetane (described in US2005215599) gave the title compound. ES-MS m/e (%): 487.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:16][C:17]([CH3:30])([CH3:29])[C:18]#[C:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([NH:16][C:17]([CH3:30])([CH3:29])[C:18]#[C:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)O
Reactant: CC(C)(N)C#CCO[Si](C)(C)C(C)(C)C
Product: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C

Procedure:
In a similar procedure to that described in Example 11 Stage 3, the product from Step 2 was reacted with 4-amino-1-tert-butyldimethylsilyloxy-4-methylpent-2-yne to give 2-(5,6-dichloro-3-pyridyloxy)-N-(1-tert-butyldimethylsilyloxy-4methylpent-2-yn-4-yl)butyramide as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 37.4 %

Procedure:
Using 5-bromosalicylic acid and 4-chloro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Methyl 7-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (238 mg, 0.878 mmol) and 2 N aqueous sodium hydroxide (1.50 mL, 3.0 mmol) were combined in methanol (5 mL) and heated to 50° C. for 90 minutes. The reaction solution was concentrated to remove the methanol. To the reaction residue was added ethyl acetate (5 mL). The resultant solution was acidified with 1N aqueous hydrochloric acid (1.5 mL) to give a final pH of 4. A precipitate formed which was filtered and dried under vacuum to give the title compound (226 mg, 100%) as a solid. 1H NMR (400 MHz, CD3OD) 3 ppm 7.89 (d, J=1.37 Hz, 1H) 7.65 (d, J=−1.37 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=O)[C:3]=12.O.[NH2:24][NH2:25]>C(O)C>[CH2:11]([N:10]1[N:9]=[CH:8][C:7]2[C:2]3[NH:25][N:24]=[C:17]4[C:16]5[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=5[CH2:14][CH2:13][C:4]([C:3]=34)=[N:5][C:6]1=2)[CH3:12]
Reactant: NN
Reactant: CCn1ncc2c(Cl)c3c(nc21)CCc1ccccc1C3=O
Solvent: O
Solvent: CCO
Product: CCn1ncc2c3[nH]nc4c3c(nc21)CCc1ccccc1-4
Yield: 97 %

Procedure:
A mixture of 11.0 g. of 4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin5(1H)one (0.035 mol.), 4.5 g. of hydrazine hydrate 98% (0.09 mol.) and 125 ml. of abs. ethanol is refluxed for 3 hours with stirring. Then the reaction solution is filtered while hot and allowed to crystallize in a refrigerator. The crystallized 2,5,7,8-tetrahydro-5-ethyl-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indacene which is filtered off, washed with alcohol and ether, melts at 229°-231°. Evaporation of the mother liquor to dryness and treatment with water yields a further crop of 1.9 g. of the product. Total yield 97%. Recrystallization from ethanol elevates the melting point to 230°-232°.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=[O:4].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=C2.Cl.[OH-].[Na+]>CN(C)C=O.O>[CH2:6]([O:5][C:3]([C:2]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([Br:14])[CH:16]=2)[NH:20][CH:19]=1)=[O:4])[CH3:7]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic anhydride (8.5 ml) was added to a solution of 5-bromoindole (10.0 g) in N,N-dimethylformamide (50 ml) at 0° C., and stirred at the same temperature for three hours. After completion of the reaction, water was added to the reaction solution and the precipitated crystalline was collected by filtration. Water (250 ml) and sodium hydroxide (50 g) were added to a solution of the resulting residue in ethanol (50 ml) and the mixture was stirred at 120° C. for eight hours. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated hydrochloric acid was added and the precipitated solid was collected by filtration. To a solution of the resulting residue in ethanol (250 ml), was added concentrated sulfuric acid (5.0 ml) and the mixture was stirred at 90° C. for three hours. Concentrated sulfuric acid (5.0 ml) was further added and stirred at the same temperature for four hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 4N aqueous solution of sodium hydroxide was added until the solution becomes pH 7. Ethanol was evaporated, the precipitated solid was collected and the resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-bromo-1H-indole-3-carboxylic acid ethyl ester (5.40 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:25])[C:18]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:19][C:13]=3[N:12]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.[K+].[Br-]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([F:25])[C:18]([N:20]4[CH:24]=[CH:23][N:22]=[CH:21]4)=[CH:19][C:13]=3[N:12]=2)=[O:34])[CH:4]=1
Reactant: COc1ccnc(CSc2nc3cc(-n4ccnc4)c(F)cc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(-n4ccnc4)c(F)cc3[nH]2)c1
Yield: 57.4 %

Procedure:
The title compound (0.32 g, 58%) was prepared by the above general procedure using 2-[[(4-methoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(imidazol-1-yl)-1H-benzimidazole (0.53 g, 1.5 mmol) (obtained in example 5), m-chloroperbenzoic acid (50%, 0.62 g, 1.8 mmol) and dichloromethane (20 mL). IR (KBr) 3500, 1048 cm-1 ; 1H NMR (CD3OD) δ 3.86 (s, 3H, OCH3), 4.72 (ABq,J=10.8 Hz, Δv=15.6 Hz, 2H, SOCH2), 6.94 (m, 2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.68 (d,J=10.8 Hz, 1H), 7.88 (d,J=7.6 Hz, 1H), 8.08 (s, 1H), 8.26 (d,J=5.6 Hz, 1H); Mass (m/z) 371 (M+.).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.Cl[C:38]([O:40][CH3:41])=[O:39]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: COC(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: COC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methyl chloroformate. LCMS (M+H)+: m/z=480.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([NH:16]C(=O)OC(C)(C)C)[C:10]1=[O:24]>Cl>[NH2:16][N:11]1[CH2:12][CH:13]([OH:15])[CH2:14][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:24]
Reactant: CC(C)(C)OC(=O)NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O
Agent: Cl
Product: NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O
Reaction time: 1 h

Procedure:
To tert-butyl (3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-ylcarbamate (1.67 g, 4.7 mmol) was added HCl (10 mL, 4 N in dioxane) and the reaction stirred for 1 hour. The reaction was then concentrated to dryness, redissolved in dichloromethane, washed with sodium hydrogen carbonate, dried with sodium sulfate and the solvent was evaporated in vacuo afford the title compound was obtained as a light yellow crystalline solid (1.11 g, 92%). MS ISP (m/e): 259.1 [(M+H)+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16](O)=[O:17])[N:13]=[N:12]1.C[N:25](C=O)C>C1COCC1>[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16]([NH2:25])=[O:17])[N:13]=[N:12]1
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
75.4 ml of Oxalyl chloride (919.8 mmol) were added at 25° C. to a stirred suspension of (2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (200.0 g, 836.2 mmol) in THF (500 ml) and DMF (0.5 ml). The stirring was maintained for 4 hr at 25° C. until the solid dissolved. Afterwards, 1000 ml of THF were added and reduced pressure (200-250 mbar) was applied leading to the distillation of 300 ml of THF and to the maintenance of the internal temperature at about 25-35° C. After that, the mixture was slightly cool to 25° C. and 160 g of ammonium chloride were added in portions followed by slow addition of 400 ml of an 8% NaHCO3 solution and 176 g of solid NaHCO3 (vigorous stirring was also needed to prevent frothing). The heterogeneous mixture was stirred for 2 hr, filtered and the solid re-suspended in 1 L water. The solid was filtered and dried (at 200 mbar/50° C.) yielding 130 g (65.3%) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, as a white solid in form R5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C=O)C.Cl.CN(C)CCCN=C=NCC>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCCC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask containing 4-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.92 mmol) was treated with N-hydroxysuccinimide (0.680 g, 5.90 mmol), treated with DMF (8 ml), cooled to 0° C., treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.226 g, 6.40 mmol), stirred at ambient temperature for 2 hours, diluted with Et2O (100 mL), washed with H2O (2×25 mL), dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.90-2.00 (m, 2H), 2.66 (t, J=7.54 Hz, 2H), 2.84 (s, 4H), 3.15-3.28 (m, 2H), 4.73 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)#[N:27]>>[NH2:19][C:13]1[O:14][CH2:15][C:16]([F:18])([F:17])[C@@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:32][CH:33]=[C:28]([CH:29]=4)[C:26]#[N:27])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)OCC2(F)F)c1
Yield: 16 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (16% yield) as a white solid. MS (ISP): m/z=433.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][C:10]#[N:11])[CH2:2][CH2:3][CH3:4].[H][H]>[Ni].CO>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][NH2:11])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOc1cccc(CC#N)c1
Agent: [Ni]
Solvent: CO
Product: CCCCOc1cccc(CCN)c1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
Raney nickel catalyst (approx 5 g) was added to a solution of 3-butyloxybenzyl cyanide (38.64 g, prepared according to example 1 D) in saturated ammoniacal methanol (700 cm3). The resulting mixture was heated at 70° C. in the presence of hydrogen (45 Atmospheres) for two hours and was then allowed to cool to room temperature overnight. The cooled mixture was filtered to remove the catalyst and was then evaporated down to give a green oil (42.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH3:24])[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:32]=1.[Li+].[OH-]>CCO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH3:24])[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[S:7][C:6]=2[CH:32]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(/C=C/C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.7 %

Procedure:
To a solution of crude (E)-ethyl 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (25 mg, 0.06 mmol) in EtOH (1.5 mL) at room temperature was added LiOH (2 N aq., 0.168 mL, 0.34 mmol), the reaction was allowed to stir at room temperature for 18 h after which time the reaction was quenched with 1 N HCl (4 mL) and concentrated in vacuo to remove EtOH. The resulting suspension was extracted with 5% MeOH/EtOAc (3×), dried, and concentrated in vacuo to give the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylic acid (4.98 mg, 0.01 mmol, 21% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.12 (s, 3H), 6.11 (d, 1H, J=15.66 Hz), 6.56 (d, 2H, J=8.59 Hz), 6.65 (d, 2H, J=9.09 Hz), 6.69 (dd, 1H, J=8.59, 2.02 Hz), 6.98 (d, 1H, J=8.59 Hz), 7.11 (d, 1H, J=2.02 Hz), 7.24 (d, 2H, J=9.09 Hz), 7.30 (d, 2H, J=9.09 Hz), 7.48 (d, 1H, J=16.17 Hz). HRMS (m/z, MH+): 418.1065.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:30]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 35.5 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid, 100 mg of 4-aminoisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 97 mg of the target compound.