Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[N:6]([CH3:22])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.9 %

Procedure:
A mixture of 4-chloro-1-(2,4-dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (0.30 g, 1.10 mmol), MeI (0.075 ml, 1.21 mmol), potassium carbonate (0.30 g, 2.2 mmol) and DMF (5 ml) was stirred at room temperature for 13 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 0.31 g (98%) of the title compound as crystals.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O=[C:13]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])(=O)C.[Na+]>Cl.O>[C:6]1([NH:5][N:1]=[C:13]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=O)C(=O)C(F)(F)F
Reactant: Nc1ccccc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=NNc1ccccc1)C(=O)C(F)(F)F

Procedure:
Sodium nitrite (2.57 g) was added portionwise to aniline (3.22 g) in concentrated HCl (6.5 ml) and water 10 ml) at 0° C. over 15 minutes. The resulting solution was added dropwise to ethyl 2,3-dioxo-4,4,4-trifluorobutanoate (6.31 g) and sodium acetate (6 g) in water (30 ml) at 0° C. to precipitate the product as a red solid which was filtered and dried in vacuo (7.15 g, 72%). The crude hydrazone was used without further purification.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1([CH3:31])[CH2:9][CH2:8][CH:7]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1([CH3:30])[CH3:29].[NH4+].[Cl-].[NH4+].[OH-].[CH2:36]1COCC1>>[C:25]([Si:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:11][CH2:10][CH:7]1[CH2:8][CH2:9][C:5]([CH3:31])([CH:4]([CH3:36])[CH:3]=[CH2:2])[C:6]1([CH3:30])[CH3:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: C1CCOC1
Reactant: CC1(C=CCBr)CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Product: C=CC(C)C1(C)CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Temperature: -55 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To Me2S.CuBr (dried twice by azeotropic distillation with toluene; 5.04 g, 24.02 mmol) in dry THF (40 mL ) at −78° C. was added dropwise CH3Li (1.4 M solution in Et2O; 34.30 mL, 48.04 mmol) over a period of 15 minutes. Stirring of the suspension at −50 to −60° C. for 30 minutes resulted in a color change to yellow, after which a solution of freshly fused ZnCl2 (98%; 3.49 g, 25.11 mmol) in dry THF (25 mL) was added dropwise at −50° C. to −60° C. over a period of 20 minutes. The reaction mixture was then stirred at −55° C. for 1 hour, the suspension is cooled to −78° C. and intermediate (7), (5.74 g, 11.49 mmol) in dry THF (10 mL) was added dropwise over a period of 30 minutes. The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm up to −40° C. over a period of 4 hours. After stirring at room temperature for 20 minutes, the mixture was poured into a saturated NH4Cl solution containing 10% of NH4OH (200 mL). The solution was stirred an additional 30 minutes then the aqueous layer was extracted with n-hexane/diethyl ether 95:5 (4×100 mL). The combined organic layers were dried over anhydrous MgSO4, the solvent removed under reduced pressure and the crude residue was purified over silica (n-hexane) to afford 3.96 g (79% yield) of the desired intermediate (8) as a colorless oil which was characterized as follows:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1c(C)n(C(C)C(=O)N2CCCC2)c2ccccc12
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)C(=O)N1CCCC1
Temperature: 70 °C
Reaction time: 10 h
Yield: 94.2 %

Procedure:
To a solution of sodium hydroxide solution (50 mg, 1.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1 H-indole-3-carboxylate (100 mg, 0.318 mmol). The reaction mixture was stirred at 70° C. for 10 hours. The mixture was quench with 10% hydrochloric acid aqueous (2 mL), extracted with dichloromethane and menthol (60 mL, 10:1). The combine organic layer was dried by anhydrous sodium sulfate, filtered and concentrated to give 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylic acid (90 mg, 92%). LCMS (M+H+) m/z: calcd 300.15. found 300.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[CH2:20][O:21][CH3:22])[N:12]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:23])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][C@H:16]4[CH2:20][O:21][CH3:22])[N:12]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: COC[C@@H]1CCCN1CCc1nc(-c2ccc(Br)cc2)oc1C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: COC[C@@H]1CCCN1CCc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)oc1C

Procedure:
Starting with 2-(4-Bromo-phenyl)-4-[2-(S)-(+)-(2-methoxymethyl-pyrrolidin-1-yl)-ethyl]-5-methyl-oxazole (See Example 27) and 4-methylsulfonylphenylboronic acid, follow a procedure significantly analogous to Example 22 to give the titled compound. MS (m/e): 455.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=[O:20])[CH:6]=1.[BH4-].[Na+].O.CCOC(C)=O>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][OH:20])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.4 %

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (4.8 g, 13.7 mmol) in MeOH (50 mL) was added sodium borohydride (0.78 g, 20.6 mmol), and the reaction was stirred at room temperature for 5 minutes. The mixture was worked-up with H2O and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[N:20]OCC)[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[S:9][CH:10]=1)[CH3:2].[H][H]>Cl.C(O)C.[Pd]>[ClH:17].[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH2:20])[C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][CH2:15][C:16]([Cl:17])([Cl:19])[Cl:18])=[O:13])[S:9][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Yield: 144.1 %

Procedure:
A solution of 10.45 g of α-ethoxyimino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester in a mixture of 10% hydrochloric acid and ethanol is catalytic-hydrogenated over 8.0 g of 5% palladium on charcoal at room temperature under atomospheric pressure. After the absorption of two equivalents of hydrogen, the catalyst in the reaction mixture is filtered off and the filtrate is concentrated to dryness under reduced pressure. By the procedure, 7.43 g of α-amino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]-acetic acid ethyl ester hydrochloric acid salt is obtained (yield, 72%). This product is suspended in ethyl acetate and the obtained suspension is washed with saturated sodium bicarbonate aq. solution, washed with water and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent, is dissolved in 60 ml of N,N-dimethylformamide and, to the solution is added 4.2 g of tetramethylguanidine and then 3.94 g of t-butyloxycarbonylazide, followed by the stirring for 15 hours at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and then saturated NaCl aq. solution and dried over anhydrous magnesium sulfate. The oily product obtained by the distillation of the solvent is purified by a column chromatography packed with silica gel. The procedure gives 4.06 g of α-t-butyloxycarbonylamino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester (yield, 46.5%). Melting point: 94°-95° C.
Reaction SMILES: C(C1C=C(C=CC=1O)N)(C)C.[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[N:34][NH:33][C:32]1[CH:31]=[CH:30][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:28][CH:27]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)c1cc(N)ccc1O
Agent: CC(C)c1cc2c(cc1O)C(=O)C(=O)N2
Agent: Cl
Product: CC(C)c1cc2c(cc1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-6-isopropyl-1H-indole-2,3-dione was prepared from 3-isopropyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ 1.12 (d, J=6.8 Hz, 6H), 3.21 (septet, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.82 (s, 1H), 9.51 (s, 1H), 10.61 (s, 1H); ESI-MS m/z 204 (M−H)−. The title compound was prepared from 5-hydroxy-6-isopropyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 1.12 (d, J=7.0 Hz, 6H), 3.21 (septet, J=6.8 Hz, 1H), 6.62(s, 1H), 6.97 (s, 1H), 7.21 (s, 2H), 7.45 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 9.11 (s, 1H), 10.70 (s, 1H), 12.74 (s, 1H); ESI-MS m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.37; H, 4.95; N, 14.84; S, 8.48.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH3:17].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 91.6 %

Procedure:
Ferulic acid (4.85 g) and then n-propyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux overnight. The disappearance of the starting material was confirmed by thin layer chromatography (TLC: n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the crude product. The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=2/1) to obtain the above-identified compound (5.48 g, 91.6%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C1CCC(N=C=NC2CCCCC2)CC1>C1C=CC=CC=1.Cl[Cu]>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of (+/-) ethyl 4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate (Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl (36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for 7 days. After cooling to room temperature, the solids were filtered out and the solution was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, the crude material was purified by flash chromatography (silicagel, 10% ethyl acetate in hexane) to afford the pure title compounds as red oils.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O.[CH:20]1([C:23](=O)[CH2:24][C:25](=[O:27])C)CC1>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[C:24]([CH:25]=[O:27])=[C:23]([CH3:20])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C=O)CCC3
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 60 mg (0.19 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone (the preparation of which is described in example 1) in 2 ml acetic acid was added 32 mg (0.25 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 24 mg (31%) cyclopropyl-[(4-(3,4-dichloro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>C1COCC1.C(Cl)Cl>[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:18]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Ic1cnccn1
Agent: CCCC[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1cnccn1)c1cccc(Br)c1F
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a stirring solution of 2-iodopyrazine (0.195 mL, 1.970 mmol) in THF (3.28 mL) at 0° C. was slowly added butyl magnesium chloride (0.985 mL, 1.970 mmol). The mixture was allowed to stir for 30 min, then 3-bromo-2-fluorobenzaldehyde (0.400 g, 1.970 mmol) was added. After 2 hr, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 30-70% EtOAc in hexanes over 19 min, tr=12 min) gave the title compound (347 mg, 1.226 mmol, 62.2% yield) as a yellow residue.
Reaction SMILES: C[N:2](C)[CH:3]=[O:4].S(Cl)([Cl:8])=O.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1C(O)=O.[OH-].[Na+]>[OH-].[NH4+]>[Cl:8][C:13]1[CH:14]=[CH:15][N:10]=[C:11]([C:3]([NH2:2])=[O:4])[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccn1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
5.0 ml (0.16 equivalent) of N,N-dimethylformamide are added dropwise at 40° C., with stirring, to 150 ml (2.06 mol) of thionyl chloride. Then, in the course of half an hour, 50 g (0.406 mol) of picolinic acid are added. The mixture is cautiously heated to 70° C. and stirred at that temperature for 24 hours, the gases formed being conveyed away through a wash bottle charged with sodium hydroxide solution. Concentration, and coevaporation a further three times with 50 ml of toluene each time, are carried out. 300 ml of diethyl ether are added to the acid chloride-hydrochloride so obtained. The mixture is cooled to 0° C. using an ice/water bath, and 250 ml of 25% ammonium hydroxide solution are cautiously added. The mixture is warmed to room temperature and stirred for 16 hours to complete the reaction. Filtration is carried out, and the filter residue is boiled in 400 ml of chloroform to remove secondary products and recrystallised from 350 ml of methanol. 4-Chloro-2-picolinic acid amide is obtained in the form of a yellowish solid, which is reacted without further purification. 31.3 g (0.2 mol) of the amide obtained in that manner are suspended in 490 ml of dichloromethane and cooled to 0° C. using an ice/water bath. After the addition of 46.5 ml of N,N-dimethylformamide, 36.7 ml of phosphorus oxychloride are added dropwise in the course of 20 minutes while maintaining the temperature, and stirring is carried out for a further 6 hours with cooling. 100 ml of water are then added and the mixture is rendered neutral with 4N sodium hydroxide solution and stirred overnight at room temperature. The organic solvent is removed using a rotary evaporator, and the aqueous phase is extracted three times using 250 ml of chloroform each time. After concentrating and drying the crude product under a high vacuum, sublimation is carried out at from 70 to 90° C. and 0.2 mbar, yielding 4-chloro-2-cyanopyridine in the form of a yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:22])=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)N3CCOCC3)cc2)=C(C)C1=O
Yield: 68.8 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol) and morpholine (0.010 ml, 0.12 mmol) were used, and a method similar to that described in Production Example 46 was employed to obtain the title compound (21 mg, 0.055 mmol, yield 69%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[OH-].[NH4+:19].O>C(COC)OC>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: [NH4+]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: COCCOC
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (prepared using the procedure as described in U.S. Pat. No. 6,737,421, EXAMPLE 2, part b) in dimethoxyethane (7.1 mL/g), was added thionyl chloride (1.33 equivalents). The mixture was stirred at 50° C. for 12 hours, cooled and slowly added to concentrated ammonium hydroxide (22 equivalents). The mixture was stirred at 50° C. for 2 hours, water was added, and the mixture was cooled and filtered. The solid was washed with water and isopropanol and dried to give the title compound (89% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[C:22]([O:24][CH3:25])=[O:23])[C:7]=2[CH:26]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34]/[CH:35]=[CH:36]/[C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[F:44].CO>C(O)C.ClCCl>[F:44][C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1/[CH:36]=[CH:35]/[CH2:34][N:19]1[CH2:20][CH2:21][C@H:16]([CH2:15][CH2:14][CH2:13][N:8]2[C:7]3[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]1
Reactant: Fc1ccc(F)c(/C=C/CCl)c1
Reactant: COC(=O)C1CNCCC1CCCN1C(=O)COc2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COC(=O)[C@@H]1CN(C/C=C/c2cc(F)ccc2F)CC[C@@H]1CCCN1C(=O)COc2ccc(OC)cc21
Temperature: 40 °C
Yield: 56.3 %

Procedure:
A solution of methyl 4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2 mL) was treated with K2CO3 (63 mg, 0.455 mmol) followed by a solution of 2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124) (86 mg, 0.455 mmol) in ethanol (1 mL). The reaction was warmed to 40° C. for 18 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with dichloromethane (2×20 mL). The organic extracts were combined, dried over MgSO4 and concentrated at reduced pressure to obtain a yellow oil. Chromatography on silica gel eluting with (0-2.5%) methanol in dichloromethane gave the title compound as a yellow oil (120 mg, 56%).