Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>C1COCC1>[C:19]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]=[C:12]3[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])[CH:8]=[CH:7][C:6]=2[O:1][CH2:2][CH2:3]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(c2)NCCO3)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)N(C(=O)c2ccccc2)CCO3)S1
Yield: 35 %

Procedure:
5-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethylene)-thiazolidine-2,4-dione (example 96) (35 mg, 0.13 mmol) in 4 ml anhydrous THF were treated with benzoylchloride (156 uL, 10 eq.) in the presence of DIEA (2 eq.) for 3 h. Excess of benzoylchloride was hydrolysed, EtOAc was added and the organic phase was washed with NaHCO3 and brine. The crude was purified on silica gel using EtOAc/cyclohexane 3:7 as eluent affording 14 mg (35%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:6]1([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][C:18]([O:17][CH3:16])=[O:27])=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:10]=2[C:9](=[O:13])[CH2:8][CH2:7]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Using General Procedure F; 6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 13, 190.0 mg, 0.96 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 245.0 mg, 0.96 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (46 mg, 0.24 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (10-20% EtOAc-hexanes) afforded 250.0 mg (75%) of the title compound as a pale-yellow solid.
Reaction SMILES: C[O-:2].[Na+].C(O[C:7]([CH:9]1[C:15](=O)[CH2:14][CH2:13][N:12]([C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:10]1)=[O:8])C.Cl[CH2:28][C:29]([NH2:31])=[NH:30]>CO>[OH:2][CH2:28][C:29]1[N:31]=[C:7]([OH:8])[C:9]2[CH2:10][CH2:11][N:12]([C:17]3[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:14][C:15]=2[N:30]=1
Reactant: N=C(N)CCl
Reactant: CCOC(=O)C1CCN(c2ncccc2C(F)(F)F)CCC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(O)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 100 °C
Yield: 26 %

Procedure:
To solution of NaOMe (1.9 mL) in MeOH (0.5 mL) was added 5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethyl ester (Intermediate B; 285 mg, 0.96 mmol), followed by 2-chloro-acetamidine (149 mg, 1.16 mmol). After heating at 100° C. in a microwave for 15 min, the mixture was cooled and concentrated. The residue was dissolved in water and extracted with CH2Cl2. The combined organic layers were dried, concentrated, and directly purified using Preparative HPLC (conditions as in Example 54) to give the title compound (86 mg, 26%). MS (ESI): mass calcd. for C22H20F6N6O, 498.16; m/z found, 499.3 [M+H]+. 1H NMR (MeOD): 8.95 (d, J=2.3 Hz, 1H), 8.47-8.45 (m, 1H), 8.29 (dd, J=8.5, 2.2 Hz, 1H), 8.04 (dd, J=7.8, 1.7 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.16 (dd, J=7.7, 4.9 Hz, 1H), 4.61 (s, 2H), 3.68-3.61 (m, 4H), 3.53 (s, 3H), 3.49-3.45 (m, 2H), 3.30-3.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[N:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][NH:26][CH3:27]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:26]([CH3:27])[CH3:25])[CH:18]=3)[N:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC
Reactant: O=Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)nn2CCO)c1
Product: CN(C)Cc1cccc(-c2nc(-c3ccc(Cl)c(Cl)c3)nn2CCO)c1
Product: Cl

Procedure:
Using 3-[5-(3,4-dichloro-phenyl)-2-(2-hydroxy-ethyl)-2H-[1,2,4]triazol-3-yl]-benzaldehyde and dimethylamine the title compound was afforded as a crude product which was chromatographed over SiO2 (Merck 230-400 mesh) using CH2Cl2/(2M NH3 in MeOH) 95:5, before salt preparation. The pure titled compound was obtained as a off-white amorphous foam (67.7% yield) after evaporation of all solvents under reduced pressure followed by drying under high vacuum (0.05 mmHg) at 50° C. for 2 h, MS: m/e=391.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: N#Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C#N)c1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 1H-Imidazole-4-carbonitrile (300 mg, 3.22 mmol) and 4-Fluoro-3-methoxynitrobenzene (552 mg, 3.22 mmol) in DMF (Volume: 6446 μl) was added K2CO3 (891 mg, 6.45 mmol). The resulting mixture was brought to 120° C. and stirred overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (698 mg, 2.86 mmol, 89% yield). LC-MS (M+H)+=245.0. 1H NMR (500 MHz, MeOD) δ ppm 8.30-8.34 (1H), 8.19-8.23 (1H), 8.09-8.12 (1H), 8.00-8.05 (1H), 7.71-7.79 (1H), 4.02-4.10 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14](OCC)[O:15]CC)=[CH:8][C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:4]
Reactant: CCOC(OCC)c1cc(C(C)(C)C)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1sc(C=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 5-diethoxymethyl-3-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.84 g, 6.1 mmol) in dioxane (10 ml) was cooled to 0° C. (ice bath). 88% formic acid (20 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 2 h. The mixture was concentrated under reduced pressure to afford the desired product which was not further purified (1.57 g, 100% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:16]([O-:18])=[O:17])[C:7](OC)=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2].[NH3:19]>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([N+:16]([O-:18])=[O:17])[C:7]([NH2:19])=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2]
Reactant: COc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Reactant: N
Solvent: CS(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])c(N)c2c1CCCC2
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of 8-acetyl-1,2,3,4-tetrahydro-5-methoxy-6-nitronaphthalene (1.0 g, 4 mmol) in 15 ml of dry dimethylsulfoxide was heated to 100° C. and ammonia was passed into the solution for 3 h. After the solution was added to 100 ml of ice-water, the crude solid was filtered off and washed with water. Recrystallization from ethanol afforded 0.71 g (75%) of the pure title compound. M.p. 170°-172° C.; 1H-NMR (DMSO-d6): 1.47-1.93 (m, 4H, 2CH2), 2.27-2.63 (m, 2H, CH2), 2.48 (s, 3H, COCH3), 2.70-3.03 (m, 2H, CH2), 7.50 (broad s, 2H, NH2), 8.33 (s, 1H, H-7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH3:20].[OH:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.[CH3:30]N(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[N:13]=[C:12]([NH2:17])[N:11]=2)[C:7]([CH3:18])=[CH:6][C:5]=1[O:19][CH2:20][CH3:30]
Reactant: Oc1cccc(S)c1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(-c2cc(Cl)nc(N)n2)c(C)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C)c(-c2cc(Sc3cccc(O)c3)nc(N)n2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (96.5 mg, 0.3 mmol) obtained in Example 1-2 and 3-hydroxybenzenethiol (0.15 ml, 1.5 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (0.6 ml) and triethylamine (0.2 ml, 1.5 mmol) were added thereto. The solution was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), twice with a saturated aqueous sodium bicarbonate solution (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:1 to 1:2) to yield 5-[2-amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-ethoxy-4-methylbenzoic acid methyl ester (110 mg) as a white solid material.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.ClC1C=CC(C(O)=O)=NC=1SC.[CH3:26][S:27][C:28]1[CH:29]=[CH:30][C:31](C(O)=O)=[N:32][C:33]=1[S:34][CH3:35]>C1(C)C(C)=CC=CC=1>[CH3:35][S:34][C:33]1[C:28]([S:27][CH3:26])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: CSc1ccc(C(=O)O)nc1SC
Agent: CSc1nc(C(=O)O)ccc1Cl
Solvent: Cc1ccccc1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1cccnc1SC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A stirred solution of 250 ml of diphenyl oxide was heated to 200° C. A 54 g quantity of the 5-chloro-6-(methylthio)-2-pyridinecarboxylic acid/5,6-bis(methylthio)-2-pyridinecarboxylic acid mixture described above was added portionwise as a solid. The mixture was stirred for 1 hour with the temperature being maintained below 235° C. The mixture was cooled to 100° C., diluted with xylene and cooled to room temperature, then extracted three times with 75 ml of 6N HCl. The combined aqueous fractions were back-washed with diethyl ether, then stirred with CH2Cl2 and made strongly basic with 25% NaOH. The organic layer was separated, washed with water, then brine, and dried (Na2SO4). The solids were removed from the organic layer by filtration, then the filtrate was evaporated leaving a brown oil which was purified on a Kugelrohr distillation apparatus and 23.6 g of an oil obtained. The components of the oil were separated employing high pressure liquid chromatography (Porasil, 3% diethyl ether/hexane) and 19.42 g of 2,3-bis(methylthio)pyridine (b.p. 85° C. at 0.3 mm Hg) and 0.77 g of 3-chloro-2-(methylthio)pyridine (b.p. 80° C. at 0.3 mm Hg) obtained, both as colorless oils.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:28](C)C=O.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][C:16]3[C:21](=[C:20]([C:24](=[O:25])[NH2:28])[CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C(=O)O)c3C2=O)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccc(C(N)=O)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-piperidin-4-yl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid (3.7 g, 10.3 mmol) in N,N-dimethylformamide (60 mL) hydroxybenzotriazole ammonium salt (3.15 g, 20.7 mmol), 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (3.34 g, 20.7 mmol) and diisopropylethylamine (5.3 mL, 30.9 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with saturated sodium carbonate aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol 97:3) to afford the title compound (2.74 g, 74%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 84.6 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (1.12 g, 10 mmol) and (S)-2-methylpyrrolidine (1.03 g, 12 mmol) in water (1 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give (S)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (1.5 g, 83%) as a colorless oil. LC-MS: [M+H]+, 178.2, tR=1.066 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+:27]([O-])=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(=O)(=O)(O)O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[NH:11][C:12]3[C:13]([N:27]=2)=[CH:14][C:15]([CH:18]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(c1ccc(NC(=O)Cc2cccc(F)c2)c([N+](=O)[O-])c1)n1ccnc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)C(c1ccc2[nH]c(=O)c(-c3cccc(F)c3)nc2c1)n1ccnc1
Yield: 67.6 %

Procedure:
A solution of 14.5 parts of 3-fluoro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]benzeneacetamide in 49 parts of pyridine and 10 parts of a potassium hydroxide solution 20% was stirred for 1 hour at 85° C. The reaction mixture was poured into crushed ice and neutralized with a sulfuric acid solution 2N. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of dichloromethane, methanol and ammonium hydroxide (95:5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of dichloromethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.3 parts (67.6%) of 3-(3-fluorophenyl)-6[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone, N4 -oxide; mp. 212.9° C. (comp. 166).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)(=O)C.O>O1CCCC1>[CH2:18]([O:17][C:15]([N:14]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH:13][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH3:19]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)NN(C(=O)OCC)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A solution of 3,4-dimethoxyphenylmagnesium bromide (prepared from 10.85 g, 50 mmol of 3,4-dimethoxybromobenzene and 1.34 g, 55 mmol magnesium) in 200 ml tetrahydrofuran (hereinafter THF) was cooled to -75° C. and added to a solution of diethyl azodicarboxylate (8.71 g, 50 mmol) in 250 ml THF at -75° C. under an inert atmosphere. The solution was allowed to warm to 0° C. and acetic acid (3 g, 50 mmol) and H2O (20 ml) were added. The organic solution was dried over MgSO4, filtered and evaporated, providing N,N'-bis(ethoxycarbonyl)-3,4-dimethoxyphenylhydrazine as a red oil (15 g, 96% yield). This material was dissolved in isopropanol (500 ml) and 15 g potassium hydroxide was added. The mixture was refluxed under nitrogen for four hours, cooled, and neutralized with acetic acid (15 ml). The mixture was evaporated, the residue was treated with ether and aqueous sodium hydroxide, and the ether solution was dried over MgSO4, filtered and distilled in vacuo. Veratrole was distilled from the mixture, followed by 3,4-dimethoxyphenylhydrazine, which was crystallized from carbon tetrachloride to provide 1.0 g off-white powder, mp 103°-106° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]2[CH3:36])[C:20]=1[CH3:37]>CN(C)C=O>[ClH:25].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]2[CH3:36])[C:20]=1[CH3:37]
Reactant: Cc1ccccc1N
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Nc2ccccc2C)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 19.6 %

Procedure:
After o-toluidine(0.32 ml, 3.0 mmol) and triethylamine(0.63 ml, 4.5 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.96 g, 3 mmol) in dimethylformamide(5 ml), 250 mg of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1>>[C:4]1([C:1](=[N:11][O:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.16 ml of acetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with diisopropyl ether and the mixture was stirred. The precipitated powder was collected by filtration, to give 370 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O1CCCC1.O.O.[OH-].[Li+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>C(#N)C.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Brc1cccc(CN2CCOCC2)c1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a stirred solution of morpholine (0.5 g, 5.8 mmol) in acetonitrile (5 ml) was added K2CO3 (2.4 g, 17.44 mmol), followed by 3-bromobenzyl bromide (1.45 g, 5.8 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a white solid (700 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=8.3 Hz, 2H), 7.19-7.15 (m, 2H), 5.18 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.58 (t, J=4.4 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][CH:17]2[CH2:22][O:21][CH2:20][C:19]([CH3:24])([CH3:23])[O:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COCC(COS(C)(=O)=O)O1
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COCC(CNc2cccc(Br)n2)O1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
6-Bromopyridin-2-amine (722 mg, 4.17 mmol) was dissolved in 8 mL of anhydrous DMF and cooled to 0° C. NaH (60% in mineral oil, 195 mg, 4.87 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 45 min until bubbling ceased. The solution was cooled to 0° C. again and (6,6-dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (520 mg, 2.32 mmol) in 2 mL of DMF was added. After the addition was completed the solution was warmed to ambient temperature and stirred overnight. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on prep HPLC and the collected fractions were combined, concentrated, basified with Na2CO3 and extracted with EtOAc three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the product as a light yellow oil (270 mg, 39%). LC-MS (m/z): 301.0/303.0 (M+H), retention time=0.86 min.