Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]([NH:16]C(OC(C)(C)C)=O)([CH3:15])[C:10]2([CH2:12][CH2:11]2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C1(C)C=CC=CC=1>[NH2:16][C:13]1([CH3:15])[C:10]2([CH2:12][CH2:11]2)[C:9](=[O:24])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (43.63 g) was dissolved in toluene, and the solution was stirred under ice-cooling. 37% Concentrated hydrochloric acid (100 mL) was added dropwise thereto, followed by stirring. After 0.5 hours, water was added to the reaction mixture. The mixture was stirred and left to stand so as to separate the aqueous layer from the organic layer. Sodium hydroxide (54 g) was added to and dissolved in the separated aqueous layer so as to alkalify the layer. The aqueous layer was extracted several times with toluene repeatedly. All the toluene layers were combined and washed with saturated brine. The washed toluene layer was dried with sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, to thereby yield the title product (21.29 g, yield: 90.2%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH3:21][N:22]([CH3:31])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(#N)C>[CH3:31][N:22]([CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: CN(C)CCC1CCCCN1
Solvent: CC#N
Product: CN(C)CCC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-(dimethylamino)ethyl]piperidine to give colorless crystals, mp. 155°-157° C. (acetonitrile).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:34]3[CH2:39][CH2:38][N:37]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:8])[CH2:36][CH2:35]3)=[N:29][CH:30]=[C:31]([CH3:33])[CH:32]=2)[CH2:25][CH2:26]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 75.7 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (181 mg) described in Preparation Example 28 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine (109 mg) described in Preparation Example 86 and by the reaction and treatment in the same manner as in Example 109, the title compound (202 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=1>>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:19][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:20])[CH:30]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: OCc1cccnc1
Product: O=C(OCc1cccnc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 3-pyridinemethanol. A colorless powder (100 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:50][CH3:51]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19]([CH2:50][CH3:51])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a 85 ml anhydrous THF solution of ethyl 7-(3-benzyloxypropoxy)-chromane-2-carboxylate (5.0 g, 13.5 mmol) and hexamethylphosphoramide (3.1 ml, 17.8 mmol) was added sodium bis(trimethylsilyl) amide 1.0M/THF solution (16.2 ml, 16.2 mmol) was added upon cooling in a dry ice-acetone bath. After stirring for 30 min at that temperature, to it was added iodoethane (3.3 ml, 41.3 mmol). The cooling bath was removed allowing the reaction mixture to warm to rt overnight. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and sat. NH4Claq. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% methyl-tert-butyl ether/hexanes to give the title compound as a clear oil 3.76 g (70%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:10][CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1C=CC=CC=1>[Cl:23][CH2:24][C:25]([N:10]([CH:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:4]1[CH:5]([CH3:9])[CH2:6][CH2:7][CH2:8][C:3]=1[CH2:1][CH3:2])=[O:26]
Reactant: CCC1CCCC(C)C1=NC(C)COC
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1=C(N(C(=O)CCl)C(C)COC)C(C)CCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
174 g (0.83 mole) of 2-ethyl-6-methyl-N-(1-methyl-2-methoxyethyl)-cyclohexylideneamine and 101 g (1 mole) of triethylamine were added dropwise one after the other with stirring and at a temperature of 5° C. to a solution of 94 g (0.83 mole) of chloroacetyl chloride in 3000 ml of benzene. The reaction mixture was then refluxed for 5 hours, cooled to room temperature, washed with water, dried with sodium sulfate, filtered and concentrated under water-jet vacuum. Distillation of the residue under high vacuum gave 150,5 g of a 2-chloro-N-(1-methyl-2-methoxy-ethyl)-N-(2-ethyl-6-methyl-cyclohexenyl)acetamide as a mixture of its isomers b.p. 140°-148°/0.1 Torr.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:41])=[C:11]([O:42][CH2:43][CH3:44])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:43]([O:42][C:11]1[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:35])([CH3:36])[CH2:33][OH:34])=[C:27]([C:37]([F:39])([F:40])[F:38])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:41])=[CH:13][NH:14][C:9](=[O:8])[CH:10]=1)[CH3:44]
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)cc1F
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(CC(C)(C)CO)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 6.88 mmol) in MeOH (50 mL) was added Pd/C (10%, 420 mg). The mixture was stirred under H2 at 25° C. for 16 h. Then the reaction residue was filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)-N-(4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (2000.18 mg, 3.84 mmol, 61% yield). TLC (DCM/MeOH=10:1, Rf=0.6): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.77-7.68 (m, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.37-7.29 (m, 1H), 7.27-7.17 (m, 2H), 6.36 (s., 1H), 4.25-4.15 (m, 2H), 3.75 (s, 2H), 2.76 (s, 2H), 1.33 (t, J=6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[C:9]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:10]2[C:9]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[CH:8][C:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)O)cc1
Yield: 88 %

Procedure:
A mixture of 0.965 g (1.72 mmol) of the product of Example 74 and 8.6 mL (8.59 mmol) of 1N NaOH in 8.6 mL of THF and 8.6 mL of methanol was heated to reflux for 18 h. The reaction mixture was cooled and neutralized with 3N HCl. The organic solvents were removed and the resulting aqueous solution was extracted with dichloromethane. The organic layer was separated, washed with water and brine, dried over Na2CO3 and concentrated in vacuo. The residue was triturated with ether to provide 0.829 g (89%) of the desired product as a cream solid. Electrospray Mass Spec 548.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Cl)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)[O-]
Reactant: ClCc1cc(Br)cnc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Cc1cc(Br)cnc1Cl
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A mixture of 5-bromo-2-chloro-3-(chloromethyl)pyridine (124 mg, 0.52 mmol) and sodium methanesulfinate (52 mg, 0.52 mmol) in dioxane (1.4 mL) and water (1.4 mL) was heated to 110° C. in a microwave reactor for 15 min. After cooling to rt, water was added to the reaction mixture which was subsequently extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-bromo-2-chloro-3-(methylsulfonylmethyl)pyridine (140 mg, 0.49 mmol, 94% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.21 (d, 1H), 4.70 (s, 2H), 3.10 (s, 3H); MS (EI) for C7H7BrClNO2S: 284, 286, 288 (Br+Cl isotopes, MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])=O)[CH:2]=1.O.NN.[OH-].[K+]>C(O)CO>[Br:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][C:9]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:13]([CH3:14])[C:12]=2[CH:15]=1
Reactant: Cc1c(C(=O)c2cccnc2)oc2ccc(Br)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c(Cc2cccnc2)oc2ccc(Br)cc12
Temperature: 120 °C
Yield: 78.4 %

Procedure:
A mixture of 5-bromo-3-methylbenzofuran-2-yl pyrid-3-yl ketone free base (2.67 g) and hydrazine hydrate (1.80 g) in ethylene glycol (30 ml) was heated at 120° C. for 2.5 hours. The mixture was cooled, potassium hydroxide (1.80 g) was added and the temperature was raised to 120° again and maintained at this temperature for 1 hour. Dilution with water and ether extraction gave an oil which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallised from petrol (b.p. 80°-100°) to give 5-bromo-3-methyl-2-(3-pyridylmethyl)benzofuran (2.00 g), m.p. 57°-58°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][N:13]3[C:12](=[O:19])[S:11]2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[N:22]([CH3:28])[C:21]1=[O:29].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[CH:37]=[CH2:38].O>CC(C)=O>[CH2:36]([N:24]1[C:23](=[O:27])[N:22]([CH3:28])[C:21](=[O:29])[N:20]([C:3]2[CH:4]=[C:5]([N:9]=[C:10]3[N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][N:13]4[C:12](=[O:19])[S:11]3)[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:25]1=[O:26])[CH:37]=[CH2:38]
Reactant: C=CCBr
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCn1c(=O)n(C)c(=O)n(-c2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)c1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 1-{2-chloro-4-fluoro-5-[(tetrahydro-3-oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a]pyridazin-1-ylidene)-amino]phenyl}-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (1.00 g, 2.27 mmol), potassium carbonate (0.627 g, 4.54 mmol) and allyl bromide (0.329 g, 2.72 mmol) in acetone is stirred overnight at 40° C. and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a white glass (0.8 g) which is identified by NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[NH:18][CH2:17][CH2:16]2.C(=O)([O-])O.[Na+]>CS(C)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1OC)NCC2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cc1)CC2
Yield: 65.6 %

Procedure:
6.3 g of 4-nitrofluorobenzene (0.045 mol) were stirred with 8.0 g of 5,6-dimethoxyindoline (0.045 mol) and 4.2 g of sodium hydrogen carbonate (0.050 mol) for 2.5 h at 80° C. in 50 ml of DMSO. After cooling, the mixture was poured onto ice, the precipitate was removed by filtration under suction and the product was dried in vacuo at 45° C. The intermediate product 5,6-dimethoxy-1-(4-nitrophenyl)-indoline was obtained in a yield of 65.6% (melting point: 176-179° C.).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:15]/[OH:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7](/[C:9](=[N:15]/[O:16][C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(N)n1

Procedure:
Sodium hydride (60% dispersion in mineral oil, 13.2 g, 0.33 mol) was added portionwise to a cold (0° C.) mixture of ethyl (Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (64.5 g, 0.3 mol) in dry THF (1 L) with vigorous stirring and the mixture was stirred for 0.5 hr. at room temperature. To the mixture was added a solution of trityl chloride (92.0 g, 0.33 mol) in dry THF (0.2 L) with cooling and stirring. The mixture was stirred for 2 hr. at ambient temperature and evaporated under reduced pressure. Chloroform (1 L) was added to the residue and the mixture was washed with water. The insoluble material was filtered and the organic layer of the filtrate was separated. The insoluble material was extracted again with a mixture of chloroform (300 ml) and methanol (50 ml) by sonication for 10 min. and subsequent filtration. The extract was combined with the separated organic layer and evaporated under reduced pressure. The residue was triturated with toluene (0.3 L) to crystallize the product as colorless prisms, which were collected by filtration, washed with a small toluene and dried in vacuo. Yield, 91.2 g (66%). The filtrate was evaporated and treated with toluene to give 19.2 g of the second crop.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1.[CH3:20][C:21]1[CH:30]=[C:29]([NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[H-].[Na+]>>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[S:11][C:10]4[N:12]=[CH:13][CH:14]=[N:15][C:9]=4[N:8]([CH2:16][O:17][CH3:18])[C:7]=3[CH:19]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: [H-]
Agent: [Na+]
Product: COCN1c2cc(CNc3cc(C)nc4ccccc34)ccc2Sc2nccnc21
Yield: 95.1 %

Procedure:
Similar to Example 1094, 307 mg of 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was treated with 354 mg of 2-methyl-4-aminoquinoline in the presence of 91 mg of sodium hydride (60% oily) to thereby give 413 mg of 8-[(2-methylquinolin-4-yl)aminomethyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine as a yellow oily substance. Then this product was deblocked by the same method as the one of Example 9 to thereby give 114 mg of the title compound as, yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=[CH2:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[CH:11]=[CH2:12]
Reactant: C=Cc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: C=Cc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2

Procedure:
6-Chloro-5-vinylindoline (D62) (0.13 g, crude) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (22 mg) as a yellow crystalline solid m.p. 195°-200° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15](OC(C)=O)=[O:16]>OP(O)(O)=O>[C:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13])(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=P(O)(O)O
Product: COc1cc(CC(=O)O)ccc1OC(C)=O

Procedure:
A mixture of (4-hydroxy-3-methoxyphenyl)acetic acid (380 mg, 2.088 mmol) and H3PO4 (2 drops) in about 20 mL of Hac/Ac2O (v/v=1:1) was refluxed overnight, and then concentrated to dryness in vacuo. The residue was diluted with water (50 mL), and the result mixture was extracted with ethyl acetate (2*50 mL). The combined organic phase was washed with brine (100 mL) and dried over Na2SO4 and concentrated to give [4-(acetyloxy)-3-methoxyphenyl]acetic acid. 1H-NMR (400 MHz, CDCl3) δ ppm 6.97 (d, J=7.8 Hz, 1H), 6.84˜6.89 (m, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH2:7]([N:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])[CH3:8]>>[CH2:7]([N:9]([CH2:13][CH3:14])[C:10]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:11])[CH3:8]
Reactant: OC1CCNC1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)N1CCC(O)C1

Procedure:
A method of preparing each of the foregoing compounds is presented in the following examples. In general, however, in the 1-methyl pyrrolidine series (compounds I and II) cyclization of 1,4-dibromo-2-butanol to yield 1-methyl-3-pyrrolidinol was followed by chlorination to give 3-chloro-1-methyl pyrrolidine. Substitution with benzylamine provided the nitrogen substituent 3-(N-benzyl)amino-1-methyl pyrrolidine which was acylated with diethylcarbamyl chloride and debenzylated to yield compound I. Methylation of 3-(N-benzyl)amino-1-methyl pyrrolidine gave compound 3-(N-benzyl-N-methyl)-amino-1-methyl pyrrolidine which was debenzylated to 1-methyl-3-(N-methyl)amino pyrrolidine and acylated with ethyl chloroformate to give compound II. Synthesis of the 1-acylated pyrrolidine compounds III and IV commenced by treated commercially available 3-pyrrolidinol with diethylcarbamyl chloride to yield 1-diethylcarbamyl-3-hydroxy pyrrolidine. The 3-benzylamino analog 3-(N-benzyl)amino-1-diethylcarbamyl pyrrolidine was obtained by treatment of 1-diethylcarbamyl-3-hydroxy pyrrolidine with thionyl chloride followed by benzylamine. Subsequent methylation yielded the compound 3-(N-benzyl-N-methyl)amino-1-diethylcarbamyl pyrrolidine which, on debenzylation gave the compound III. Subsequent methylation of III yielded the compound IV.
Reaction SMILES: [CH2:1]([N:13]1[C:17]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[N:16][N:15]=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+]>>[CH2:1]([N:13]1[C:17]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:16][N:15]=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnnc1CCC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCn1nnnc1CCC(=O)O

Procedure:
In a manner similar to Example 34, methyl 1-dodecyl-1H-tetrazole-5-propanoate was saponified with KOH to give 1-dodecyl-1H-tetrazole-5-propanoic acid. The acid was condensed with 2,4,6-trimethoxyaniline to give the title compound, mp 57°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(N)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.1 %

Procedure:
{4-[(6,7-Dimethoxy-4-quinolinyl)oxy]phenyl}-(4-nitrophenyl)carboxamide (100 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (9 ml/5 ml), 10% palladium-carbon (69 mg) was added, and the admixture was stirred at room temperature under hydrogen for 22 hours. The reaction mixture was filtered using Celite. The filtrate was then distilled under reduced pressure to remove the solvents, and the resultant residue was purified by column chromatography on silica gel eluting chloroform/acetone to obtain 85 mg of the title compound (yield: 91%).