Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](N)[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:29]#[N:30].[Na+].[C:32](=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N:30]([CH3:29])[CH3:32])[CH:23]=3)[CH:18]=[CH:17][C:15]2=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1ccc2ccc(=O)n(C3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(1-benzyl-4-piperidinyl)-7-aminocarbostyril (0.7 g), methanol (10 ml) and 37 % formalin (1.4 ml) is added NaBH3CN (0.3 g) in portions. Thereafter, acetic acid (0.7 ml) is added thereto in portions at room temperature and the mixture is stirred at the same temperature for 1 hour. After completion of the reaction, water is added to the reaction mixture and the mixture is neutralized with an aqueous potassium carbonate and then extracted with ethyl acetate. The extract is concentrated by distilling off the solvent to give 1-(1-benzyl-4-piperidinyl)-7-dimethylaminocarbostyril (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)CCl.[NH2:26][C@@H:27]([CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:26][C@@H:27]([CH2:36][N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[C@H:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[OH:29])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CCCC(=O)N[C@@H](CN2CCOCC2)[C@@H](O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
Methylene chloride (10 ml), 4-(4-methoxyphenyl)butanoic acid (388.0 mg, 2.0 mmol), triethylamine (0.70 ml, 5.0 mmol) and EDC (580 mg, 3.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (472.0 mg, 2.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=20:1) to obtain the title compound (549 mg, yield 66%) as colorless oil.
Reaction SMILES: C(O)C.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[OH-].[Na+].ClCCl>C(O)(=O)C>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1ccc(N(c2ccc(F)c(Cl)c2)[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(C(=O)O)cc2)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To an ethanol solution containing 1.7 g of 3(S)-[(3-chloro-4-fluorophenyl)-(4-ethoxycarbonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3.7 mmol) was added 6 ml of a 5 N sodium hydroxide solution, followed by stirring at room temperature for 15 hours. Dichloromethane and acetic acid were added to the reaction solution to make the reaction solution acidic. After washing with water three times and with an aqueous saturated sodium hydrogencarbonate solution once, the solvent was distilled off under reduced pressure to thereby obtain 1.50 g of white powdery 3(S)-[(4-carboxyphenyl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1(C)C=CC=CC=1>[C:1]([S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[S:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: SCc1ccccc1
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: S=C(SCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of benzoic acid (1.22 g), benzyl mercaptan (1.24 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 10 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by column chromatography packed with.neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, benzyl dithiobenzoate (2.22 g, 91%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]([Cl:9])[C:6]=1[CH:7]=O.[C:11]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:13])[CH3:12]>C(#N)C.O.[Br-].[Li+]>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]([Cl:9])[C:6]=1/[CH:7]=[CH:12]/[C:11](=[O:13])[CH3:14]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Cl)sc(Cl)c1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: CC(=O)/C=C/c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a stirred solution of 2,4,5-trichloro-thiophene-3-carbaldehyde (10.3 g; 48 mmol) and lithium bromide (0.10 g; 1.2 mmol) in acetonitrile (100 mL) at 15° C. under nitrogen was added acetylmethylene-triphenylphosphorane (15.6 g; 49 mmol). The reaction mixture was stirred for 3 hours at ambient temperature then poured in water (200 ml) and extracted with dichloromethane (3×70 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel (eluant: cyclohexane/ethyl acetate 90:10) to afford 11.2 g (91% of theory) of (E)-4-(2,4,5-trichloro-thiophen-3-yl)-but-3-en-2-one as yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.N>C(O)C.ClCCl.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([CH:5]=[C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(N)cc2)CC1
Temperature: 85 °C
Yield: 70.1 %

Procedure:
tert-Butyl 4-(3-fluoro-4-nitrobenzylidene)piperidine-1-carboxylate (2.97 mmol, 1 g), iron(II) sulfate heptahydrate (20.42 mmol, 5.68 g) and ammonia (10.02 mmol, 11.39 ml) were combined in ethanol (20 mL) and heated at 85° C. overnight. The reaction mixture was diluted with dichloromethane and water then filtered through celite. The organic phase of the filtrate was dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 3% methanol/dichloromethane) to afford the intermediate tert-butyl 4-(4-aminobenzylidene)piperidine-1-carboxylate (600 mg).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:19][CH2:20][CH3:21])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:33][CH:13]([CH3:12])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH2:19][CH2:20][CH3:21])=[O:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(OC(=O)CC(C)C)OC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCCC(OC(=O)CC(C)C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (800 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl 3-methylbutanoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 37 (120 mg, 15% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.95 (m, 11H), 1.21-1.41 (br. m, 5H), 1.68-1.73 (m, 4H), 1.89-2.02 (m, 3H), 2.10-2.22 (m, 3H), 2.80-2.89 (m, 2H), 6.65 (t, J=5.6 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 12.04 (s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl.[Cl-].[Na+].O>[Br:31][CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CO)s1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(CBr)s1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 2-hydroxymethyl-5-nitro-thiophene (18.8 g, 118 mmol) in dichloromethane (500 ml) at 0° C. was added triphenylphosphine (3 1.5 g, 120 mmol) followed by carbon tetrabromide (39 g, 118 mmol). The mixture was stirred for 2 hours, poured into half saturated brine and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent removed at reduced pressure. The crude product was purified by silica gel chromatography using 15% ethyl acetate/hexane as the eluant to give 2-bromomethyl-5-nitrothiophene (19 g, 61%) as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]#[N:25])=[CH:16][CH:15]=2)[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:36]([O+](CC)CC)[CH3:37].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]#[N:25])=[CH:16][CH:15]=2)[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:26][CH2:36][CH3:37])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)c2ccccc12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCOc1nccc2c1C(c1ccc(C#N)c3ccccc13)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
93 mg (0.262 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-1-naphthonitrile are dissolved under an argon atmosphere in 5 ml of abs. dichloromethane, and 99.4 mg (0.268 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 60 mg (59.8% of theory) of the title compound are obtained.
Reaction SMILES: N(OC(C)(C)C)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:30])([F:29])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1N.O>FC(F)(F)C(O)=O>[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:29])([F:30])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1[N:8]=[N+:9]=[N-:10]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reaction time: 2 h

Procedure:
0.46 g (4.5 mmol) of tert-butyl nitrite and 0.3 g (4.5 mmol) of sodium azide were added to a solution of 1 g (3 mmol) of 2-chloro-5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-4-fluoroaniline in 20 ml of trifluoroacetic acid. The mixture was subsequently stirred for 2 hours and then admixed with 50 ml of water. The resulting product was extracted from the aqueous phase using 100 ml of methyl tert-butyl ether. The extract was washed with 10% strength aqueous sodium hydroxide solution, then dried over magnesium sulfate and finally concentrated. The crude product was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1:1). Yield: 0.7 g; 1H NMR (400 MHz; in (CD3)2SO): δ[ppm]=4.10 (s,3H), 7.53 (d,1H), 7.77 (d,1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:17][C:16]=2[F:35])=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH3:36]OC(OC)OC>CN(C)C=O>[C:1]([C:4]1[C:9]2[N:8]([CH:36]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[C:16]([F:35])=[CH:17][C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]2)=[CH:19][C:20]=1[F:21])(=[O:3])[NH2:2]
Reactant: COC(OC)OC
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: CN(C)C=O
Product: CSc1nc(Nc2c(F)cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12

Procedure:
A solution of the product of Example 16F (615 mg, 1.2 mmol) and trimethoxymethane (5 g, 46.9 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 1 hour and at 55° C. for 3 hours. The mixture was filtered to give the title compound. MS: 495 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:16]4[N:17]=[CH:18][N:19]=[C:15]4[C:14]([NH:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:13][CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.FC(F)(F)C(O)=O>ClCCl.O>[NH:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:14]2[C:15]3[N:16]([N:17]=[CH:18][N:19]=3)[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[C:2](=[O:1])[NH:3][CH2:4]4)=[CH:12][N:13]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc4c(c3)CNC4=O)n3ncnc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NCc2cc(-c3cnc(NC4CCNCC4)c4ncnn34)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 20.4 %

Procedure:
The product of Step 2 (64 mg, 0.14 mmol) is suspended in dichloromethane (0.5 mL), trifluoroacetic acid (0.25 mL) and H2O (3 drops). The reaction mixture is stirred and room temperature for 40 min. The mixture is purged with nitrogen and then basified to pH 9 with 2M NaOH (aq.). The aqueous layer is extracted with dichoromethane and ethyl acetate. The combined organics are dried (MgSO4) and solvent is removed in vacuo to yield the title compound as an off-white solid (10 mg, 20%). 1H-NMR (400 MHz, d6-DMSO) =1.13 (t, 2H, J=6.8), 1.57-1.70 (m, 2H), 2.58-2.72 (m, 2H), 3.02-3.08 (m, 2H), 4.13-4.30 (m, 1H), 4.50 (s, 2H), 7.81 (d, 1H, J=8), 7.92 (s, 1H), 8.03-8.11 (m, 2H), 8.18 (s, 1H), 8.63 (s, 1H), 8.69 (s, 1H). LCMS: Rt 6.55 min (86.9%), m/z (APCI) 350 (M+H)+.
Reaction SMILES: CO[C:3](=[O:31])[N:4]=[C:5](SC)[C:6](=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[C:7]1[CH:16]=[C:15]([O:17][CH3:18])[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[F:19].[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[NH:41][NH2:42])=[O:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[N:41]1[C:3](=[O:31])[NH:4][C:5]([CH:6]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[C:7]2[CH:16]=[C:15]([O:17][CH3:18])[C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[C:8]=2[F:19])=[N:42]1)=[O:35]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)OCCO2
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2 g of [2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 24 ml of DMF there were added 720 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 1.2 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[NH:15][N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:20]=[CH:21][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][CH2:29][OH:28])[CH:35]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[NH:15][N:16]=1
Reactant: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(-c4cnn(CCO)c4)cc2OCC3)n1

Procedure:
8-Bromo-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole under microwave conditions to give 254. MS (ESI+) 378.2
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[O:14]CC.C(Cl)(=O)C>CCCCCC>[CH2:11]([C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1)[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: CCc1ccc(N)c(C(=O)O)c1
Solvent: CC(=O)Cl
Solvent: CCCCCC
Product: CCc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 83.3 %

Procedure:
A mixture of 2-amino-5-ethylbenzoic acid (20.28 g) and ethyl chlorocarbonate (53.5 g) was stirred for 50 minutes at 100° C. and then cooled to 90° C. To the mixture was added dropwise acetyl chloride (13.81 g) in the course of 15 minutes and the reaction mixture was stirred for 2 hours at 100° C. After the resultant mixture was cooled to ambient temperature, to the mixture was added hexane and allowed to stand at ambient temperature to give crystals, which were separated by filtration, washed with hexane and dried under reduced pressure to give crystalline 6-ethyl-2H-3,1-benzoxazine-2,4(1H)-dione (19.55 g).
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[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.[O:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][NH2:52])[CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[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[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:33]([NH:52][CH2:51][CH2:50][N:47]2[CH2:48][CH2:49][O:44][CH2:45][CH2:46]2)=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: NCCN1CCOCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NCCN4CCOCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (68 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-morpholino-1-ethanamine (30 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 84%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][CH:9](OCC)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)C.CC1C=CC(COC(NNC(C2[CH:43]=[N:42][CH:41]=CN=2)=O)=O)=CC=1.[C:44](=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.CN(C)C=O>[CH4:6].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10](=[CH:41][N:42]([CH3:43])[CH3:44])[CH:9]=[O:8])=[CH:13][CH:14]=1
Reactant: CCOC(COc1ccc(OC)cc1)OCC
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C
Product: COc1ccc(OC(C=O)=CN(C)C)cc1
Temperature: 0 °C

Procedure:
Dry dimethylformamide (20 ml) was added dropwise to a stirred solution of phosphorus oxychloride (18 ml) maintained at a remperature of 0° C. The reaction mixture was allowed to warm to room temperature and p-methoxyphenoxyacetaldehyde diethyl acetal (16 g) was added with stirring. The mixture was cautiously heated with stirring to a temperature of 90° C. and then maintained at that temperature for 6 hr. The mixture was then cooled and poured slowly onto crushed ice (c. 1 kg) and the pH of the solution adjusted to pH10 by the addition, with stirring, of solid potassium carbonate. A benzene (95%)/alcohol (5%) solution (500 ml) was added to the reaction mixture and the total mixture heated just below its boiling point for 2 hr. The mixture was cooled, the organic layer was separated and dried, and the solvent removed by distillation under reduced pressure to give a black oil. The product crystallised from ethanol, after treatment with charcoal, to give 2-(p-methoxyphenoxy)-3-(dimethylamino)-acrolein (6.4 g) which was characterised by p.m.r. spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:16](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2ccccn2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
According to Scheme 1 Method B: 3-Methoxyaniline (1.62 mmol, 0.18 mL) was added to a solution of picolinic acid (1.62 mmol, 0.20 g), EDCI.HCl (2.44 mmol, 0.47 g), Et3N (3.25 mmol, 0.45 mL), hydroxybenzotriazole (1.95 mmol, 0.30 g) in DCM (6 mL) at room temperature. The reaction mixture was stirred at 50° C. for 12 hours. The organic phase was washed with a saturated solution of NaHCO3 and with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to afford N-(3-methoxyphenyl)picolinamide (1.46 mmol, 0.33 g, 90%) as an orange liquid.