Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30]C)=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH2:33]OC)=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].Cl>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([O:32][CH3:33])=[CH:26][CH:27]=[CH:28][C:29]=2[OH:30])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(O)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-methoxymethoxyphenyl)-L-phenylalanine ethyl ester (938 mg) in EtOH (25 mL) was added HCl (4 N in dioxane, 5 mL), and then the mixture was stirred under N2 for 4 h at room temperature. The mixture was diluted with AcOEt, washed with H2O and brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (silica gel; eluent: AcOEt/hexane 1:2) to afford N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-hydoxyphenyl)-L-phenylalanine ethyl ester (795 mg). ESMS m/Z 488 (MH+), 486 (M−H)−.
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=2[F:6])[N:18]=1
Reactant: N#CSCC(=O)c1cccc(F)c1F
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(-c2csc(Br)n2)c1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (40 ml) solution was added to a solution of 2-(2,3-difluorophenyl)-2-oxoethyl thiocyanate (5.67 g, 26.6 mmol) in acetic acid (40 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.74 g (91.8%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9](O)=[C:6]([O:7]C)[CH:5]=1)=[O:3].C([O-])([O-])=[O:14].[K+].[K+].C(Br)C1C=CC=CC=1>CC#N>[CH3:1][C:2]([C:4]1[CH:12]=[CH:11][CH:9]=[C:6]([OH:7])[C:5]=1[OH:14])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)=O)ccc1O
Agent: BrCc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of acetovanillone (33) (4.70 g, 28.3 mmol) in MeCN (60 mL) was added K2CO3 (8.05 g, 58.3 mmol) and KI (0.20 g, 1.2 mmol). The mixture was stirred under N2 atmosphere and benzyl bromide (34) (4.0 mL, 34 mmol) was added dropwise. The reaction mixture was reflux for 24 h and then cooled to 25° C., then resulting precipitate was filtered off. The filtrate was evaporated and purified by column chromatography (SiO2, n-hexane: CH2Cl2=1:2) to give 30. White solid; yield: 70.3%; mp 87-88° C.; 1H-NMR (CDCl3. 200 MHz): δ 2.51 (s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.86 (d, J=8.2 Hz, 1H), 7.21-7.55 (m, 7H); 13C-NMR (CDCl3, 50 MHz): δ 26.19, 56.05, 70.79, 110.53, 112.13, 123.07, 127.18, 128.10, 128.68, 130.72, 136.28, 149.49, 152.41, 196.80; Anal. calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.02; H, 6.25.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[CH3:15][O:16][CH2:17][CH2:18][CH2:19][N:3]1[CH:2]([CH3:1])[CH2:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[S:4]1(=[O:12])=[O:11]
Reactant: CC1Cc2ccsc2S(=O)(=O)N1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1C(C)Cc2ccsc2S1(=O)=O
Temperature: -20 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
The product from Step B (800 mg, 3.94 mmol) was dissolved in DMF (10 mL) and the solution was cooled to -20° C. Sodium hydride (236 mg of an oil dispersion, 5.91 mmol) was added followed by 3-methoxypropyl bromide (1.8 mL, 11.82 mmol) and this mixture was warmed to 0° C. and stirred for 4 hr. The reaction mixture was poured into ice/water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 10% methanol/methylene chloride) to give the desired product (890 mg, 82%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C=O.O1CCOCC1>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c[nH]c(-c2ccccc2)n1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c[nH]c(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
To a suspension of 1.88 g (0.01 mol) of 2-phenylimidazole-4-carboxylic acid in a mixture of 3 ml of ~37% formaldehyde and 3 ml of 1,4-dioxane is added 2.1 g (0.02 mol) of sodium carbonate, and the resultant mixture is heated at 60°-70° C. for 5 hours, with stirring. After completion of the reaction, 5 ml of water is added, and the mixture is allowed to stand for 2 hours, on cooling. The resultant solid is recovered by filtration and recrystallized from ethyl acetate and filtered to afford 2-phenyl-4-hydroxymethylimidazole as a solid, m.p.168°-170° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[N:5]=[C:4]([CH3:11])[CH:3]=1.O1CCCC1.[CH3:17][NH2:18]>>[OH:10][C:6]1[N:5]=[C:4]([CH3:11])[CH:3]=[C:2]([NH:18][CH3:17])[C:7]=1[C:8]#[N:9]
Reactant: Cc1cc(Cl)c(C#N)c(O)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(C)nc(O)c1C#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a pressure vessel were added 4-chloro-2-hydroxy-6-methylnicotinonitrile (337 mg, 2.0 mmol), methylamine tetrahydrofuran solution (2 mol/L, 15 mL), and magnetic stirrer. The pressure vessel was sealed, and it was stirred at 90° C. for 2 hours. After being cooled to room temperature, the vessel was opened, and the reaction solution was transferred to an eggplant-shaped bottle. The solvent and excess methylamine were removed by rotary evaporation. The residue was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 2-hydroxy-6-methyl-4-(methylamino)nicotinonitrile (200 mg, 61% yield) as a brown solid. 1H NMR (300 MHz, methanol-d4): δ 5.89 (s, 1H), 3.56 (d, J=10.8 Hz, 3H), 2.94 (s, 1H), 2.55 (s, 1H), 2.24 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[S:42]C=3CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:14]=[CH:13][S:42][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3sccc32)n1
Product: CCc1nc(NC2CCCc3sccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.10, 6.91, 5.32, 4.47, 2.83, 2.53, 2.10, 1.93, 1.27; (MS/CI) calcd for C16H20BrN3S+H 369.9, found 369.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.C([Sn](CCCC)(CCCC)[C:34]1[O:35][CH:36]=[CH:37][N:38]=1)CCC>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(-c3ncco3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 52.6 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 2-(tributylstannanyl)-1,3-oxazole (0.209 mL, 1.0 mmol) and Pd (PPh3)4 (57.8 mg, 0.05 mmol) in 1,4-dioxane (3 mL) was heated to reflux for 11 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with EtOH/hexane to yield the title compound (113 mg, 53% yield) as a yellow solid: mp 223-225° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 7.02 (1H, d, J=1.9 Hz), 7.16 (1H, t, J=8.3 Hz), 7.31-7.51 (6H, m), 7.77-7.83 (2H, m), 7.96 (1H, dd, J=11.5, 1.7 Hz), 8.34 (1H, s), 8.55 (1H, d, J=2.6 Hz). Anal. Calcd for C23H16FN5O3.0.1H2O: C, 64.06; H, 3.79; N, 16.24. Found: C, 63.92; H, 3.67; N, 16.23.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)(=[O:36])[CH2:34][CH3:35]
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][C:18](=[CH:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][C:18](=[CH:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc(C2CCC(=CC(=O)O)CC2)c(OCOC)c1
Solvent: CO
Product: O=C(O)C=C1CCC(c2ccc(O)cc2O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was loaded with (±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetic acid (25 mg, 74 μmol), acidic dowex resin (75 mg) and methanol (15 ml) then stirred at 60° C. for 3 hr. The reaction mixture was filtered through a celite plug, washing with methanol. The solvent was removed under reduced pressure to give a yellow oil (15 mg) which was purified by preparative TLC (ethyl acetate/petroleum ether, 3:1, v/v), furnishing the title compound (6.5 mg, 35%) as an oil. m/z(ES+) 339 (M+H+).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:10]2[CH3:22])=[CH:5][C:4]=1[S:24](=[O:27])(=[O:26])[NH2:25].C(OC(C)C)(C)C>C(O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11](=[N:14][C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:24](=[O:26])(=[O:27])[NH2:25]
Reactant: Cc1ccc(N=C2SCC(O)(c3ccc(Cl)c(S(N)(=O)=O)c3)N2C)cc1
Agent: Br
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: Cc1ccc(N=c2scc(-c3ccc(Cl)c(S(N)(=O)=O)c3)n2C)cc1
Temperature: 25 °C

Procedure:
0.02 mole (9.8 g) of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-(4-methylphenyl-imino)-thiazolidin-4-ol hydrobromide are boiled in 120 ml of ethanol for 2 hours under reflux. After cooling to room temperature, 200 ml of diisopropyl ether are added and the crystals are filtered off. Melting point 265° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:14]2[CH:15]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:40]5[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=5)[CH:3]=4)[N:8]([S:25]([C:28]4[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:9]=3)[CH:12]=[N:13]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccc(F)cc4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccc(F)cc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 29.41 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.129 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 17) (50 mg, 0.155 mmol) using sodium carbonate (41 mg, 0.387 mmol) and Pd(PPh3)2Cl2 (4 mg, 0.0064 mmol) in DME/water (10/1 ml). This afforded 25 mg (29.41% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent. MS: m/z=660.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+:11].[Cl-]>ClCCl>[C:1]1([CH2:7][C:8]([NH2:11])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=S)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of secondary amine I and TEA in anhydrous dichloromethane, are added dropwise a solution of phenylthioacetyl chloride (prepared from phenylthioacetic acid and thionyl chloride) in anhydrous dichloromethane at 0° C. The reaction mixture is warmed to room temperature, stirred for 2 hours, then sat'd NH4Cl solution and dichloromethane are added. The organic layer is washed with brine, dried over Na2SO4, and concentrated to afford α-phenylthioacetamide II, which is used for the next reaction without purification.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:14](=[O:15])[NH:13][CH3:12])[CH3:2]
Reactant: CN=C=O
Reactant: CCC1NCCc2[nH]cnc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC1c2nc[nH]c2CCN1C(=O)NC

Procedure:
A solution of 1.51 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 2.28 g of methyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. The solution is cooled and filtered. The solid collected is dissolved in 30 ml of methanol and treated with 7 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in ethyl acetate. 1.05 g of the title compound, m.p. 240°, are collected.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH:5]1([C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]3[CH2:19][O:18]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH:5]1([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C@H:17]3[O:18][C:2]([NH2:3])=[N:1][CH2:19]3)=[CH:20][CH:21]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N#CN
Reactant: c1cc(C2CCCCC2)ccc1OCC1CO1
Agent: [Na]
Solvent: CO
Product: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.64 g, 10 mmol) in methanol (10 mL) was added dropwise 2-(4-cyclohexyl-phenoxymethyl)-oxirane (2.32 g, 10 mmol) after which the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (50 mL) was added after which the resulting white precipitate was removed by filtration through celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give the title compound.
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7](=O)(=O)[N:6]1[CH3:18])=[O:4].[NH2:19][C:20]1[C:25](=[O:26])[C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[O:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:18][N:6]1[CH:5]([C:3]([NH:19][C:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH:21]=2)=[O:4])[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1coc2ccccc2c1=O
Solvent: Cc1ccccc1C
Product: CN1Sc2ccccc2C(=O)C1C(=O)Nc1coc2ccccc2c1=O
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A 500 ml round flask, which is connected to a distillation head and a condenser, is charged with 3.5 g (0.013 mole) of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide, 2.1 g (0.013 mole) of 3-amino-4-oxo-4H-1-benzopyrane and 100 ml of dry xylene. Then nitrogen gas is blown into the resulting suspension for 5 minutes. The reaction mixture is subsequently subjected to a slow distillation lasting 15 hours, in the course of which procedure complete solution is attained after heating for only 10 minutes. The solvent is replaced every 2 hours. The reaction mixture is then cooled to 50° C. The precipitate which has formed is collected by filtration, washed with ethanol and dried, yielding 2-methyl-3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxide in the form of brownish crystals with a melting point of 290° C. (with decomp.).
Reaction SMILES: ClC1C(Cl)=CC=CC=1[NH2:4].N1C=CC=CC=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 175.8 %

Procedure:
A solution of 2,3-dichloroaniline (162.0 g) in p-toluenesulfonyl chloride (190.7 g) is heated at 100° C. for one hour allowing the temperature to rise to 115° C. with the exotherm. The thick mixture is then cooled to 50° C. and pyridine (250 ml) is added carefully. The reaction mixture exotherms to 150° C. After stirring for one hour the mixture is cooled and poured into water (2.5 liter). The precipitated solid is collected and dried to yield 301 g of tosylamide, m.p. 112°-118° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C@@H:2]([C@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(C)=CC=CC=1>O>[CH2:11]([N:18]1[C:6](=[O:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1

Procedure:
L-Tartaric acid (30 g) and benzylamine (22 mL) were added to xylene (150 mL), and the mixture was heated under reflux at 150° C. for 3 hours while water was removed with Dean-Stark apparatus. After the reaction mixture was left to cool overnight, the resultant crystals were collected by filtration, and were washed with acetone. The thus-obtained crude product was recrystallized from ethanol, to thereby give the title compound (23.2 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].[Cl-].[Na+]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:27]=[O:28])[CH:11]=[CH:10]2
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-bromo-6-methoxynaphthalene (4.00 g, 16.87 mmol) in 100 mL of anhydrous THF under nitrogen atmosphere at -78° C. was added a 1.6M solution of n-butyllithium in hexane (10.6 mL, 16.96 mmol). The reaction mixture turned into a yellow suspension 5 minutes after the addition of butyllithium. The suspension was stirred at -78° C. for 1 hour and then warmed to -23° C. Anhydrous N,N-dimethylformamide (4.0 mL, 51.7 mmol) was added. The reaction mixture was stirred at -23° C. for 30 minutes. Saturated sodium chloride solution (50 mL) was added to quench the reaction. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with anhydrous magnesium sulphate, filtered, and concentrated under reduced pressure. The residue oil was chromatographed by 10% ethyl acetate in hexanes on silica gel to give 2.86 g (91%) of 6-methoxy-2-naphthaldehyde as a white solid. 1HNMR (300 MHz, CDCl3) δ10.10 (1H, s), 8.26 (1H, s), 7.95-7.78 (3H, m), 7.28-7.18 (2H, m), 3.97 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.[N:21]1[C:28](Cl)=[N:27][C:25](Cl)=[N:24][C:22]=1Cl.Cl>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][N:21]2[CH2:28][N:27]([NH:1][C:2]3[CH:20]=[CH:19][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])=[CH:4][CH:3]=3)[CH2:25][N:24]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])=[CH:19][CH:20]=3)[CH2:22]2)=[CH:20][CH:19]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCCCCCCCCCC)cc3)CN(Nc3ccc(C(=O)OCCCCCCCCCC)cc3)C2)cc1
Temperature: 90 °C

Procedure:
83 g of decyl p-aminobenzoate and 18.5 g of cyanuric chloride in 1,000 ml of xylene were heated at 140° C. for 8 hours. After the evolution of hydrogen chloride was complete, the reaction solution was cooled to 90° C., washed twice with saturated sodium bicarbonate solution and once with water, and then cooled to room temperature. The white crystals precipitated were filtered off under suction and dried.