Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:19])[CH:6]([C:17]#[N:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])C.C([OH:23])C.O>CS(O)(=O)=O>[OH:19][C:5]1[C:4](=[O:3])[NH:18][C:17](=[O:23])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Reactant: CCO
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCCCCCCC1=C(O)C(=O)NC1=O
Reaction time: 8 h

Procedure:
1 G. of the 3-cyano-2-oxotridecanoic acid ethyl ester is dissolved in 5 ml of methanesulfonic acid and the mixture allowed to stand overnight at room temperature. The reaction mixture is worked up by first pouring into ethanol-water (20 ml ethanol--5 ml water). After standing for several hours, the ethanol is removed by evaporation. The aqueous acidic residue is diluted further with water and then extracted with chloroform. The chloroform solution is then washed well with water, dried and evaporated to give the desired 3-hydroxy-4-(n-decyl)-3-pyrroline-2,5-dione. Recrystallization from hexane or cyclohexane provides pure 3-hydroxy-4-(n-decyl)-3-pyrroline-2,5-dione, mp 109°-111° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.S(Cl)(Cl)=O.C[N:16](C=O)C.[OH-].[NH4+]>C(Cl)Cl>[CH3:1][C:2]1([C:8]([NH2:16])=[O:10])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(C(=O)O)CC=CCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C(N)=O)CC=CCC1
Reaction time: 8 h

Procedure:
To a solution of 1-methylcyclohex-3-ene-1-carboxylic acid, 52a, (54.0 g, 385.2 mmol) dissolved in CH2Cl2 (200 mL) was added thionyl chloride (56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to reflux for 3 hrs, then cooled and concentrated in vacuo. The residue was redissolved in 200 mL of CH2Cl2. To the reaction was added ammonium hydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction was stirred overnight. The reaction was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc), yielding 25 g of 1-methylcyclohex-3-ene-1-carboxamide.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: OB(O)c1ccc(F)cc1Cl
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: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Yield: 96 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-chloro-4-fluorobenzene boronic acid (82 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc ×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O. Impurities still seen. Sent to MDAP for purification to afford the title compound in a 96% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[N:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][O:1][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCC1CCN(c2ccncc2)CC1
Product: COC(=O)CCc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Yield: 14 %

Procedure:
Following the method of Example 96, but starting from 4-(4-hydroxymethylpiperidin-1-yl)pyridine and methyl 3-(4-hydroxyphenyl)propionate, the title compound was prepared in 14% yield: m.p. 96.5°-98.5° C.; NMR (d6DMSO) δ 8.13(2H, d), 7.11(2H, d), 6.83(4H, m), 3.97(2H, dm), 3.81(2H, d), 3.56(3H, s), 2.87(2H, dr), 2.77(2H, t), 2.57(2H, t), 2.01(1H, m), 1.84(2H, m), 1.30(2H, m); m/e 355 (M+H)+ ; calculated for C21H26 N2O3.0.75H2O: C, 68.5; H, 7.2; N, 7.8. found: C, 68.5; H, 7.5; N, 7.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(=N)NO)C=C(C)C=1O[CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])C>>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
3-Ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert-butyl ester (5.94 g) is prepared starting from the above 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert.butyl ester (6.53 g, 27.6 mmol) following the procedures given for N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.87 min; [M+H]+=368.11; 1H NMR (CDCl3): δ1.17 (t, J=7.5 Hz, 3H), 1.53 (s, 9H), 2.28 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.17-3.26 (m, 1H), 3.38-3.46 (m, 1H), 3.65-3.75 (m, 2H), 3.83 (d, J=5.5 Hz, 2H), 3.91-3.97 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.5 Hz, 1H), 7.59 (s, 1H), 7.60 (s, 1H), 7.68 (t, J=5.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)C(CCC(=O)O)(Cc2ccccc2Cl)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Methylbenzaldehyde (3.00 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.20 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (10 ml.), and the sticky solid which forms after scratching is collected and air-dried, yield 7.4 g., m.p. 120°-147°C. Recrystallization from methylcyclohexane, followed by recrystallization from n-butyl chloride, yields a white solid with m.p. 166°-168.5°C.
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24]>>[ClH:25].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[NH:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Agent: Cl
Product: O=C(c1ccco1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 81.1 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with furan-2-carbonyl chloride as described in Example 2 to obtain 1-furoyl-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 81.1%; m.p.: 245°-246° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]#[N:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1COCC1>[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]4[NH:38][C:7]5=[N:6][CH:5]=[CH:4][N:3]=[C:2]5[CH:1]=4)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Cc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cnc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A solution of 2-methyl-pyrazine (580 μL, 6.4 mmol) in THF (4 mL) was added to 4.7 mL of 1.5M lithium diisopropylamide:THF complex in hexanes at −40° C. and the resulting deep red solution stirred at −40° C. for 0.5 hours. A solution of 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.00 g, 3.2 mmol) in THF (5 mL) was added at −40° C. and the reaction mixture stirred at this temperature for 0.5 hours, then at room temperature for 18 hours. A further 1 equivalent of lithium diisopropylamide complex was then added and the reaction mixture stirred at reflux for 24 hours. The mixture was cooled to room temperature, water (10 mL) added and the mixture concentrated in vacuo. The residue was partitioned between water (60 mL) and DCM (2×60 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (65 mg, 6%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.74-1.80 (m, 6H), 2.00 (m, 2H), 2.42-2.55 (m, 6H), 2.60 (t, 2H), 3.80 (m, 4H), 4.00 (t, 2H), 6.60 (s, 1H), 6.86 (d, 2H), 7.21 (d, 2H), 8.05 (d, 1H), 8.39 (d, 1H). HRMS ESI+ m/z 407.2437 [MH]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[ClH:19].Br[C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:31][C:32]3[N:33]=[CH:34][NH:35][CH:36]=3)[CH2:29][CH2:28][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:26][C:25]=2[CH:49]=1>>[ClH:19].[ClH:19].[NH:35]1[CH:36]=[C:32]([CH2:31][N:30]2[C:24]3[CH:23]=[CH:22][C:21]([C:6]4[S:7][CH:8]=[CH:9][CH:10]=4)=[CH:49][C:25]=3[CH2:26][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:28][CH2:29]2)[N:33]=[CH:34]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccs3)cc2C1
Yield: 10 %

Procedure:
Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH:11]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[O:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]1=2
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1OCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)C(Br)c1cc(Cl)ccc1OCO2
Temperature: 80 °C
Yield: 27 %

Procedure:
To a solution of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin (21.4 g, 76.1 mmol) and N-bromosuccinimide (13.5 g, 76.1 mmol) in tetrachloromethane (275 mL) was added azobisisobutyronitrile (200 mg, 1.2 mmol). The mixture was heated at 80° C. for 24 h. Another 3 x azobisisobutyronitrile (200 mg, 1.2 mmol) was added within the 24 h. The mixture was filtrated and the solution phase concentrated in vacuo. The residue was added dichloromethane (30 mL) and ether (100 mL). The mixture was filtered and the solution phase concentraded in vacuo. The residue was submitted to flash chromatography eluting with heptane/ethyl acetate (3:1) to give 7.4 g (27%) of 12-bromo-2,10-dichloro-12H-5,7-dioxadibenzo[a,d]cyclooctene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1>>[CH3:22][O:21][C:16]1[CH:15]=[C:14]([Br:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1cc(Br)ccc1O
Product: COc1cc(Br)ccc1OCc1ccc2ccccc2c1
Yield: 62 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with 4-bromo-2-methoxyphenol to give 3-methoxy-4-(naphth-2-ylmethoxy)bromobenzene (62%), m.p. 108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[NH2:20][C:21]([NH2:23])=[NH2+:22]>>[NH2:22][C:21]([NH2:23])=[N:20][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
in stage e) finally, as described in EP 0 758 644 (p.9, lines 10-20), by reaction of 2-methyl-4,5-di(methylsulfonyl)benzoyl chloride with guanidinium chloride to give the end-product N-diaminomethylene-2-methyl-4,5-di(methylsulfonyl)benzamide, the guanidino group is introduced.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Cl.Cl[CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[S:22]1[C:18]([CH2:17][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:19][N:20]=[CH:21]1
Reactant: ClCc1cncs1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(OCc2cncs2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 292 mg, 7.30 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (602 mg, 3.47 mmol) in dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred for 30 minutes prior to the addition of a solution of 5-(chloromethyl)thiazole hydrochloride (1.18 g, 6.85 mmol) and diisopropylethylamine (2.42 mL, 13.89 mmol) in dimethylformamide (3 mL) at 0° C. The reaction mixture was then heated up to 80° C. and stirred overnight. Since the LCMS monitoring still indicated the presence of starting material, an additional portion of sodium hydride (60% in oil, 139 mg, 3.47 mmol) was added. The reaction mixture was then stirred again at 80° C. After 17 hours stirring at 80° C., the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a solution of sodium hydroxide (5×50 mL) and with brine (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using petroleum ether/dichloromethane/ethyl acetate (7/0/3 to 2/0/8, then 0:5:5 to 0/2/8) as eluent. A second purification was performed on silica gel, using petroleum dichloromethane/acetone (9/1 to 8/2) as eluent. The title product was obtained as a yellow oil (150 mg, 16%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=S)[CH3:2].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)CCC>O>[CH3:2][C:1]1[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=S)Nc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1nnc(-c2ccccc2)n1-c1ccccc1
Yield: 18 %

Procedure:
First, 5.04 g of thioacetanilide, 5.44 g of benzoylhydrazine, and 50 mL of 1-butanol were put in a round-bottom flask provided with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with a microwave (2.45 GHz, 100 W) for 2 hours and 45 minutes to perform heating. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried over magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the resulting residue was purified by silica gel column chromatography which uses ethyl acetate as a developing solvent, so that 3-methyl-4,5-diphenyl-4H-1,2,4-triazole (abbreviation: HMptz) was obtained (pale yellow powder, 18% yield). The synthesis scheme of Step 1 is shown below.
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>O1CCCC1.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>[CH2:16]([O:15][C:13]([C:12]([CH3:18])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][C:5]([OH:6])=[O:4])[CH:22]=[CH:21][CH:20]=1)[CH3:19])=[O:14])[CH3:17]
Reactant: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1

Procedure:
Ethyl 2-[3-(allyloxycarbonylmethyl)phenoxy]-2-methylpropionate (6.40 g, 20.9 mmol) was dissolved in tetrahydrofuran (150 mL). Subsequently, triphenylphosphine (2.42 g, 2.09 mmol) and piperidine (41.34 mL, 41.8 mmol) were added thereto. Under argon atmosphere, tetrakis(triphenylphosphine)palladium (2.42 g, 2.09 mmol) was added, the resultant mixture was stirred for three hours at room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure, followed by addition of chloroform and washing sequentially with 3M hydrochloric acid, water, and saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol/acetic acid=50/1/0.5), whereby the target compound was obtained (6.88 g, 25.84 mmol, >q.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2ccccc2O1
Product: O=C(Cl)C1CCc2ccccc2O1

Procedure:
A solution of 3,4-dihydro-1-benzopyran-2-carboxylic acid (0.59 g 3.3 mmol) in thionyl chloride (15 ml) was stirred at 20° C. for 16 hours. Excess thionyl chloride was evaporated, azeotroping with dry toluene, to give 3,4-dihydro-1-benzopyran-2-carboxylic acid chloride as a yellow oil (νmax (film) 1805 cm-1) which was used immediately.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[O:13]1[C:17]2[CH:18]=[CH:19]C=CC=2N=C1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:19][CH:18]3[CH2:17][O:13]3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: c1ccc2ocnc2c1
Product: Cc1ccc2ccc(OCC3CO3)cc2n1

Procedure:
Compound 81 was prepared in the manner of compound 6 substituting 7-hydroxy-2-methyl-quinoline for compound 8 in part C-5 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12](=[O:24])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:15][C:16]=1Cl.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][C:16]2[CH:15]=[N:14][N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:24])[C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c(Cl)c(SCc2ccc(Cl)cc2)cnn1-c1ccccc1
Yield: 84 %

Procedure:
The reaction of 15.8 g (100 millimoles) of 4-chlorobenzyl mercaptan with 24.1 g (100 millimoles) of 4,5-dichloro-2-phenylpyridazin-3(2H)-one and 10.1 g (100 millimoles) of triethylamine is carried out as described in Method 2 and gives 30.5 g (84%) of a material which is found to be pure by thin-layer chromatography and has a melting point of 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH2:32][CH2:33][OH:34].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:34][CH2:33][CH2:32][NH:31][C:14]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18][CH:17]=1)=[O:16]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2.06 g (8.21 mmol) of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid suspended in 40 mL of methylene chloride was mixed with 1.63 g (10.1 mmol) of 1,1′-carbonyldiimidazole at room temperature and stirred at room temperature for 1.5 hours. The reaction solution was further stirred with 1.8 mL (30 mmol) of 2-aminoethanol overnight, and after addition of 40 mL of saturated aqueous sodium hydrogen carbonate, 20 mL of water and 200 mL of methylene chloride, was allowed to separate. The organic layer was washed with 80 mL of 1 M hydrochloric acid, with 40 mL of saturated aqueous sodium hydrogen carbonate and with 20 mL of saturated aqueous sodium chloride twice, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (2.30 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[I:10]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[I:10][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:4]=1[NH2:5]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc(Cl)cc(Cl)c1I
Yield: 45.7 %

Procedure:
Dissolve 3,5-dichloroaniline (10 g, 61.5 mmol) in 1:1 acetic acid/methylene chloride (200 mL). Add N-iodosuccinimide (16.9 g, 61.5 mmol) as a solid and stir at room temperature in the absence of light for 8 hours. Pour the solution into saturated sodium hydrogen carbonate (200 mL) and extract into methylene chloride (100 mL). Wash with saturated sodium hydrogen carbonate (200 mL), dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound (8.1 g, 45%); mp 61°-63° C.