Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: C1CSCCN1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCSCC1
Yield: 36 %

Procedure:
N-Cyclopropyl-N-[1-(3-thiomorpholin-4-yl-hexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (41) was prepared as follows. N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and thiomorpholine (2 mL) were heated together at 130° C. for 3 days in a sealed Reacti-vial. The vial was cooled in ice and then the cooled mixture was evaporated to dryness in vacuo in a Speed-Vac®. The residue was chromatographed over flash silica eluting with ethyl acetate:hexane (1:1) to give the title compound 41 (110 mg, 36%) as a white solid. LC: 100%. MS: m/z=548.3, 549.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.15 (1H, s), 8.06 (1H, d, J=7.5 Hz), 7.88 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.73 (1H, d, J=17.7 Hz), 4.10 (1H, m), 3.95 (1H, d, J=17.7 Hz), 3.05 (2H, m), 2.84 (2H, m), 2.74 (2H, m), 2.67-2.43 (6H, m), 2.15 (1H, m), 1.96 (1H, m), 1.75 (3H, m), 1.52-1.22 (4H, m), 0.98 (1H, m), 0.93-0.70 (6H, m).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:32]([CH3:33])[CH3:31])[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: O=C(CCl)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Reactant: CNC
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)CC(=O)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Temperature: 100 °C

Procedure:
2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (120 mg, 0.222 mmol) in 2 ml dioxane and 0.145 ml (0.81 mmol) 5.6 N dimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred and heated to 100° C. for 4.5 h. The mixture is cooled and the solvent evaporated. The residue is shaken with THF (5 ml), dichloromethane (3 ml), methanol (2 ml) and saturated sodium bicarbonate (2 ml). The two clear layers are separated and the organic phase is treated with 1 g silica gel. The solution containing the silica gel is evaporated and the solid put on top of a flash chromatography column containing 33 g of silica gel. The column is eluted using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as colorless crystals; m.p. 272-273° C.; MS-ES+: (M+H)+=453.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[CH:9]=1
Reactant: CC1(c2ccc(N)nc2)CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(c2cnc(N)c(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To an ice cold solution of 5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (50 mg, 0.26 mmol) in DCM (5 mL) was added NBS (50.9 mg, 0.28 mmol) in two portions. The reaction mixture was stirred at ambient temperature for 40 min. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered off, and concentrated to give 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol, 99% yield) as yellow color residue. LCMS (m/z): 271/273 (MH+), 0.41 min.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([OH:11])[C:9]#[N:10].[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]1[C:24](Cl)=[O:25].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([O:11][C:24]([CH:18]1[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[C:17]1([CH3:27])[CH3:16])=[O:25])[C:9]#[N:10]
Reactant: N#CC(O)c1cccc(OC=C(Cl)Cl)c1
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)OC(C#N)c2cccc(OC=C(Cl)Cl)c2)C1(C)C

Procedure:
To a solution of 9.8 g of 3-(2,2-dichlorovinyloxy)-mandelonitrile and 7.5 g of 2,2-dimethyl-3-(1-isobutenyl)-cyclopropanecarboxylic acid chloride in 100 cc toluene is added a solution of 3.5 g of pyridine in 200 ml toluene dropwise within 10 minutes. The resultant suspension is stirred for 15 hours at 20°-25° C., washed with dilute HCl and totally concentrated.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH2:28][CH3:29])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH2:28][CH3:29]
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes (1.01 g, 60%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C([O-])(O)=O.[Na+]>COCCOC.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>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][CH:21]=[CH:22]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
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: COCCOC
Product: COc1ccc(-c2cncc(C#N)c2-c2ccc3[nH]ccc3c2)cc1OC
Yield: 60.1 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), indole-5-boronic acid (77 mg, 0.48 mmol), Pd(PPh3)4 (25 mg, 0.022 mmol) and aqueous saturated NaHCO3 (3 mL) in DME (4.0 mL) was heated at reflux for 5 h. The reaction mixture was partitioned between water and EtOAc. The combined organics were dried over Na2SO4 and concentrated to give a brown syrup, which was purified by preparative thin-layer chromatography eluting with 3% MeOH/CH2Cl2 to give 94 mg (61%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yl)nicotinonitrile 221 as an off-white solid. MS: 356.2 (M+H); melting range: 215-217° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(#N)C>[CH2:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:18]([CH3:17])(=[O:20])=[O:19])[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCSC1=NC(=O)CS1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCSc1nc(OS(C)(=O)=O)cs1
Yield: 78.7 %

Procedure:
8 g of 2-n-propylthio-1,3-thiazoline-4-one and 4.8 g of anhydrous sodium carbonate were suspended in acetonitrile, followed by stirring. 7.9 g of methanesulfonyl chloride was added dropwise to the suspension below 10° C. After the addition, the reaction was continued under stirring at room temperature for 2 hours. The reaction solution was poured into water and extracted by ether. The ether layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to 9.1 g of the objective compound as a yellow oil (yield: 78.8%)
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14](O)=[O:15])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]([CH2:62][OH:63])[C:58]([O:60][CH3:61])=[O:59]>CN(C=O)C>[C:8]1([C:5]2[N:6]=[N:7][CH:2]=[C:3]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[C:14]([NH:56][CH:57]([CH2:62][OH:63])[C:58]([O:60][CH3:61])=[O:59])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.8 %

Procedure:
The solution of compound 6 (50 mg, 1.81 mmol) in DMF (0.5 mL), DIPEA (93 mg, 0.72 mmol), HATU (138 mg, 0.36 mmol) were sequentially added and stirred for 10 min at rt. Then methyl 2-amino-3-hydroxypropanoate (84 mg, 0.54 mmol) was added and stirred overnight at rt. Reaction was quenched by addition of ice cold water. The precipitated solid was filtered, washed with hexane, dried over anhydrous Na2SO4 and azeotroped with toluene to furnish methyl 2-(3,5-diphenylpyridazine-4-carboxamido)-3-hydroxypropanoate (20 mg, 29%) as an off white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:35])[CH3:34]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([CH2:21][NH:35][CH2:33][CH3:34])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(Cc3ccccc3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1
Solvent: C1CCOC1
Product: CCNC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
Toluene-4-sulfonic acid (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (2.0 g, 0.004 mmol) were dissolved in 2.0 M solution of EtNH2 in THF (14 mL) in an autoclave and heated to 80° C. over night. The volatiles were removed and the crude product subjected to column chromatography (silica gel, heptane/ethyl acetate 1:1) to yield the title compound (1.2 g, 81%) as a yellow oil.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:30][CH2:29]4)=[CH:40][CH:39]=3)[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN1CCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Trimethylaluminium (2M in toluene, 1.51 mL, 3.02 mmol) was added dropwise to 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (299 mg, 1.21 mmol) and methyl 4-(4-ethylpiperazin-1-yl)benzoate (300 mg, 1.21 mmol) in toluene (6.0 mL) at 25° C. The resulting suspension was stirred at 60° C. for 24 h under nitrogen. The reaction mixture was added to methanol (100 mL) and was treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (288 mg, 51%) as a cream solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:41]([CH:43]([NH2:46])[CH2:44][CH3:45])[CH3:42]>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2[NH:46][CH:43]([CH2:44][CH3:45])[CH2:41][CH3:42])(=[O:3])[CH3:2]
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Reactant: CCC(N)CC
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 50 °C

Procedure:
(2R,3R,4 R,5R)-4-(acetyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yl acetate (125 mg) was dissolved in isopropanol (5 ml) and the solution was treated with diisopropylethylamine (0.06 ml) followed by 1-ethylpropylamine (0.044 ml). The mixture was heated at 50° C. under nitrogen for 16 h. The solvent was removed in vacuo and the mixture partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with (i) dichloromethane, (ii) ether and (iii) ethyl acetate, gave the title compound as a colourless oil (108 mg). TLC SiO2 (ether) Rf=0.26.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].CS[C:11](=[NH:13])[NH2:12].OS(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[C:11]([NH2:13])=[NH:12]
Reactant: NCCCCCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)NCCCCCCN
Reaction time: 15 h

Procedure:
To 2.3 g. of 1,6-diaminohexane dissolved in 50 ml. of H2O was added dropwise with vigorous stirring a solution of 2 g. of S-methylthiopseudourea.H2SO4 in 20 ml. of H2O. After the completion of addition, the stirring was continued for 15 hours, after which the precipitate (the diadduct) was filtered. The filtrate was concentrated to a viscous oil which upon the addition of 50 ml. of MeOH precipitated 718 mg. of white powder.
Reaction SMILES: C(C1NC=CN=1)(=S)N.[CH2:9]1[NH:14][C:12](=[O:13])[NH:11][CH2:10]1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([N:11]1[CH2:10][CH2:9][NH:14][C:12]1=[O:13])=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NCCN1
Reactant: S=C=NCc1ccccc1
Agent: NC(=S)c1ncc[nH]1
Product: O=C1NCCN1C(=S)NCc1ccccc1
Reaction time: 6 h

Procedure:
The starting thiocarbamoylimidazole required for the above reaction is made as follows: 86g ethyleneurea and 149g benzylisothiocyanate are treated together with stirring for 6 hrs. at 150°. Upon cooling, a solid mass is obtained, which is triturated with ether and then with hot alcohol and filtered. Recrystallization from chloroform-methanol gives 1-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:23])[CH2:6][S:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:3])[CH3:2].[OH:24]O>C(O)(=O)C>[CH:1]([NH:4][C:5](=[O:23])[CH2:6][S:7]([CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:10])=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)CSCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)NC(=O)CS(=O)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A suspension of 2.0 gm (6.1 millimols) of [2-(4-biphenylyl)-2-oxo-ethylthio]-acetic acid isopropylamide in 20 ml of glacial acetic acid was admixed with 1.3 ml of 30% hydrogen peroxide, and the mixture was stirred at room temperature for 2 hours. The reaction product was precipitated with water and recrystallized from ethyl acetate after drying. Yield: 71.4% of theory; m.p. 138°-1/3°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:16]=2)=[C:9]([O:25][C:26](=[O:28])[CH3:27])[CH:8]=1)[CH3:2].C1(SC2C=CC=CC=2)C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:16]=2)=[C:9]([O:25][C:26](=[O:28])[CH3:27])[CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(OCC2=CC3(CCCC3)CCC2)c(OC(C)=O)c1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCC2=CC3(CCCC3)CCC2)c(OC(C)=O)c1
Yield: 76.8 %

Procedure:
To a solution of (E)-3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-acrylic acid ethyl ester (0.43 g) obtained in Step 4 in ethyl acetate (8 mL) were added 10% palladium carbon (86 mg) and a 0.1M ethyl acetate solution of diphenyl sulfide (1.08 mL), followed by stirring under increased pressure (0.4 MPa) in an atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane→ethyl acetate:hexane (volume ratio)=1:19 to 1:9) to give 3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.332 g).
Reaction SMILES: C([Li])CCC.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:6]3[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(O)c1cc[nH]c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (7.0 mL, 2.0 M, 14 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (0.67 g, 6.0 mmol) in THF (35 mL) at −78° C. Stirring for 45 min at −78° C. and 30 min at 0° C., 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.86 g, 5.0 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (200 mL), washed with 2N HCl (2×20 mL), NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using CH2Cl2/MeOH (20:1) on silica gel to 0.40 g (18%) of a white solid as the title compound. MS (ESI) (M+H)+=445.98.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>CN(C)C=O>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[CH:17][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23]
Reactant: CCc1ccc2ncnc(N)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccc(CC)cc12)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 4-amino-6-ethylquinazoline (6.35 g) and diethyl ethoxymethylenepropanedioate (9.52 g) in N,N-dimethylformamide (25 ml) was stirred for 3 hours at 110° C. and then cooled to ambient temperature. A small volume of water was added to the resultant mixture to precipitate crystals, which were separated by filtration and washed with water. The crystals were dissolved in chloroform, washed with an aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(6-ethyl-4-quinazolinylamino)methylene]propanedioate (8.40 g). Further, crystals (2.75 g) of the same compound were recovered from the motor liquor in the same manner as mentioned above.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2].CO.[NH3:18]>O1CCCC1>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:18])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[CH:2]
Reactant: C#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Yield: 53.2 %

Procedure:
7.3 g (0.036 mol) Methyl 4-ethynyl-3-nitrobenzoate (Compound II-1), 300 ml methanol and 200 ml tetrahydrofuran were added into a reaction flask, stirred, and ammonia gas was passed through for 1 hour. Then the mixture was reacted at room temperature for 24 hours. After completion of the reaction monitored by TLC, the mixture was concentrated under reduced pressure with most of the tetrahydrofuran and methanol evaporated, then extracted with 300 ml ethyl acetate. The organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and separated by column chromatography to obtain 4-ethynyl-3-nitrobenzamide (compound I-1), 3.6 g (0.0019 mol), yield 53.2%.