Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1(C2CCC(=O)CC2)C=CC=CC=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CNC
Agent: O=C1CCC(c2ccccc2)CC1
Product: CN(C)C(=O)c1ccc(C2CCC(=O)CC2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
4-(4-Oxocyclohexyl)benzoyl chloride [obtainable by reacting 0.75 mol (130.7 g) of 4-phenylcyclohexanone with 1 mol of oxalyl chloride and 2 mol of AlCl3 in dichloromethane, followed by hydrolysis with ice-water/HCl] is added to an aqueous solution (15%) of 3 mol of dimethylamine and the mixture is stirred for 2 hours at 0 to 5°. It is worked up in conventional manner to give 125.2 g of N,N-dimethyl-4-(4-oxocyclohexyl)benzamide, m.p. 118°; yield: 68% based on 4-phenylcyclohexanone.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C[O-].[Na+].CO>C(OCC)C>[O:23]=[C:17]([CH2:15][C:14](=[O:16])[C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)c1cnc(Oc2ccccc2)nc1

Procedure:
A mixture consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Example 38, Step B, 214 mg, 1.00 mmol) and diethyl oxalate (0.14 mL, 150 mg, 1.0 mmol) in diethyl ether (10 mL) under a nitrogen atmosphere at room temperature was stirred for ten minutes. Sodium methoxide (65 mg, 1.2 mmol) was subsequently added followed by methanol (1.0 mL). The solution was stirred overnight at room temperature. The off-white precipitate which had formed was collected by filtration and washed with diethyl ether. The solid was dissolved in water and the pH adjusted to 3 using acetic acid. The solid precipitate which formed was filtered and washed with water. The solid was air dried to afford a mixture comprising both the ethyl and methyl esters.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:36][CH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH:37]1([CH2:36][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC1CCC1)N1CCC(F)(F)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and (bromomethyl)cyclobutan in N,N-dimethylformamide, to give the desired product as a white foam (73%).
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35]=[O:36])[N:19](COCC[Si](C)(C)C)[C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:6])=[O:5])([CH3:3])[CH3:2]>C(O)C.O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35]=[O:36])[NH:19][C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C=O)n(COCC[Si](C)(C)C)c3-c3ccccc3)cc21
Solvent: O
Solvent: CCO
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C=O)[nH]c3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 10 %

Procedure:
Add to a solution of 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(formyl)-5-(phenyl)-imidazolyl)-benzimidazole (100 mg, 0.185 mmol) in ethanol (4 mL) HCl (37%, 4 mL) and stir at room temperature for 4 hours. Dilute the mixture with water (20 mL) and wash with EtOAc (3×10 mL). Add to the aqueous phase NaOH (15%) until pH=6-7 and extract the mixture with EtOAc (3×20 mL). Dry (MgSO4) the combined organic layers and concentrate in vacuo. Purify the residue in solid phase extraction (SPE) cartridge (Oasis™) and then by HPLC to obtain a white solid, 8 mg, 10% yield. MS(ES+): m/z=410 (M+H)+
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)CC/C=C\CCCCCCCC.[C:29]([O-:32])(=[O:31])[CH3:30].[K+].C(O)(=O)C>>[C:29]([O:32][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCC/C=C/CCCCl
Agent: CCCCCCCC/C=C\CCCCl
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCCCC=CCCCOC(C)=O
Reaction time: 10 h

Procedure:
495 g (2.2 moles) of the mixture of trans-4-tridecenyl chloride and cis-4-tridecenyl chloride synthesized in Example 1, 432 g (4.4 moles) of potassium acetate, and 264 g (4.4 moles) of acetic acid were mixed under an atmosphere of nitrogen (N2) and stirred at 180°-185° C. for 10 hours. Thereafter, this mixture was washed with 600 g of purified water and then with 600 g of a 5% aqueous solution of sodium bicarbonate. The resulting organic layer was purified by distillation. Thus, there was obtained 548 g (2.2 mole) of 4-tridecenyl acetate having a trans to cis ratio of 78:22 and a purity of 98%. This product is a sex pheromone component of the tomato pinworm (Keiferia lycopersicella) known as an insect pest of tomato fields principally in the United States of America.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:10]([C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:3])[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1)[CH3:27]
Reactant: CCOC(=O)CCl
Reactant: Cc1cn(Nc2ccncc2F)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(c1ccncc1F)n1cc(C)c2ccccc21
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in oil, 1.48 g) in 10 ml of dimethylformamide (DMF) at ice bath temperature was added dropwise a solution of N-(3-fluoro-4-pyridinyl)-3-methyl-1H-indol-1-amine (8.5 g) in 40 ml of DMF. when addition was complete, the mixture was stirred for 15 minutes at ice bath temperature, and then cooled to -20° C. Ethyl chloroacetate (3.95 ml) was added dropwise in 10 ml of DMF. The mixture was stirred at -20° C. for one hour. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtering, the solvent was evaporated to yield an oil (12.2 g) which was eluted with 10% ethyl acetate/DCM on a silica gel column via HPLC. The desired fractions were evaporated to yield 6.9 g of a solid, m.p. 105°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:26]=[C:27]([CH2:31]O)[N:28]([CH3:30])[N:29]=2)[CH:21]=[CH:22][C:23]=1[Cl:24].CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:31][C:27]3[N:28]([CH3:30])[N:29]=[C:25]([C:20]4[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=4)[CH:26]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(Cl)c(Cl)c2)cc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(Cl)c(Cl)c4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [5-(3,4-dichloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(3,4-dichloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.
Reaction SMILES: CN(C)C.[F:5][C:6]1[C:11]([F:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:8][C:7]=1[C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.[Cl:29][C@@H:30]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C:31](Cl)=[O:32]>ClCCl>[F:5][C:6]1[C:11]([F:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:8][C:7]=1[C:22]1[N:23]=[CH:24][C:25]([O:28][C:31](=[O:32])[C@@H:30]([Cl:29])[C@@H:34]([CH3:37])[CH2:35][CH3:36])=[CH:26][N:27]=1
Reactant: CC[C@H](C)[C@H](Cl)C(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1F
Agent: CN(C)C
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cn2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
--Trimethylamine (234 mg, 2.31 mmol) was added to a solution of the difluorophenylhydroxy-pyrimidine 35 (740 mg, 2.31 mmol) and (2S, 3S)-2-chloro-3-methylpentanoyl chloride 36 (388 mg, 2.31 mmol) in dry dichloromethane (8 ml) with stirring under nitrogen at room temperature for 2 h. Dichloromethane was added and the mixture was washed with dilute hydrochloric acid (twice), saturated sodium bicarbonate solution and brine, dried and evaporated. The residue was purified by flash chromatography (10% ethyl acetate-light petroleum) to give the ester 37 (670 mg, 58%) (from MeOH), m.p 66.2° C., [α]D26 +1.5° (c 2.4 in CHCl3); νmax /cm-1 (KBr) 2920, 1765 (CO), 1615, 1510, 1470, 1420, 1300, 1230, 1120 and 1080; δ 0.89 (3H, t,J6.5, Me), 1.00 (3H, t,J6.5, CH3CH2CH(CH3), 1.15 (3H, d,J7, CH(CH3)), 1.25-1.55 (10H, m), 1.76 (2H, m, CH3CH2CH(CH3), 1.85 (2H, quint, OCH2CH2), 2.25 (1H, m, CHMe), 4.11 (2H, d, J6.5, OCH2), 4.44 (1H, d, J7, CHCl), 6.84 (1H, ddd, J8, 7 and 2, 5'-H), 7.85 (1H, ddd, J8, 7 and 2, 6'-H) and 8.71 (2H, s 4- and 6-H); m/z 470 (M+), 468 (M+), 358 (M+ -C8H16), 356 (M+ -C8H16), 336, 237 and 224.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:15])[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)CCNCC2)cn1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1
Yield: 58 %

Procedure:
A mixture of 4-(6-methoxypyridin-3-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(6-methoxypyridin-3-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 58% yield.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 73 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-tert-butylbenzoyl chloride (0.244 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.47 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-tert-butylbenzamide (0.221 g, 73%). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.43 (d, 2H), δ 6.95 (t, 1H), δ 3.59 (q, 2H), δ 3.50 (t, 2H), δ 1.31 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.2, 155.4, 131.4, 127.2, 125.8, 51.1, 39.7, 35.2, 31.4 ppm; HRMS (ESI) calcd for C13H18N4O (M+) 246.1480. Found 246.1479.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[N:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.C(N(CC)CC)C.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6](=[O:11])/[C:5]/2=[N:12]\[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1/C(=N\c2cccc(C(F)(F)F)c2)c2cc(Br)ccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.2 %

Procedure:
A mixture of (3z)-5-bromo-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2h-indol-2-one (100 mg, 0.272 mmol), copper (II) acetate (54 mg, 0.33 mmol), triethylamine (82.8 mg, 0.817 mmol), and benzene boronic acid (40 mg, 0.325 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine), giving the desired product (22 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:6]2=[O:13].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]2=[O:13]
Reactant: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CC2Cc3c(C)cc(C)c(O)c3C2=O)cc1

Procedure:
16.09 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one was dissolved in a mixed solvent of 150 ml of ethyl acetate with 100 ml of acetic acid, this solution was let subjected to catalytic reduction at room temperature under 3 atmospheric hydrogen gas pressure in the presence of 1.5 g of palladium black as the hydrogenation catalyst. After the catalytic reduction, the catalyst was removed by filtration, and the filtrate was concentrated by removing the solvent under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane: ethyl acetate =9:1) to obtain 8.5 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzyl)-1H-inden-1-one as in the form of colorless oily substance.
Reaction SMILES: [C:1]([CH:3](C#N)[CH2:4][S:5][CH2:6][CH:7](C#N)[C:8]#[N:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:20]Br>ClC(Cl)C>[C:1]([CH2:3][CH2:4][S:5][CH:6]=[C:7]([Br:20])[C:8]#[N:9])#[N:2]
Reactant: N#CC(C#N)CSCC(C#N)C#N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: N#CCCSC=C(Br)C#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 17.2 %

Procedure:
28 g of bis-cyanoethyl sulphide were dissolved in 50 ml of dichloroethane, and 110 g of potassium carbonate were added. 64 g of bromine were then added dropwise at 20° to 30° C. The mixture was stirred at 40° C. for 16 hours, a further 40 g of potassium carbonate were added and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, the filtrate was washed with water and concentrated and the residue was chromatographed. 5.5 g of 2-bromo-2-cyano-vinyl 2-cyano-ethyl sulphide were obtained as an oil, 1H-NMR: δ=2.6-3.0 (2H), 3.0-3.4 (2H) and 7.5-7.9 (1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CC(C)=O.[SH2]=N.[C:17]1([NH:23][C:24](C2C=CC=CC=2C(O)=O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([NH:23][C:24]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)N1CCc2ccccc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 90.5 %

Procedure:
A solution of 1.35 g 1,2,3,4-tetrahydroisoquinoline with 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, at ambient temperature. The reaction mixture was stirred for 45 minutes, then diluted with 150 ml water, cooled to 5° C. and the precipitated crystalline product was filtered, washed with water and dried. 1.18 g N-phenylcarbamoyl-1,2,3,4-tetrahydroisoquinoline was obtained with a melting point of 145°-146° C.
Reaction SMILES: [NH:1]1[C:10](=S)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3].C([NH2:14])C.C>O>[NH:1]1[C:10]([NH2:14])=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[N:4][C:2]1=[S:3]
Reactant: CCN
Reactant: S=c1[nH]c(=S)c2[nH]cnc2[nH]1
Solvent: O
Product: Nc1[nH]c(=S)nc2nc[nH]c12
Yield: 97.4 %

Procedure:
6.67 g (16 mmoles) of dithioxanthine and 52 ml of 70% ethylamine in water were heated to 150° C. in a pressure reactor (250 psi) for 12 hours under nitrogen. The solution was treated with charcoal (5%), filtered, and evaporated in vacuo to dryness. The residue was suspended in water, acidified with 1N HCl to pH 4 and neutralized to pH 8 with sodium bicarbonate. The solid was collected, washed and dried to give 6.66 g (97.4%) of crude thioisoguanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]#[N:15])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].[F-].[K+].CN(C=O)C>O>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]#[N:15])[CH:11]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: N#Cc1cc(O)n(-c2ccc(Cl)cc2)n1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-cyano-5-hydroxypyrazole (59.7 mg, 0.273 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (93.7 mg, 0.27 mmol), KF (15.7 mg, 0.27 mmol) and DMF (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ether (3×25 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 81 mg (62%) of 4-isopropyl-6-methoxy-2-[1-(4-chlorophenyl)-3-cyanopyrazol -5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 135° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=[O:29])[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].Cl([O-])=O.[Na+].[OH-].[Na+].[C:37](#N)C>O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][O:29][CH3:37])[C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:2])[CH3:3]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=O)cccc21
Reactant: CC#N
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: O
Product: COCc1cccc2c1nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-4-carbaldehyde (37 mg, 0.091 mmol) and sodium chlorite (12 mg, 0.11 mmol) in water (1 mL) and acetonitrile (1 mL) was stirred at room temperature for 8 hrs. An additional amount of sodium chlorite (12 mg) was added and stirring was continued overnight. 1M NaOH was added and the mixture was extracted with ethyl acetate (twice). The aqueous phase was acidified with 1M HCl until pH 4. The resulting suspension was extracted with ethyl acetate (2×10 mL) and the combined organic phases washed with water, brine, and dried (MgSO4). The pure title compound (8 mg, 21%) was obtained as a white solid:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C)C=O>[CH2:7]([O:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[C:13]([O:21][CH3:22])[CH:14]=1)[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: COc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Potassium carbonate (4.44 g, 32.156 mmol) and allyl bromide (2.78 ml, 32.156 mmol) were added to a stirred solution of 4-chloro-3-methoxybenzoic acid (3 g, 16.078 mmol) in N,N-dimethylformamide (30 ml) and allowed to stir at room temperature for 18 hours. The reaction mixture was partitioned between diethyl ether (200 ml) and water (150 ml), the organic phase extracted and further washed with water (150 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound as an orange oil in 98% yield, 3.57 g.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(Cl)cc2)c1C=NO
Reactant: COC(=O)c1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CON=Cc1c(C)nn(C)c1Oc1ccc(Cl)cc1
Reaction time: 5 h
Yield: 64 %

Procedure:
2.0 Grams (0.00755 mole) of 5-(4-chlorophenoxy)-1,3-dimethyl-pyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethylformamide, and after adding 0.5 g (0.0125 mole) of powdery sodium hydroxide, the resulting mixture was thoroughly stirred. To this solution was added 1.73 g (0.00755 mole) of methyl 2-bromomethylbenzoate, and reaction was carried out at from 70° to 80° C. for 5 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 2.0 g cf the desired compound.