Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:29]O.O>C(O)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[C:15]([CH3:18])([CH3:17])[S:16](=[O:29])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 1.5 h

Procedure:
Sodium tungstate dihydrate (500 mg.) was added to a solution of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate (31.5 g.) in acetic acid (150 cc.), and to the mixture was added, dropwise, 30% hydrogen peroxide (9.1 cc) while cooling in an ice bath. The mixture was stirred for 1.5 hours, and then water was added thereto. The precipitate was collected by filtration, washed with water and dried to yield crystals (33.2 g.) of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide, m.p. 165.5°-168.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:5](OC)=[O:6].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:6]=[C:5]1[N:12]2[CH:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][C:20]=3[C:11]2=[N:10][CH:9]=[C:4]1[C:3]([O:2][CH3:1])=[O:29]
Reactant: CCC(CC)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCC(CC)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)OC)cnc3c2c1
Temperature: 255 °C
Yield: 78.1 %

Procedure:
A mixture of dimethyl[[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (5.3 g) and diphenyl ether (32 ml) was heated at 255° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were filtered off, washed with hexane and dried. The crude crystals were dissolved in a mixture of chloroform and methanol (10:1) under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystals, which are recrystallized from a mixture of chloroform and hexane to give methyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (3.81 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[N+:18]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O>[NH2:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]#[N:15]
Reactant: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c(N)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of compound 27 (11.8 g, 36.36 mmol) in THF (200 mL) was combined with a solution of sodium hydrosulfite (37.98 g, 218.1 6 mmol) in water (50 mL). The combined solution was stirred vigorously overnight at 45° C. The reaction was monitored by TLC (25% EtOAc in hexanes), and was complete after 16 hrs as indicated by absence of the starting material. The reaction was removed from heat and THF was evaporated. Aqueous solution was filtered to yield a white solid. The solid was washed with water and dried in a vacuum oven overnight to yield compound 28 (9.077 g, 97% HPLC purity, 84.6% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.55 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.28 (dd, J1=2 Hz, J2=7 Hz, 1H), 7.19 (d, J=2 Hz, 1H), 6.99 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.50 (d, J=2 Hz, 1H), 6.04 (s, 2H).
Reaction SMILES: [C:1]1([C@@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH2:20][C@H:19]([CH2:23][NH:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=4[N+:33]([O-])=O)[C:28]#[N:29])[CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH:38](OC)(OC)OC>[Fe].C(O)=O.CCOC(C)=O>[C:1]1([C@@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH2:20][C@H:19]([CH2:23][N:24]4[C:25]5[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[CH:31][C:32]=5[N:33]=[CH:38]4)[CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(NC[C@H]2CCCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c1
Reactant: COC(OC)OC
Agent: [Fe]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: N#Cc1ccc2ncn(C[C@H]3CCCC4(C3)O[C@H](c3ccccc3)[C@@H](c3ccccc3)O4)c2c1
Temperature: 64 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a 3 L flask fitted with an overhead stirrer was added 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (131 g, 279 mmol), iron (156 g, 2790 mmol), MeOH (1 L), EtOAc (1 L), trimethyl orthoformate (0.308 L, 2790 mmol) and formic acid (0.107 L, 2790 mmol). The mixture was heated to 64° C. Every 15 min an additional 2-3 eq of iron, formic acid and trimethyl orthoformate was added. After 3 h, the solution was cooled to RT and filtered through Celite© and washed with EtOAc. The filtrate was concentrated to give 1-{[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (125 g, 100% yield). MS (m/z) 450.2 (M+H+). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Br[C:12]#[N:13]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]#[N:13]
Reactant: N#CBr
Reactant: CCc1ccc(Cl)c(N)c1
Solvent: O
Product: CCc1ccc(Cl)c(NC#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To a heterogeneous slurry of 2-chloro-5-ethylaniline (1.6 g, 10 mmol) in 60 mL of water at 4° C. was added solid BrCN (0.848 g, 8 mmol) slowly. After 5 minutes the cooling bath was removed and the heterogeneous reaction mixture was stirred at room temperature for 24 hours to yield the product in water suspension. The precipitates were collected by filtration, washed with water (100 mL), and dried under vacuum to yield the pure title compound (1.45 g, 80% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1COCC1.CCOC(C)=O>[C:12]1([S:18]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reaction time: 0.25 h

Procedure:
0.89 g (22.2 mmol) sodium hydride (60%) were added to 2.0 g (17.1 mmol) indole in 30 mL THF while cooling with an ice bath and the mixture was stirred for 15 min at this temperature. Then 2.2 mL (17.0 mmol) benzenesulphonic acid chloride were added and the mixture was stirred overnight at RT. The reaction mixture was combined with water and EtOAc and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:23]([S:42][CH2:43][C@@H:44]([C:46]([NH:48]CC(N)=O)=[O:47])[NH2:45])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:45][C@H:44]([C:46]([NH2:48])=[O:47])[CH2:43][S:42][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)CNC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
1.00 g (3.36 mmol) of N-[(9H-Fluoren-9-ylmethoxy)carbonyl]glycine was dissolved in 30 ml dichloromethane. 1.41 g (3.36 mmol) S-Trityl-L-cysteinylglycinamide, 0.59 ml (3.36 mmol) N,N-diisopropylethylamine and 1.28 g (3.36 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 300 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1, dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.63 g (2.06 mmol, 81% of theory) of the desired product.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].[CH2:7]([Li])[CH2:8][CH2:9]C.CCCCCC.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.IC(C)C>C1COCC1>[C:18]1([N:24]=[C:25]([S:26][CH:8]([CH3:9])[CH3:7])[CH2:2][CH2:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: S=C=Nc1ccccc1
Reactant: C#C[Si](C)(C)C
Solvent: CCCCCC
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)SC(CC[Si](C)(C)C)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Ethynyltrimethylsilane (0.93 g) was dissolved to dry THF (30 ml), n-butyl lithium/hexane solution (1.6 mol/l; 5.6 ml) was added dropwise thereto at −78° C., then it was warmed to 0° C. The reaction mixture was cooled to −78° C., THF (5 ml) solution of phenyl isothiocyanate (1.24 g) was added dropwise to the reaction mixture. Then it was gradually warmed to 0° C. After that, THF (5 ml) solution of 2-iodopropane (1.52 g) was added dropwise thereto under ice-cooling, then stirred for 14 hours at room temperature. The reaction solution was concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=15/1) to obtain isopropyl N-phenyl-3-(trimethylsilyl)thiopropioimidate (1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: NCc1ccc(F)cc1F
Product: CN1CCCn2c1cc(NCc1ccc(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (2,4-difluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].I[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([O:15][CH3:26])[C:11]([F:12])([F:13])[F:14]
Reactant: CI
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccncc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccncc1)(C(C)c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (Example 11) by 0-methylation: 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (45 mg) was dissolved in dry DMF (4 mL) under argon at room temperature. To the mixture was added sodium hydride (8.4 mg, 50% in mineral oil) and the mixture was allowed to stir for 30 minutes. Iodomethane (22 mg, 0.01 mL) was added and stirring was continued for 1 hour at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl acetate in heptane (10 to 40%) to give the desired material as light yellow oil (28 mg). MS (m/e)=364.1 [MH+].
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:7]1=[O:32])[CH3:2].[OH-].[K+].[C:37](=[O:40])(O)[O-:38].[Na+].O>C(O)(C)(C)C>[F:16][C:15]([F:18])([F:17])[C:37]([OH:38])=[O:40].[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]([NH2:20])=[O:38])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[C:7]1=[O:32])[CH3:34]
Reactant: O=C([O-])O
Reactant: CCN(CC)CCn1c(=O)n(Cc2cccc(C(F)(F)F)c2)c2c(C(F)(F)F)cc(C#N)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCN(CC)CCn1c(=O)n(Cc2cccc(C(F)(F)F)c2)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 60 °C
Yield: 51 %

Procedure:
A solution of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-1H-benzimidazole-5-carbonitrile (226.3 mg) in t-butanol (10 ml) was stirred with heating at 60° C. To the solution was added powdered potassium hydroxide crashed in mortar (652.3 mg), and the mixture was stirred with heating at 60° C. for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 2 to give the title compound (145.8 mg, 51%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:19]2[N:18]=C(C)O[C:15](=[O:21])[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.O1CCCC1>[NH2:18][C:19]1[C:10]([Cl:9])=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: Cc1nc2c(Cl)cccc2c(=O)o1
Reactant: Br[Mg]c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Nc1c(Cl)cccc1C(=O)c1ccccc1
Yield: 38.8 %

Procedure:
Phenylmagnesium bromide (3.11 mL, 3.0 M in ether, 9.34 mmol) was added at room temperature to a solution of 8-chloro-2-methyl-4H-3,1-benzoxazin-4-one (2.15 g, 10.9 mmol) in benzene (10 mL) and tetrahydrofuran (3 mL). The reaction was refluxed for 2h, cooled, and quenched with 2N hydrochloric acid (10 mL). The layers were separated and the organic phase washed with 5% sodium hydroxide, dried over magnesium sulfate, and concentrated. The residue was refluxed in ethanol (12 mL) and 6N hydrochloric acid (6 mL) overnight, then concentrated in vacuo. The residue was dissolved in benzene (30 mL) and treated with 5N ammonium hydroxide (20 mL). The organic extract was dried and concentrated. The crude product was purified by chromatography (silica gel, 0 to 5% ethyl acetate in hexane gradient elution), giving the title compound (0.84 g). 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=7 Hz, 2H), 7.54 (t, J=7 Hz, 1H), 7.49–7.42 (m, 3H), 7.39 (d, J=8 Hz, 1H), 6.56 (t, J=8 Hz, 1H), 6.58 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH:24]=[CH:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]C(C)(C)C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[CH2:28][CH:29]1[CH2:31][CH2:30]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH:24]=[CH:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:28][CH:29]3[CH2:31][CH2:30]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1C1C=CCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1C1C=CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.5 h

Procedure:
2.0 g (5.4 mmol) of tert.butyl 8-chloro-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.5 g (2.1 mmol) of tetraethyl orthotitanate and 25 ml of hydroxymethyl-cyclopropane are stirred at 130° for 23 hours, portions each of about 2 ml of solvent being distilled off in vacuo three times. The mixture is subsequently evaporated in vacuo, the residue is treated with water and chloroform, stirred for 30 minutes, filtered over siliceous earth and the organic phase is separated. The aqueous phase is extracted twice with chloroform, the organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate/n-hexane, there is obtained cyclopropylmethyl 8-chloro-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 189°-190°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(Cl)c2ccc(Cl)cc2)cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-methylbenzyl)-isoindolin-1-one (400 mg, 1.13 mmol), thionyl chloride (295.8 mg, 2.48 mmol, 0.18 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one was produced as a viscous yellow oil (418 mg, 1.13 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-methylbenzyl)isoindolin-1-one (418.1 mg, 1.13 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (285 mg, 2.85 mmol) and dried K2CO3 (390.41 mg, 2.85 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a green oil (359 g). Purification by flash column chromatography yielded the title product as a colourless viscous oil (242.1 mg, 0.55 mmol, 50%) 1H NMR: (300 MHz, DMSO) δ ppm 1.19 (m, 1H, H16/16′), 1.67, 2.05 (m, 1H, H16/16′) 2.21 (s, 3H, H12), 3.85 (m, 1H, HO, 4.06 (d, 1H, J=15.21 Hz, H9/9′), 4.32 (m, 1H, H15) 4.53 (d, 1H, J=15.21 Hz, H9/9′), 4.81, 5.74, (dd, 1H, H18/19) 5.20, 5.66 (dd, 1H, H18/19), 6.95 (m, 4H, H10, H11, H13, H14), 7.25 (m, 5H, H1-H5), 7.65 (m, 2H, H6-H7) 7.74 (d, 1H, H8). IR: 1380, 1467, 1699, 2922 cm−1. HR-MS (EI): Calculated mass: [M+H]+446.1517. Found: 446.1517.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.Cl[C:17](OC)=[S:18].N1C=CC=C[CH:22]=1>>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:17]([CH3:22])=[S:18])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: COC(=S)Cl
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: c1ccncc1
Product: CC(=S)OC1CCN(C)C(=O)N1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and methyl chlorothioformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methylthiocarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: OCCCCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1

Procedure:
To 500 ml of toluene in a 1000 ml round bottom flask, fitted with a condenser and magnetic stirrer, are added 14 g (0.05M) of 4-hydroxy-4'-nitrostilbene potassium salt, 14 g of 6-iodo-1-hexanol, and 0.5 g of 18-crown-6 ether. The mixture is refluxed for about 10 hours, and the solution is filtered hot and the product crystallizes from the toluene solution on cooling, mp 154°-157° C.
Reaction SMILES: C(O)(=O)C(O)=O.[NH2:7][CH2:8][CH:9]([OH:11])[CH3:10].N1C=CC=CC=1.[C:18](=[S:20])=[S:19].[CH3:21]I>C(N(CC)CC)C>[OH:11][CH:9]([CH3:10])[CH2:8][NH:7][C:18](=[S:20])[S:19][CH3:21]
Reactant: CI
Reactant: S=C=S
Reactant: CC(O)CN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CSC(=S)NCC(C)O
Reaction time: 1 h

Procedure:
40 G (0.242 mmole) of 1-amino-2-propanol oxalate was suspended in 180 ml. of pyridine and 101 g. of triethylamine was added. The mixture was stirred mechanically for 1 hour, there cooled to 0° and 38 g. of carbon disulfide (0.5 mole) was added dropwise. After 2 hours at 0° C., 36 g. of methyl iodide (0.254 mole) was added dropwise and almost all solids dissolved. The mixture was stored in a refrigerator overnight (0°-5° C.). The mixture was poured into 2.4 l. of 3 N H2SO4 and extracted with ether 3 times. The ether extracts were washed with water, 3 N H2SO4, water, aqueous NaHCO3 solution and water, dried over Na2SO4 and stripped down to 18.79 g. (47%) of oily methyl N-(2-hydroxypropyl) dithiocarbamate.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[CH:7][C:6]=1[C:16]([O:18]CC)=O.[CH3:21][NH2:22].O>CN(C=O)C>[C:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]=[CH:7][C:6]=1[C:16]([NH:22][CH3:21])=[O:18])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Reactant: CN
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
Four and seven tenths grams (0.096 mol) of sodium cyanide were added to a solution of 12.0 g (0.048 mol) of 94.66% pure 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester in 28.8 ml of DMF at room temperature. The solution was heated for 6 hours at 100° C. and cooled to room temperature. The reaction mixture was stirred overnight and 13.0 g (0.17 mol) of 40% aqueous methylamine was added dropwise. The resulting mixture was stirred for 6 hours at room temperature and 28.8 ml of water was slowly added. The mixture was stirred for 10 minutes and the precipitated solid was collected by filtration. This solid was washed with water and vacuum dried to provide 8.3 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide as a white solid. The product analyzed 95.81% pure by high pressure liquid chromatography, corresponding to a corrected yield of 77.4% product.