Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:28][CH3:29])=[CH:24][CH:25]=5)[C:20]4=[O:30])[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5][CH2:4]1>O1CCCC1>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:14][CH2:15][N:16]([C@H:19]4[CH2:27][C:26]5[C:21](=[CH:22][C:23]([O:28][CH3:29])=[CH:24][CH:25]=5)[C@H:20]4[OH:30])[CH2:17][CH2:18]3)[C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(c1)C(=O)C(N1CCN(c3cccc4c3OCCO4)CC1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@H](O)[C@@H](N1CCN(c3cccc4c3OCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.8 g (73.8 mmol) of sodium borohydride are added in fractions over the course of 15 minutes at room temperature to 28.0 g (73.6 mmol) of the compound obtained in Step 2 in 220 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature, and then for 4 hours at reflux. After evaporation, the residue is taken up in 1 litre of dichloromethane, washed twice with 500 ml of water and then dried over magnesium sulphate. After concentration, the residue is chromatographed over silica (eluant:dichloromethane/methanol 99/1, then 98/2). The product eluted first corresponds to the cis isomer. Its stereochemistry was demonstrated by IR, in solution in chloroform, according to the method described by H.-J. Rimek el al. (Justus Liebigs Ann. Chem., 1969, 726, 25-29).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([CH2:15][NH:16][C:17]3[C:22]([NH2:23])=[CH:21][C:20]([I:24])=[CH:19][N:18]=3)=[CH:13][C:12]=2[O:27][CH3:28])=[CH:5][CH:4]=1.F[CH:31](F)C1N=CC(COC2C=CC(CN)=CC=2OC)=CC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:29][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[C:17]4=[N:18][CH:19]=[C:20]([I:24])[CH:21]=[C:22]4[N:23]=[CH:31]3)=[CH:13][C:12]=2[O:27][CH3:28])=[CH:5][CH:4]=1
Reactant: COc1cc(CN)ccc1OCc1ccc(C(F)F)nc1
Reactant: COc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(C(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: CCO
Product: COc1cc(Cn2cnc3cc(I)cnc32)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99 %

Procedure:
To a stirred solution of N2-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodopyridine-2,3-diamine [prepared from (4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine using the procedures described in Example 3-45-4 and Example 3-45-5] (3.10 g, 6.05 mmol) in ethanol (50 mL) was added triethyl orthoformate (3.0 mL, 18.02 mmol). The mixture was treated with p-toluenesulfonic acid monohydrate (50 mg, 262.86 μmol) and was heated to reflux. After 45 min, the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The mixture was concentrated, and the residue dissolved in chloroform (150 mL). The solution was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide 3.15 g (99%) of 3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridine as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.[CH3:21][C:22]([O:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:27])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=[C:2]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:26](=[O:27])[O:25][C:22]([CH3:23])([CH3:21])[CH3:24])=[CH:34][CH:33]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Temperature: 90 °C
Yield: 35 %

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.0 g, 3.27 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 DME:water:ethanol (7 mL). [4-[(2-Methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid (1.165 g, 4.91 mmol), 2M sodium carbonate solution (4 mL) and dichlorobis(triphenylphosphine)palladium catalyst (115 mg, 0.16 mmol) were then added to the solution and refluxed at 90° C. for 5 hours under nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate and water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness. The crude oil was dissolved in dichloromethane and filtered to remove insoluble material. A beige solid precipitated from the filtrates and the filtrates were filtered again. The solid was analysed and found to be the excess boronic acid and the filtrates contained the product and some impurities. The filtrates were purified by chromatography on silica, eluting with 0-40% ethyl acetate in isohexane, to give the desired compound as an orange oil (530 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([S:22]SCC)[CH3:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:22][CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Reactant: CCSSCC
Product: CCSc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Yield: 86 %

Procedure:
Prepared in analogy to example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and diethyl disulphide. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 86%). MS (m/e): 330.3 (M+H+, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]([O:11]C)=[O:10])=[CH:6][NH:7][CH:8]=1.I[CH2:14][CH3:15].[OH-].[Na+]>C(O)C.CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]([OH:11])=[O:10])=[CH:6]1)[CH3:15]
Reactant: CCI
Reactant: COC(=O)c1c[nH]cc1C
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCn1cc(C)c(C(=O)O)c1
Yield: 73.1 %

Procedure:
In the same manner as in Reference Example 37 and using 60% sodium hydride (340 mg, 8.62 mmol), N,N-dimethylformamide (25 mL), methyl 4-methyl-1H-pyrrole-3-carboxylate (1.00 g, 7.19 mmol), iodoethane (860 μL, 10.8 mmol), ethanol (6 mL) and 8N aqueous sodium hydroxide solution (1.8 mL) as starting materials, the title compound (805 mg, 73%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: NCCc1cccs1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2cccs2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 70.2 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(2-thienyl)ethylamine (0.0234 g, 0.184 mmol) gives the title compound (0.0495 g, 70.3%): TOF MS ES+ 384.1 (M+H)+, HRMS calcd for C20H22N3O3S 384.1382 (M+H)+, found 384.1375, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitiile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.1 min, 100% purity.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)=O.[ClH:13]>C1(C)C=CC=CC=1>[Cl:13][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 0.17 h

Procedure:
5-Chloromethyl furfural was prepared by reaction of fructose with concentrated hydrochloric acid in toluene in a well-stirred two-phase system. The reaction was conducted at 85° C. for 10 minutes. The product was recovered by decanting the organic layer and removing toluene under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16]C3C=CC(CN(C)C4CCOCC4)=CC=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])OC1C=CC(N2CCOCC2)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[O:12]=[S:11]1(=[O:13])[C:5]2[CH:4]=[CH:3][CH:2]=[CH:32][C:6]=2[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[CH2:9][CH2:10]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.7 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-fluoro-4-morpholinophenyl borate (156 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the. mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate and washed with saturated brine. The extract was heated at 70° C., and crystals were dissolved. The solution was dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from ethanol to give yellow crystals of 7-(3-fluoro-4-morpholinophenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 61) (149 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[NH:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C=O)C.O>[NH2:19][C:18]1[S:17][C:3]2[C:4](=[O:16])[NH:5][C:6]([S:8][CH2:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[N:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CSc2nc3nc(N)sc3c(=O)[nH]2)cs1
Reaction time: 2 h

Procedure:
The product from example 20 step a) (24.3 g) and potassium thiocyanate (37.1 g) was stirred in dry DMF (400 ml) with pyridine (13.1 ml) at 0° C. Bromine (4.5 ml) was added over 1 hr. After stirring 2 hrs the mixture was poured into water. The resulting solution was concentrated to low volume then water added. The resulting solid was collected, taken up in 2M hydrochloric acid and precipitated by the addition of saturated sodium bicarbonate solution. The solid was collected, washed with water and dried to give the sub-title compound, (8.7 g).
Reaction SMILES: [C:1](C1C=C(C=CC=1)COC1C=CC(C[C@]2(S(C3C=CC4OCOC=4C=3)(=O)=O)[C@@H](CC(C)C)OC(C)(C)N2CN)=CC=1)#[N:2].[CH2:43]([O:50][C:51]1[CH:89]=[CH:88][C:54]([CH2:55][C@H:56]([NH:76][C:77](=[O:87])[O:78][C@@H:79]2[C@H:86]3[C@H:82]([O:83][CH2:84][CH2:85]3)[O:81][CH2:80]2)[C@H:57]([OH:75])[CH2:58][N:59]([S:64]([C:67]2[CH:72]=[CH:71][C:70]([OH:73])=[C:69]([CH3:74])[CH:68]=2)(=[O:66])=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:1]([C:48]1[CH:49]=[C:44]([CH:45]=[CH:46][CH:47]=1)[CH2:43][O:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:55][C@H:56]([NH:76][C:77](=[O:87])[O:78][CH:79]2[CH:86]3[CH:82]([O:83][CH2:84][CH2:85]3)[O:81][CH2:80]2)[C@H:57]([OH:75])[CH2:58][N:59]([S:64]([C:67]2[CH:72]=[CH:71][C:70]([OH:73])=[C:69]([CH3:74])[CH:68]=2)(=[O:65])=[O:66])[CH2:60][CH:61]([CH3:62])[CH3:63])=[CH:88][CH:89]=1)#[N:2]
Reactant: CC(C)C[C@H]1OC(C)(C)N(CN)[C@@]1(Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: Cc1cc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)ccc1O
Product: Cc1cc(S(=O)(=O)N(CC(C)C)C[C@@H](O)[C@H](Cc2ccc(OCc3cccc(C#N)c3)cc2)NC(=O)OC2COC3OCCC23)ccc1O

Procedure:
The alkylation step was carried out as described for N-(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl-oxycarbonyl-, (4S,5R)-4-[4-(3-cyanobenzyloxy)-benzyl]-5-i-butyl-[(3,4-methylenedioxyphenyl)sulfonyl]-aminomethyl-2,2-dimethyl-oxazolidine. The deacetylation step was carried out as described previously for (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[[(4-hydroxy-3-methylphenyl)sulfonyl](isobutyl)amino]propylcarbamate. The final product was isolated by preparative HPLC. (Column: Luna C18, Solvent: 75% to 100% MeOH/0.1% formic acid, tret: 4.08 min.) (Y=6%, 2 steps, overall.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Clc1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(Br)cc(-c2ccc(Cl)cn2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of methyl 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.10 g, 0.29 mmol) in DMF (1.5 mL) and water (0.49 mL) were added 2-bromo-5-chloropyridine (0.17 g, 0.88 mmol), palladium(II) aceate (3.3 mg, 0.015 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (25.0 mg, 0.044 mmol) and diisopropylamine (0.10 mL, 0.73 mmol). The mixture was heated to 80° C. After 1 h, the mixture was filtered and the filtrate was purified by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (78 mg). MS 326.0 (M).
Reaction SMILES: CC1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)[N:5]=2.[OH-].[Na+].O>CCO>[NH2:10][C:9]1[C:4](=[S:3])[NH:5][C:6]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: Cc1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reaction time: 6 h

Procedure:
A slurry of 2-methyl-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (17.0 g, 63.8 mmol) in 128 mL EtOH was added sodium hydroxide 10 M in water (128 mL, 1276 mmol). Argon was bubbled through the resulting slurry for 5 min, then the reaction flask was fitted with a water-cooled reflux condenser, flushed with argon, and the reaction mixture was heated to vigorous reflux under argon. After 6 h, the reaction mixture was cooled and the EtOH was removed in vacuo. The resulting slurry was poured onto ice and neutralized with 260 mL 5N aq. HCl to pH 4. A light yellow precipitate resulted. The solid was collected by filtration through a glass frit, rinsing with 2×200 mL water, and the solid was dried under a bag of nitrogen overnight. Further drying in vacuo for several hours gave 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione as a light yellow solid. MS (ESI) m/z: calculated: 242.1; Observed: 243.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9]>>[C:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)Cl
Reactant: C1CCNCC1
Product: CCC(=O)N1CCCCC1

Procedure:
This compound was prepared by a method analogous to that of description 9 using piperidine in place of heptamethyleneimine and propionyl chloride in place of acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=O)[CH:20]=2)[CH:12]=1)[CH3:9].O.[NH2:32][NH2:33].CCCCCC.C(OCC)(=O)C>C(O)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[O:27][CH:28]=[N:32][N:33]=3)[CH:20]=2)[CH:12]=1)[CH3:9]
Reactant: NN
Reactant: COC(=O)c1cccc(COc2cccc(CN(C)C/C=C/C#CC(C)(C)C)c2)c1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(-c3nnco3)c2)c1
Yield: 10.2 %

Procedure:
173 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(3-methoxycarbonylbenzyloxy)benzylamine was dissolved in 3 ml of ethanol, and 100 mg of 98% hydrazine hydrate was added. The mixture was heated under reflux for 3 hours. After the reaction mixture was evaporated under reduced pressure, water and ethyl acetate were added to the residue to extract it. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was separated by filtration and the solvent was evaporated. The residual carbohydrazide was added to 4 ml of trimethyl orthoformate and the mixture was heated under reflux for 8 hours. After evaporating the excess trimethyl orthoformate, the residue was extracted with a mixture of ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was separated by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography Wakogel C-200, 30 g; eluting solvent: hexane/ethyl acetate=2/1] and medium-pressure liquid chromatography column: Lobar column, size A, Lichroprep Si 60 (E. Merck Co.); eluting solvent: hexane/ethyl acetate=3/1→2/1) to give 18 mg (yield 10%) of the captioned compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][C:12](=O)[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+].[N+:42]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])#[C-:43].C(O)(=O)C>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][C:12]2[N:13]([CH:43]=[N:42][C:44]=2[C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: O=C1CN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc2N1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncn2c1CN=C(C=Cc1ccc(Cl)c(Cl)c1)c1ccccc1-2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
100 mg (2.5 mmol) of 60% sodium hydride disperion in mineral oil were added to a solution of 728 mg (2.2 mmol) of (E)-5-(3,4-dichlorostyryl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 5 ml of anhydrous dimethylformamide at room temperature under a nitrogen atmosphere and stirred for 30 minutes. The mixture was cooled to −20° C., 431 mg (2.5 mmol) of diethyl chlorophosphate were added and stirring was continued for a further 30 minutes at −10° C. before being added to a solution prepared by addition of 1.65 ml (3.3 mmol) of 2M lithium diisopropylamide to a solution of 375 mg (3.32 mmol) of ethyl isocyanoacetate in 5 ml of anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 2 hours then warmed to −30° C. and 180 mg (3 mmol) of acetic acid were added followed by water and ethyl acetate. The organic phase was washed twice with water, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/methanol (49:1) for the elution. The product was dissolved in 1 ml of ethyl acetate and 10 ml of diethyl ether and left to crystallize. There was obtained 116 mg of ethyl (E)-6-(3,4-dichlorostyryl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as a light-brown solid. MS: m/e 425.9 [M+H]+.
Reaction SMILES: C([C:3](=[C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1)[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11]C)=[O:5])#N.CCCCC(COC(C1C=CC=CC=1O)=O)CC>>[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:14][CH:13]=1)(=[O:5])[CH:3]=[CH:15][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCC(CC)COC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: CCCCC(CC)COC(=O)c1ccccc1O
Product: O=C(C=Cc1ccccc1)OCc1ccccc1

Procedure:
2-ethylhexyl α-cyano-β-phenylcinnamate, sold under the trade name Uvinul N 539
Reaction SMILES: [C:1]([C:3]1[C:9]([CH3:10])=[C:8]([C:11]#[N:12])[CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].Cl.Cl[C:15]([NH2:17])=[NH:16].CS(C)(=O)=O.[OH-].[Na+]>O>[NH2:17][C:15]1[N:16]=[C:1]([NH2:2])[C:3]2[C:4](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[C:9]=2[CH3:10])[N:5]=1
Reactant: N=C(N)Cl
Reactant: Cc1c(C#N)ccc(N)c1C#N
Agent: CS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(C#N)ccc2nc(N)nc(N)c12
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A mixture of 0.3 g (1.91 mmol) of 2,4-dicyano-3-methylaniline, 0.44 g (3.82 mmol) of chloroformamidine hydrochloride, and 0.7 g of dimethylsulfone was heated to 170°-175° C. The mixture solidified after a time, and was allowed to cool to room temperature. Water (20 ml) was added, and the resulting mixture was made basic with 1 molar aqueous sodium hydroxide solution, filtered, and washed with water. The solids were triturated with methanol to yield 0.167 g of 2,4-diamino-5-methyl-6-quinazolinecarbonitrile, mp>270° C. The infrared, mass, and proton magnetic resonance spectra corresponded to those of a known sample of the compound.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:5]2[CH2:11][CH:10]([CH3:12])[C:9](=O)[C:6]=2[S:7][CH:8]=1.Cl.C1(C)C=CC=CC=1>C1COCC1.CO.O>[Br:3][C:4]1[C:5]2[CH2:11][C:10]([CH3:12])=[CH:9][C:6]=2[S:7][CH:8]=1
Reactant: CC1Cc2c(Br)csc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC1=Cc2scc(Br)c2C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
A total of 1.30 g (34.4 mmol) of NaBH4 were added to a solution of 5.0 g (21.5 mmol) of the resulting 3-bromo-5-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 60 ml of THF-methanol (2:1, vol.) over 1 h at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred for 10 h at ambient temperature, then diluted with 20 ml of water, and acidified with 10% HCl to pH=1. The crude product was extracted with 3×100 ml of CH2Cl2. The combined extracts were washed with the saturated aqueous Na2CO3, dried over K2CO3, and evaporated to dryness. To the yellow oil obtained, 150 ml of toluene were added. This toluene solution was treated with a catalytic amount of pTolSO3H (ca. 0.2 g) for 10 min at reflux, cooled to room temperature, and, then, passed through a short Silica Gel 60 column (40-63 μm, d 20 mm, l 50 mm). This column was additionally eluted with 300 ml of hexanes-methyl-tert-butyl ether mixture (10:1, vol.). The chromatographed product was evaporated to dryness. This procedure gave 4.61 g (99%) of beige crystalline product of 3-bromo-5-methyl-4H-cyclopenta[b]thiophene (containing 3-5% of 3-bromo-5-methyl-6H-cyclopenta[b]thiophene).