Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].C[O:13][CH:14](OC)[CH2:15][C:16]([CH3:18])=[CH2:17].Cl.N1C=CC=CC=1>CCOCC>[CH:14]([C:15](=[C:16]([CH3:18])[CH3:17])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:13]
Reactant: C=C(C)CC(OC)OC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C1CCC(C)=C1CC(C=O)=C(C)C
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A mixture of 7.6 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 8.1 g of 1,1-dimethoxy-3-methyl-3-butene was heated under nitrogen in an oil bath of 100° C for 15 hours in the presence of 100 mg of freshly prepared dry pyridine hydrochloride with continuous removal of the methanol formed. The mixture was then heated for 7 hours to 150° C and finally poured on to a mixture of ice and ether. The ethereal phase was washed bicarbonate solution and water, dried with anhydrous magnesium sulphate and concentrated under reduced pressure. After distillation of the oily crude product, there were obtained 6.5 g of 2-(2-formyl-3-methyl-2-butenyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.003 about 80° C; nD20 = 1.5148; IRfilm : νmax = 3100, 2780, 1675, 1635, 1440, 1375, 1155, 1060 and 895 cm-1. The compound has a woody, floral, fruitily sweetish fragrance.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[C:24]3[CH:53]=[CH:52][N:51](S(C4C=CC(C)=CC=4)(=O)=O)[C:25]=3[N:26]=[C:27]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][N:36]4S(C4C=CC(C)=CC=4)(=O)=O)=[CH:32][C:31]=3[O:49][CH3:50])[N:28]=2)[C:14]=1[C:15]([NH2:17])=[O:16].O>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[N:28]=[C:27]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][NH:36]4)=[CH:32][C:31]=3[O:49][CH3:50])[NH:26][C:25]3=[N:51][CH:52]=[CH:53][C:24]=23)[C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a degassed solution of naphthalene (14 g, 109 mmol) in THF (300 mL) were added sodium cubes (2.6 g, 108 mmol). The cubes were crushed, and then stirred for 4 h. A total of 60 mL of the resulting deep green solution was added dropwise to a −78° C. solution of 2-fluoro-6-({2-({5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-yl}amino)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (3.7 g, 4.99 mmol) in THF (100 mL). Water (5 mL) was then added, the resulting mixture was allowed to warm to rt, and filtered. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a yellow solid (710 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88 (t, J=8.33 Hz, 2H), 3.39 (t, J=8.15 Hz, 2H), 3.76 (s, 3H), 5.07 (br s, 1H), 6.24 (s, 1H), 6.83 (s, 1H), 6.89-7.02 (m, 2H), 7.40 (s, 1H), 7.50 (q, J=7.69 Hz, 1H), 7.64 (s, 1H), 8.03 (s, 1H), 8.10 (s, 1H), 8.47 (d, J=8.42 Hz, 1H), 10.46 (s, 1H), 11.39 (s, 1H); ESIMS (M+H)+=434.17.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[NH:37][NH2:38]>>[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[C:30]2[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:38]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2ccc(F)cc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[CH2:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:7].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:4]([NH:1][C:2]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[N:21]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:19][CH:18]=3)[CH:12]=2)[C:8]([CH2:6][CH3:7])=[N:9]1)=[O:3])[CH3:5]
Reactant: CCN=C=O
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(CC)c2ccc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)cc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
Isocyanatoethane (0.014 mL, 0.18 mmol) was added to a solution of 3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50 mg, 0.14 mmol) in pyridine (2 mL) and the mixture was heated at 100° C. for 16 hours. Upon cooling, water and ethyl acetate were added and the product was washed once with 0.1 N HCl, once with water and once with brine. The combined organics were dried, the solvent was removed, and the reside was purified by column chromatography on silica gel, eluting with 20% ethyl acetate in hexanes for 5 minutes, a linear gradient to 50% ethyl acetate in hexanes over 15 minutes, and then 50% ethyl acetate for an additional 10 minutes, to afford 32 mg (54%) of N,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide. LC/MS (EI) tR 4.33 (Method C), m/z 438.2 (M++1), 1H NMR (CDCl3) δ 1.0 (t, 3H), 1.4 (t, 3H), 2.9 (t, 2H), 3.0 (s, 3H), 3.4 (m, 2H), 6.5 (s, 1H), 7.0 (d, 1H), 7.1 (s, 1H), 7.4 (d, 2H), 7.5 (m, 1H), 7.8 (s, 1H), 7.9 (d, 2H), 8.4 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].CS([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)(=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To 3,4-dichlorophenol (13.8 g) dissolved in a 60 ml THF/60 ml DMSO mixture was added 9.5 g of t-BuOK. The temperature rose to about 40° C. and then 19.8 g of 2,5-bis(methylsulfonyl)pyridine was added. The reaction mixture was warmed to 50° C. and the temperature maintained at 50° C. for 1 hour. The reaction mixture was cooled, poured into approximately 3 volumes of water and the solid collected. The solid was dried on a porous plate and then recrystallized from CH2Cl2 /ethanol to give 23.5 g of 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)pyridine as shiny white plates, m.p. 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[CH2:14]C(C)(C)N[C:17](=O)[C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH2:41]>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>[CH3:5][C:6]1([CH3:23])[NH:7][C:14](=[O:41])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([C:28]5[CH:29]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: OB(O)c1cncnc1
Reactant: CC1(C)Cc2sc(N3CCOc4ccc(Br)cc43)nc2C(=O)N1
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cncnc5)cc43)sc2C(=O)N1
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of Example 39 (0.135 g, 0.34 mmol), 5-pyrimidinylboronic acid (0.084 g, 0.68 mmol), K3PO4 (0.143 g, 0.68 mmol), water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (catalytic) in DME (5 mL) was heated to 120° C. under microwave irradiation for 30 minutes. After cooling to r.t. the reaction mixture was filtered and purified by preparative HPLC (Method 7) to give the title compound (0.008 g, 6%) as a pale yellow solid. δH (CD3OD) 9.12 (1H, s), 9.01 (2H, s), 8.44 (1H, d, J 2.3 Hz), 7.40 (1H, dd, J 8.5 and J 2.3 Hz), 7.14 (1H, d, J 8.5 Hz), 4.47-4.40 (2H, m), 4.21-4.14 (2H, m), 2.92 (2H, s), 1.41 (6H, s). Exchangeable proton was not observed. LCMS (ES+) 393.0 (M)+, RT 2.83 minutes (Method 2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.CN(C(ON1N=NC2[CH:27]=[CH:28][CH:29]=[N:30]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][CH:29]3[CH2:27][CH2:28]3)=[O:13])=[CH:14][CH:15]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
4-(2-Amino-thiazol-4-yl)-benzoic acid (4.4 g, 20 mmol) was dissolved in DMF (100 mL) and treated with HATU (1.1 eq. 8.4 g) and DIEA (2.1 eq, 7.5 mL) and stirred for 15 minutes. Then cyclopropyl amine (1.1 eq, 1.5 mL) was added and the mixture stirred at ambient temperature for 1 hr. The reaction was diluted with 100 mL of water, extracted with EtOAc (3×100 mL) dried with brine (100 mL) and then Na2SO4 and the solvents removed. The resulting solid was triturated with ether to give the product >95% purity by HPLC. MS: 260.3 (M+H).
Reaction SMILES: C([CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23])#N.Cl.[C:25]([O-:28])(O)=[O:26].[Na+]>[OH-].[Na+]>[C:25]([CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]=1[CH3:23])([OH:28])=[O:26]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCC#N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCC(=O)O

Procedure:
Combine N-(2-cyanoethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (4.0 g, 12 mmol) with 350 ml 1.0 N NaOH. Reflux 2 hours, allow to cool, add concentrated HCl, and then solid NaHCO3. Extract with ether, dry and concentrate. Recrystallize from ether-hexane to give title compound as a solid product, m.p. 175°-176° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (5-(methyl-propyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M73) (0.46 g, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (223 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50][NH2:51])([CH3:47])[CH3:46]>C(Cl)(Cl)Cl.O>[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50][NH:51][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])=[O:43])([CH3:47])[CH3:46]
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (63 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (103 mg, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7].[OH-:21].[K+].CI.[CH3:25][O:26][CH2:27]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([N:5]([CH2:25][O:26][CH3:27])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:7])=[O:21]
Reactant: O=C(NCc1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Reactant: [OH-]
Reactant: COCCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCN(C(=O)Nc1ccc(Cl)cc1)C(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.3 g of N-(2,6-dichlorobenzyl)-N'-(4-chlorophenyl)-urea and 1.88 g of powdered potassium hydroxide (90%) are dissolved 40 ml of dimethyl formamide, after which 4.7 g of methyl iodide are added drop by drop to the clear solution. The resulting reaction is exothermic. After stirring for two hours the solution is diluted with ice water and the solid substance is isolated. Yield 10.3 g. Melting point 124°-126° C. In a completely similar manner but using methoxymethylchloride instead of methyliodide, N-(2,6-dichlorobenzoyl)-N-(methoxymethyl)-N'-(4-chlorophenyl)-urea is produced, Melting point 121.5°-122.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>CN(C)C=O.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: CCC=CC1C(C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCC=CC1C(C(=O)Cl)C1(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Fifty grams (50 g) of 2,2-dimethyl-3-(1-butenyl)cyclopropanecarboxylic acid, 350 ml of hexane and 0.6 g of N,N-dimethylformamide were mixed together. At 50° C., 39 g of thionyl chloride was eye-dropped thereto over 30 minutes. Subsequently, the reaction mixture was stirred for 1 hour at 50° C. The reaction mixture was then concentrated under reduced pressure to provide 48 g of 2,2-dimethyl-3-(1-butenyl)cyclopropane carboxylic chloride.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]#[N:23]>CN(C)C=O>[C:22]([CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:23]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.6 %

Procedure:
To a stirred solution of 2.7 g (15 mmol) of tert-butyl piperazine-1-carboxylate in 30 mL of anhydrous N,N-dimethylformamide was added 2.4 g (17 mmol) of potassium carbonate followed by 2.1 g (17 mmol) of bromoacetonitrile. The resulting heterogeneous mixture was stirred at ambient temperature of 12 h, quenched with water then extracted with ethyl acetate. The combined organic layers were washed with water then brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-75% acetone in hexanes gradient to afford the title compound as clear gum (1.0 g, 30%). 1H-NMR (500 MHz, CDCl3) δ 3.53 (s, 2H), 3.48 (t, J=5.0 Hz, 4H), 2.53 (t, J=5.0 Hz, 4H), 1.45 (s, 9H). LC-MS: m/z (ES) 226.2 (MH)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[CH:8]([N:6]1[CH2:7][CH:4]([NH2:1])[CH2:5]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 12 (5.7 g, 21.6 mmol), triphenylphosphine (11.3 g, 43 mmol) and water (5 ml) was heated to reflux for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue purified by chromatography on silica gel (90:9:1 CHCl3 : MeOH:NH4OH).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH:8]1(SCl)[CH2:13][CH2:12][CH2:11][CH2:10]C1.O.C[N:18]([CH3:21])C=O>>[C:21]1([NH:18][C:6](=[N:3][C:4]2[CH:5]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:7])[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: CN(C)C=O
Reactant: ClSC1CCCCC1
Reactant: CCN(CC)CC
Solvent: O
Product: CC(=Nc1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The N,N'-diphenylacetamidine which is prepared according to the above paragraph is then placed in a flask along with an acid scavenger comprising triethylamine using dimethylformamide as a solvent. The mixture is cooled to a temperature of 0° C. and maintained thereat while an equimolar amount of cyclohexanesulfenyl chloride is slowly added thereto dropwise. The temperature of the reaction will range from about 0° to about 10° C. with continuous stirring. Following the completion of the addition of the cyclohexanesulfenyl chloride, the reaction mixture is stirred for an additional period of 1 hour while allowing the temperature of the solution to reach room temperature. Following this, water is added and the organic layer which separates out is thereafter washed several times with water, dried over magnesium sulfate and subjected to vacuum to remove the dimethylformamide solvent. The resulting material will slowly crystallize and the crystals comprising N,N'-diphenyl-N-cyclohexylthioacetamidine will be recovered by filtration.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([NH2:32])=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([C:27]1[S:31][C:30]([NH:32][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])=[CH:16][CH:15]=2)=[N:29][C:28]=1[CH3:33])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(-n3ccccc3=O)cc2)sc1C(=O)NCc1ccccc1
Yield: 58 %

Procedure:
Following the procedure as described in Example 11, making variations only as required to use 4-(2-oxopyridin-1-yl)-benzoic acid in place of 5-phenylpentanoic acid to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 58% yield; 1H NMR (CDCl3, 300 MHz) δ 12.96 (s, 1H), 8.63 (t, J=5.9 Hz, 1H), 8.18 (d, J=8.6 Hz, 2H), 7.66 (dd, J=1.7, 6.9 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.50 (ddd, J=2.0, 6.8, 9.0 Hz, 1H), 7.35-7.20 (m, 5H), 6.48 (d, J=9.0 Hz, 1H), 6.32 (dt, J=1.1, 6.8 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 2.52 (s, 3H); MS (ES+) m/z 445.4 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][O:14][CH2:15][C:16](=O)[CH3:17].N1CCCC1.C1(C)C=CC=CC=1>O>[CH3:13][O:14][CH2:15][C:16]1([CH3:17])[CH2:2][C:1](=[O:3])[C:4]2[C:11](=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=2)[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: COCC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: COCC1(C)CC(=O)c2cc(C#N)ccc2O1

Procedure:
a mixture of 50 g of 3-acetyl-4-hydroxybenzonitrile, 70 ml of methoxy-2-propanone, 6 ml of pyrrolidine and 300 ml of toluene is boiled in a water separator for 3 hours. The mixture is evaporated, the residue is worked up in the customary manner (ethyl acetate/dil. hydrochloric acid) and 2-methoxymethyl-2-methyl-6-cyano-4-chromanone is obtained, m.p. 79°-81° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21]C(C#N)=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CCOCC[O:30][CH2:31][CH3:32].[OH-:33].[K+].Cl>O>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:32]([C:31]([OH:30])=[O:33])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOCCOCC
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1

Procedure:
5-n-Decyl-2-(4'-cyanophenyl)pyrimidine (2.0 g) was refluxed together with diethyl glycol (15 ml) and potassium hydroxide (1.0 g) for 1 day. The reaction mixture was poured in a mixed solution of water (100 ml) and concentrated hydrochloric acid (50 ml) and the mixture was stirred for half a day under heating. The precipitated crystal was collected and washed with water and then recrystallized from ethanol to obtain the titled compound (2.0 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]4[CH2:27][CH2:28][C@H:13]4[C:12]=23)[N:4]=1.C(N(C(C)C)[CH:32]([CH3:34])[CH3:33])C.[CH2:38](Br)[CH:39]=[CH2:40]>C(Cl)Cl>[CH2:34]([N:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]4[CH2:27][CH2:28][C@H:13]4[C:12]=23)[N:4]=1)[CH2:40][CH:39]=[CH2:38])[CH:32]=[CH2:33]
Reactant: C=CCBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)no1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)no1
Yield: 88.6 %

Procedure:
3 g (7.7 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 50 ml of methylene chloride, 14.2 ml (72 mmol) of N-ethyldiisopropylamine and 5.14 g (3.6 mmol) of allyl bromide were stirred at room temperature overnight and at 40° for 4 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 390 g of silica gel while eluting with ethyl acetate. There were obtained 1.50 g (41%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the dihydrochloride with methanolic hydrochloric acid.