Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH3:19])=[O:17].CS(C)=O.C[O-].[Na+]>CO>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C

Procedure:
To a solution of 9.86 g. (50 mmoles) of N-methylsaccharin and 10.8 ml. of methyl chloroacetate (123.8 mmoles) in 50 ml. of dimethylsulfoxide was added at the rate of 0.15 ml./minute 9.2 g. (170 mmoles) of sodium methoxide in 30 ml. of methanol. After the addition was complete an additional 2.7 g. (50 mmoles) of sodium methoxide in 11 ml. of methanol was added at the same rate for a total addition time of about 6 hours.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(N(CC)CC)C.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348 mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, phenacetyl chloride (0.106 g, 0.626 mmol). m.p. dec. 213° C.; 1H NMR (250 MHz, DMSO-d6) δ3.69 (s, 2 H), 6.85 (s, 1 H), 7.29 (m, 4 H), 7.53 (m, 3 H), 7.83 (m, 2 H), 9.40 (bs, 1 H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([Cl:15])=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nonc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2nonc2c1
Yield: 79.8 %

Procedure:
In a 500 ml reactor fitted with mechanical stirring, thermometer, addition funnel, reflux condenser and nitrogen inlet, [2,1,3]-benzoxadiazole-5-carboxylic acid (28 g) was suspended in toluene (245 ml). To this suspension was added thionyl chloride (39.4 g) and DMF (0.35 ml). The resulting mixture was heated to reflux and maintained for 3 hours. A short pass column was installed and toluene was distilled (atmospheric pressure, 124 ml) off to remove excess reagent. After cooling the remaining toluene was distilled off, which resulted in a thick oil. This oil was distilled (90° C., 2 mm Hg) to remove impurities and the product crystallized on standing (79.8% yield), mp: 55-58° C.
Reaction SMILES: [NH2-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.Cl[CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[N:12]([CH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCCC1CCCl
Reactant: c1ccc(NC2Cc3ccccc3C2)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCCC1CCN(c1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of sodamide (256 mg, 6.58 mmol) in toluene (10 mL) was added a solution of indan-2-yl-phenyl-amine (7; 1.0 g, 4.78 mmol) in toluene (5 mL) at 0° C. The reaction mixture was stirred at rt for 3 hours. A solution of 2-(2-chloroethyl)-1-methyl-pyrrolidine hydrochloride (18; 0.808 g, 4.39 mmol) in toluene (5 mL) was added to the reaction mixture and the resulting mixture was refluxed for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on neutral alumina eluting with 0.8% methanol-DCM to provide compound 19.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12].O>ClCCl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccnnc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of pyridazine-4-carboxaldehyde (3.646 mmol, 1 eq) in dry dichloromethane (25 ml), (methoxycarbonylmethylene)triphenylphosphorane (5,550 mmol, 1.2 eq) was added portionwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured into water (200 ml) and extraction with DCM (3×100 ml) followed. Organic layers were combined, dried over phase separator cartridge to giving crude product which was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of MeOH in DCM: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 3-pyridazine-4-yl-acrylic acid methyl ester (4.142 mmol, yield=89%, purity=96%). [M+H]+=165.11 1H NMR (300 MHz, CDCl3) δ/ppm 3.82 (s, 3H), 6.64-6.68 (m, 1H), 6.72 (s, 1H), 9.22 (dd, J=5.3, 1.0 Hz, 1H), 9.27 (s, 2H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Yield: 90.1 %

Procedure:
To a solution of 1c (760 mg, 3.44 mmol) in CHCl3 (10 mL) was added N-bromosuccinimide (673 mg, 3.78 mmol). The resultant mixture was stirred for 1 h, then mixed with saturated NaHCO3 solution (100 mL), and extracted with methylene chloride (100 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then provided the title compound (930 mg, 90%) as a yellow solid: MS (ES) m/z 300 (M+H)+; 1H NMR (400 MHz, CDCl3) δ7.96 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.52 (brs, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11]>>[CH3:1][C:2](=[C:4]([O:8][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: CC(C)C(=O)C(C)C
Reactant: C[Si](C)(C)Cl
Product: CC(C)=C(O[Si](C)(C)C)C(C)C

Procedure:
Reaction between 2,4-dimethyl-3-pentanone (1.2.4.3), trimethylsilyl chloride, and base gave 2,4-dimethyl-3-trimethysilyloxy-2-pentene (1.2.4.4) which was reacted with 1-fluoropyridinium triflate (1.2.4.5) to form 2,4-dimethyl-2-fluoro-3-pentanone (1.2.4.6). This product was reacted with (CH3)3S(O)+I− to form the title compound (1.2.4.2). 1.2.4.7 2,2-Bis-isopropyl oxirane.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][NH:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a suspension of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (9.2 g: 9 mMol.) in a mixture of anisole (18 ml) and nitromethane (72 ml) is added dropwise a solution of aluminum chloride (9.6 g: 72 mMol.) in anisole (31 ml) at -30° C. After stirring for 1 hour at the same temperature, the reaction mixture is quenched with ethanol (25 ml), stirred for several minutes, diluted with 1N-hydrochloric acid (75 ml) and water (500 ml), and washed with ethyl acetate. The aqueous layer was separated, concentrated to remove the organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with a mixture of methanol and water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (4.19 g). Yield: 90%.
Reaction SMILES: [Br:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][CH:35]=1.C(N(C(C)C)CC)(C)C>C(#N)CCC>[Br:1][CH:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[CH2:14][CH2:13][CH2:12]1)=[O:22])([CH3:20])([CH3:19])[CH3:21]
Reactant: CCOC(=O)c1cnc(N)cn1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2cn1
Temperature: 120 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (213 mg, 0.38 mmol, 1.0 eq), ethyl 5-aminopyrazine-2-carboxylate (CAS-Nr. 54013-06-8, 70.5 mg, 0.42 mmol, 1.1 eq.) and diisopropylethylamine (0.055 mL, 0.42 mmol, 1.1 eq) in 2.3 mL butyronitrile was added predried 3 Å mol sieves. The mixture was heated overnight at 120° C. The reaction mixture was partitioned between DCM/water and was filtered through a phase separator. The remaining volatile organic components were removed by the use of a rotary evaporator. In parallel we conducted the same experiment in the absence of diisopropylethylamine following the same protocol. The crude materials of both experiments were combined and purified via MPLC (Biotage Isolera, 25 g Snap-cartridge; eluent: hexane/ethyl acetate (1/1)→ethyl acetate) to deliver 69 mg (14%, yield based on combined amount of tert-butyl (1-{4-[bromo(phenyl)acetyl]-phenyl}cyclobutyl)carbamate) of the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][C:12]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:24](O)=O>>[C:1]12([C:11]3[CH:16]=[C:15]4[C:14]([CH2:17][CH2:18][NH:19][CH2:24]4)=[CH:13][C:12]=3[O:20][CH:21]([CH3:23])[CH3:22])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Oc1cc(CCN)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: O=CO
Product: CC(C)Oc1cc2c(cc1C13CC4CC(CC(C4)C1)C3)CNCC2
Temperature: 60 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of the product of Step E (0.4 g, 0.78 mmol) in HCOOH (3 ml) (CH2O)n (0.026 g, 0.87 mmol) was added and the mixture was stirred for 18 h at 60° C. This was evaporated to dryness and the residue was purified by FCC (SiO2) to give the desired product (0.17 g, 41%), as light yellow paste. 1H-NMR (CDCl3) 1.36 (d, 6H, J=6 Hz); 1.74 (s, 6H); 2.03 (s, 3H); 2.08 (s, 6H); 2.7 (tr, 2H, J=5.91 Hz); 3.10 (tr, 2H, J=5.99 Hz); 3.91 (5, 2H); 4.55-4.64 (m, 1H); 6.53 (s, 1H); 6.82 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)nc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)nc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-morpholinopyridin-3-yl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.04 g, 11% yield). MS: m/z 517.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]1[C:15]1[CH:27]=[CH:26][C:18]2[NH:19][C:20](=O)[O:21][C:22]([CH3:24])([CH3:23])[C:17]=2[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:15]2[CH:27]=[CH:26][C:18]3[NH:19][C:20](=[S:37])[O:21][C:22]([CH3:24])([CH3:23])[C:17]=3[CH:16]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.3 g, 35 mmol, 1 eq) in toluene (130 mL) was added Lawesson's reagent (1.58 g, 3.9 mmol, 1.1 eq) and the reaction mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was dissolved in acetone/dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the product (0.51 g, 38%) as yellow crystals. 1H NMR (DMSO-d6) δ1.35 (s, 9H), 1.64 (s, 6H), 6.47 (d, 1H, J=3.6 Hz), 7.07 (d, 1H, J=8.1 Hz), 7.32 (d, 1H, J=3.6 Hz), 7.37 (dd, 1H, J=1.8, 8.1 Hz), 7.43 (d, 1H, J=1.8 Hz), 12.28 (s, 1H); MS (ESI) [M−H]−=382; Anal. Calcd. For C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C, 62.53; H, 5.6; N, 10.87.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (40 mg, 0.18 mmol) was suspended in CH2Cl2 (2 ml) and treated with triethylamine (52.6 μl, 0.378 mmol) followed by 4-fluorobenzenesulfonyl chloride (38.6 mg, 0.198 mmol). The reaction was stirred 1 hr at ambient temperature and chromatographed on a silica gel column eluted with 20% hexane in CH2Cl2. The product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to provide the title compound: (mp 169°-174°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:17][NH2:18].[ClH:19]>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:18][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: O=CC1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Product: CNCC1(c2ccc(F)c(F)c2)CCCCC1

Procedure:
The title compound was synthesized from 1-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (131 mg, 0.58 mmol) and methyl amine (320 μL, 0.64 mmol, 2.0 M in THF) according to General Procedure H, followed by HCl salt formation. The HCl salt was recrystallized from CH3CN to give pure (1-(3,4-difluorophenyl)cyclohexyl)-N-methylmethanamine hydrochloride as colorless crystals. HPLC Rt=8.15 min; 1H NMR (400 mHz, MeOH-d4) 7.36-7.21 (m, 3H), 3.11 (s, 2H), 2.55 (d, J=3.67 Hz, 3H), 2.15-2.12 (m, 2H), 1.67-1.31 (m, 8H); LC-MS 7.04 min, (M+1)+ 240 @ 7.19 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:11].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:11][CH:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:24]
Reactant: NC1CCc2c(F)cccc21
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCl)NC1CCc2c(F)cccc21
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a stirred, cold (0° C.) solution of 7.0 grams (0.046 mole) of 4-fluoroindanylamine (known compound) and 5.7 grams (0.056 mole) of triethylamine in 100 mL of methylene chloride was added 5.4 grams (0.051 mole) of 2-chloroethyl isocyanate. The cold reaction mixture was stirred for three hours at which time it was filtered. The filter cake was rinsed with methylene chloride. The filtrates were combined and concentrated under reduced pressure to a residue. The residue was triturated with hexanes and the mixture filtered. The filter cake was dried under reduced pressure to yield 4.0 grams of [(2-chloroethyl)amino]-N-(4-fluoroindanyl)carboxamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]1[CH:4]=[CH:5][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCO/C=C/C(=O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one (6.1 g, 28.0 mmol) was added to a solution containing 1H-benzo[d]imidazol-2-amine (3.73 g, 28.0 mmol) and Triethylamine (3.91 mL, 28.0 mmol) in Toluene (Volume: 100 mL). Heated the reaction to 120° C. for 2 hours. Let the reaction cool to room temperature and concentrated under vacuum. Diluted with water and filtered. Collected solid and dried under vacuum to afford crude 2-(trichloromethyl)benzo[4,5]imidazo[1,2-a]pyrimidine (8.04 g, 28.1 mmol, 100% yield).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[C:15](Cl)=[O:16])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:21]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:20]=1)[C:15](=[O:16])[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Sc1ccccn1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Sc2ccccn2)cc(C(C)(C)C)c1
Reaction time: 5 h

Procedure:
To a stirred solution of 2-mercaptopyridine (2.78 g, 25.0 mmol) in CH2Cl2 (50 mL) was added a solution of 3,5-di-tert-butylbenzoyl chloride (6.31 g, 25.0 mmol) in CH2Cl2 (125 mL) over 10 min. After 5 h, TLC showed complete consumption of the 2-mercaptopyridine, then 2 N NaOH was added. The organic phase was isolated, washed with water, then dried (Na2SO4) and the solvent was removed to afford a white solid. The solid was recrystallized in hexane affording a white solid (5.05 g, 62%): mp 73-74° C.; 1H NMR δ 1.36 (s, 18H), 7.31-7.36 (m, 1H), 7.67-7.70 (m, 1H), 7.75-7.80 (m, 2H), 7.85-7.88 (m, 2H), 8.66-8.69 (m, 1H); 13C NMR δ 32.0, 35.7, 122.6, 124.2, 128.9, 131.4, 136.9, 137.7, 151.1, 152.3, 152.5, 190.8; Anal. Calcd for C20H25NOS: C, 73.35; H, 7.69; N, 4.28. Found: C, 73.40; H, 7.75; N, 4.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])SC)=[CH:4][N:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])[N:18]([CH3:19])[CH3:17])=[CH:4][N:3]=1
Reactant: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Temperature: 30 °C
Yield: 93.4 %

Procedure:
1-(2-chloro-5-pyridylmethyl)-2-methyl-3-nitroisothiourea (1.3 g) was dissolved in ethanol (20 ml) and to the solution was added an aqueous solution (50%) of dimethylamine (0.5 g) at room temperature, followed by one-day stirring at 30° C. The ethanol in the solution was distilled off under reduced pressure and it was purified on a chromatographic column (the eluent was a mixture of methanol and chloroform) so as to obtain the desired 3-(2-chloro-5-pyridylmethyl)-1,1-dimethyl-2-nitroguanidine (1.2 g) having a melting point in the range of from 158° to 160° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].C([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])#C>>[OH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: C#Cc1ccccc1O
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2O)c1)c1ccccc1
Yield: 7 %

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 1-ethynyl-2-hydroxybenzene were reacted to give the title compound as a white solid (6 mg, 7%).
Reaction SMILES: [NH:1]([C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:7]=2[CH:6]=1)=[O:4])[NH2:2].C(O)C.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>Cl.O1CCCC1>[CH:32](=[N:2][NH:1][C:3]([C:5]1[S:28][C:8]2[NH:9][N:10]=[C:11]([NH:12][C:13](=[O:27])[C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:7]=2[CH:6]=1)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN)cc34)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN=Cc5ccccc5)cc34)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
N-(5-Hydrazinocarbonyl-1H-thieno[2,3-c]pyrazol-3-yl)-4-(4-methylpiperazin-1-yl)-benzamide (0.150 g, 0.318 mmol, 1 eq.), ethanol (1 mL) and, by syringe, benzaldehyde (0.048 mL, 0.47 mmol, 1.3 eq.) are placed in a dry 5 mL round-bottomed flask under argon. Two drops of 5 N hydrochloric acid are added to the suspension. The reaction mixture is stirred at a temperature in the region of 50° C. for 3 hours, the solvent is then evaporated off and the residue is placed directly on a column of neutralized silica gel. Elution is performed with a methanol/dichloromethane mixture (10/90 by volume). The product obtained is directly added to a mixture of 1 mL of tetrahydrofuran and 0.5 mL of 5 N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. N-[5-(Benzylidenehydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide is obtained in the form of a white solid (0.029 g, 16%). MS: ES m/z=488 MH+ base peak. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 2.53 (partially masked s, 3H); 2.87 (m, 4H); 3.47 (m, 4H); 7.03 (d, J=9.0 Hz, 2H); from 7.39 to 7.49 (m, 3H); 7.79 (d, J=7.5 Hz, 2H); 8.01 (d, J=9.0 Hz, 2H); 8.28 (s, 1H); 8.39 (s, 1H).