Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:19][CH2:20][Cl:21])[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O)CCC>C(Cl)(Cl)Cl>[ClH:21].[CH2:2]([N:9]([CH2:19][CH2:20][N:32]1[CH2:33][CH2:34][C:29]([OH:28])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31]1)[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: NC(=O)c1ccccc1N(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: NC(=O)c1ccccc1N(CCN1CCC(O)(c2ccccc2)CC1)Cc1ccccc1
Yield: 53.8 %

Procedure:
A mixture of 19.5 g 2-[Benzyl(2-chloroethyl)amino]benzamide hydrochloride, 15.75 g powdered anhydrous Na2CO3, 10.6 g 4-hydroxy-4-phenylpiperidine and 250 ml butanol was refluxed 20 hours, cooled and an equal volume of chloroform added. The mixture was filtered and the filtrate concentrated on the rotovap to dryness. The residue was dissolved in 500 ml ether, a little dry ice added, the mixture filtered and concentrated to dryness. The residue in 300 ml ether was treated with dry HC1 and filtered to give 15 g product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.CCCCCCC.C[O:21][C:22]([C:24]1[C:29]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:28][CH:27]=[CH:26][N:25]=1)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:22]([C:24]2[C:29]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:28][CH:27]=[CH:26][N:25]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nccnc1Nc1cccnc1
Reactant: Nc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: O=C(Nc1cccc(Cl)c1)c1nccnc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroaniline (140 mg, 1.1 mmol) was dissolved in 4 mL dioxane and trimethylaluminium-solution 2M in heptane (0.55 mL, 1.1 mmol) was added. The solution was stirred for 1 hr at room temperature and 3-(pyridin-3-ylamino)-pyrazine-2-carboxylic acid methyl ester (127 mg, 0.55 mmol) was added. The reaction mixture was stirred for 2 hrs at 80° C., cooled and quenched with 0.5 mL water. Sodium sulfate was added, stirred for 10 minutes, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:2->0:100 gradient) and the desired product was obtained as a yellow solid (13 mg, 7.2%), MS: m/e=326.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]S(O)(=O)=O.CO>>[CH3:18][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 948.5 %

Procedure:
As in Example 2, a melt of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.44 g (0.0045 mol) of methanesulfonic acid was introduced and reacted over the course of 4 hours with 175 g (5.46 mol) of gaseous methanol (vaporized at 160° C.). 10 g (92%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 98% (GC).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.N1CCCCC1>CO>[CH3:17][O:16][C:11]([C:12]1[CH:14]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([NH2:10])=[CH:7][CH:6]=2)[N:1]=1)=[O:15]
Reactant: Nc1ccc(C=O)c(N)c1
Reactant: COC(=O)C(C)=O
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1ccc2ccc(N)cc2n1

Procedure:
For example, 2,4-diaminobenzaldehyde 53.7 (Apin Chemicals) is reacted with one molar equivalent of methyl pyruvate 53.2 in methanol, in the presence if a base such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 53.8. Basic hydrolysis of the product, employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 53.9. The amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 53.10 by reaction with sodium nitrite and tetrafluoboric acid. The diazonium salt is heated in aqueous solution to afford the 7-hydroxyquinoline-2-carboxylic acid, 53.11, Z=OH. Alternatively, the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 53.11, X═Br. Alternatively, the diazonium tetrafluoborate 53.10 is reacted in acetonitrile solution with the sulfhydryl form of an ion exchange resin, as described in Sulfur Lett., 2000, 24, 123, to prepare 7-mercaptoquinoline-2-carboxylic acid 53.11, Z=SH.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]OC)[CH:9]=1.B(Cl)(Cl)[Cl:15].O>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][Cl:15])[CH:9]=1
Reactant: COCc1csc(CC(=O)OC)c1
Reactant: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc(CCl)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of (4-methoxymethyl-thiophen-2-yl)-acetic acid methyl ester (0.70 g, 3.50 mmol) in dichloromethane (20 mL) is treated with boron trichloride (3.50 mL, 1.0 M, 3.50 mmol) in a dropwise maner. After stirring at room temperature for 30 min the mixture is poured into water and extracted with dichloromethane (3×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified by chromatography (silica gel, 5-10% ethyl acetate in heptane) to give (4-chloromethyl-thiophen-2-yl)-acetic acid methyl ester (0.58 g, 81%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.18 (s, 1 H), 6.95 (s, 1 H), 4.52 (s, 2 H), 3.80 (s, 2 H), 3.72 (s, 3 H).
Reaction SMILES: O[CH:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[C:4](=O)[O:3]1.O.[NH2:18][NH2:19]>CS(C)=O>[OH:15][C:6]1[C:5]2[C:4](=[O:3])[NH:18][N:19]=[CH:2][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: NN
Reactant: O=C1OC(O)c2c1c(O)nc1ccccc21
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]ncc2c1c(O)nc1ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.54 g (0.0025 mol) of (RS)-1,4-dihydroxy-1,3-dihydrofuro[3,4-c]quinolin-3-one was dissolved in 5 ml of dimethyl sulphoxide while gassing with argon. 0.125 g (0.0025 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 4 days. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.28 g (53%) of 5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:20]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:21][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1c(Cl)n(Cc2ccccc2)c2ccccc12
Solvent: CCO
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a slurry of 1.35 g of 1-benzyl-2-chloroindole-3-carbaldehyde in 30 ml abs. EtOH was added 1 ml of ethyl cyanoacetate and 3.5 ml of piperidine, and the mixture was stirred at room temperature for 2.5 days. 30 ml of ice/water was added, and the precipitate was isolated by filtration and dried to give (1b). Yield 1.6 g of (1b), m.p. 155-156° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([OH:9])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:30]([NH2:41])[CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([NH:41][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1)=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N(CCC#N)CC(=O)O
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCC#N)CC(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
In a manner similar to the preparation of compounds of formula (Yc3) above, to 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]acetic acid (8.3 g, 39 mmol) dissolved in CH2Cl2 (100 mL) was added carbonyldiimidazole (6.2 g, 38 mmol). After stirring for 30 minutes, homopiperonylamine, hydrochloride (8.0 g, 41 mmol) and diisopropylethylamine (7.5 mL, 43 mmol) were added. After stirring for 18 hours, most of the solvent was removed in vacuo and the residue was partitioned with ethyl acetate and 1N HCl. The organic layer was separated, washed with aqueous bicarbonate and brine, dried (Na2SO4), and the solvent was removed in vacuo to give 13 g of 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]([C:23]2[S:27][C:26]([C:28]3([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)[CH:9]=[C:10]([NH:12][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:11]=1.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[OH:34][C:28]1([C:26]2[S:27][C:23]([C:8]3[CH:9]=[C:10]([NH:12][C:13]4[N:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][N:14]=4)[CH:11]=[C:6]([CH3:5])[CH:7]=3)=[CH:24][N:25]=2)[CH2:29][CH2:30][N:31]([C:1](=[O:3])[CH3:2])[CH2:32][CH2:33]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To a mixture of acetic acid (9 μL, 0.15 mmol) and Si-carbonyl diimidazole (266 mg, 0.287 mmol) was added a solution of 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) and hydroxybenzotriazole (26 mg, 0.17 mmol) dissolved in N,N-dimethylformamide, and the resultant suspension was shaken in a Bohdan block overnight at room temperature. The reaction mixture was filtered and concentrated in vacuo, and the resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 1-{4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone. MS EST: [M+H]+ m/z 478.1. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.95 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 1H), 4.25-3.99 (m, 1H), 3.73 (m, 1H), 3.41-3.34 (m, 1H), 3.07-2.97 (m, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 2.25-2.14 (m, 1H), 1.93 (m, 2H), 1.75 (m, 1H). rhSYK activity=+++
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].ClCCl.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:7])[S:3]([N:17]1[CH2:16][CH:15]2[CH2:11][N:12]([C:19]3[CH:20]=[CH:21][C:22]4=[N:27][N:26]=[C:25]([C:28]([F:31])([F:29])[F:30])[N:23]4[N:24]=3)[CH2:13][CH:14]2[CH2:18]1)(=[O:5])=[O:4]
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Reaction time: 1 h
Yield: 29.9 %

Procedure:
N,N-Dimethylsulfamoyl chloride (0.027 g, 0.19 mmol) and then dichloromethane were added sequentially to a mixture of diisopropylethylamineamine (0.044 g, 0.34 mmol) and 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.05 g, 0.17 mmol) in toluene (1.5 mL). The reaction mixture was stirred for 1 hour and evaporated to give an involatile residue. The residue was purified by preparative hplc using a Phenomenex Luna C18 100A column (10μ silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give N,N-dimethyl-2-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-sulfonamide (0.0206 g, 30%) as a white solid.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1.Br[CH2:19][CH3:20].C(O)(C)C>CN(C=O)C.C1(C)C=CC=CC=1>[Br:4][C:5]1[C:6](=[O:17])[N:7]([CH2:19][CH3:20])[CH:8]=[C:9]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1
Reactant: O=c1[nH]cc(-c2cnccn2)cc1Br
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCn1cc(-c2cnccn2)cc(Br)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1.5 g of sodium methoxide is added to a stirred mixture of 3-bromo-5-(2-pyrazinyl)-2(1H)-pyridone (6.3 g) in DMF (200 ml) warmed to a temperature of 80° C. 4 ml of bromoethane are added to the warmed reaction mixture which is stirred for 30 minutes at 80° C. The reaction mixture is cooled to RT, stirred overnight, filtered and the filtrate acidified to pH 5.7 by addition of methanolic HCl. The acidified filtrate is evaporated resulting in a thick red oil. The oil is treated with hot isopropanol and the inorganic salts filtered off. The isopropanol solution is warmed, charcoal added, and filtered while hot. The filtrate is evaporated resulting in a tan solid which is dissolved in warm toluene and chromatographed on a column of silica gel (40 g per g tan solid) dispersed in toluene. The column is eluted increasing concentrations of ethyl acetate in toluene followed by methanol and ethyl acetate. The purified product is recrystallized from decane and toluene. The initial crop of crystals is identified as the O-ethylated product isomer while the addition of toluene caused the crystallization of a second crop of crystals which is identified as the desired N-ethyl pyridone, M.P. 129°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1I.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>>[F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[CH:20]=[CH2:21]
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2F)c1I
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Product: C=Cc1c(Oc2ccc([N+](=O)[O-])cc2F)ccnc1N

Procedure:
The title compound was prepared from 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine and tributylvinyltin via a Stille coupling reaction in the same manner as described in Step B of Example 33. 1H NMR (DMSO-d6) δ 8.35 (dd, 1H, J=10.7, 3.1 Hz), 8.09 (d, 1H, J=9.2 Hz), 7.85 (d, 1H, J=5.6 Hz), 7.31-7.15 (m, 1H), 6.54 (dd, 1H, J=17.8, 11.7 Hz), 6.24 (br s, 2H), 6.20 (d, 1H, J=5.6 Hz), 5.71 (d, 1H, J=17.8 Hz), 5.46 (d, 1H, J=11.7 Hz); MS(ESI+): m/z 276.17 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10](=[C:15]([NH:17]C)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[CH3:20][NH:21]N>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:21]([CH3:20])[N:17]=[C:15]([CH3:16])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CNN
Reactant: CNC(C)=C(C(=O)OC)C(=O)c1ccc(F)cc1Cl
Solvent: CCOCC
Product: COC(=O)c1c(C)nn(C)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 2-chloro-4-fluoro-α-[1-(methylamino)ethylidene]-β-oxobenzenepropanoate (i.e. the product of Step B) (15.91 g, 55.82 mmol) and methylhydrazine (3 mL, 56 mmol) in diethyl ether (150 mL) was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as a colorless oil (15 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]#[N:11].S(Cl)(Cl)=O.O.[CH3:17][N:18]([CH3:21])[CH:19]=O>>[C:10]([C:3]1[C:4]([CH:7]([CH3:9])[CH3:8])=[N:5][S:6][C:2]=1[N:1]=[CH:17][N:18]([CH3:21])[CH3:19])#[N:11]
Reactant: CN(C)C=O
Reactant: CC(C)c1nsc(N)c1C#N
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)c1nsc(N=CN(C)C)c1C#N

Procedure:
To a solution of 6.7 g of 5-amino-4-cyano-3-isopropylisothiazole in 30 ml of dimethylformamide was slowly added 10.4 ml of thionyl chloride and the mixture was heated under reflux for 3 hours. The mixture was poured into 300 ml of water and the water-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethanol. The solution was treated with decolorizing charcoal, then was diluted with 300 ml of water. The small amount of solid which separated was removed by filtration and was discarded. As the solution stood undisturbed, tan solid separated which was collected and recrystallized from methylcyclohexane to give 3.0 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylformamidine, m.p. 95°-97°. A small amount was sublimed at 120° under 0.03 mm without change in melting point. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][I:10].CC[O:13][CH2:14][CH3:15]>>[I-:10].[CH3:9][N+:2]1([CH3:1])[CH:7]2[CH2:6][CH2:5][CH:4]1[CH2:3][C:14](=[O:13])[CH2:15]2
Reactant: CCOCC
Reactant: CI
Reactant: CN1CCCCC1=O
Product: C[N+]1(C)C2CCC1CC(=O)C2
Product: [I-]
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred solution of N-methylpiperidone (20.0 g, 143.7 mmol) in 150 mL of ether was added dropwise methyliodide (22.4 g, 158.1 mmol) in 100 mL of ether. The exothermic reaction was controlled by the rate of addition of methyl iodide and the mixture was stirred overnight after the addition. The white solid was filtered off by suction and dried in an oven, giving 35.0 g (86.6%) of the title compound.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[C:10]([F:16])[CH:9]=1.[OH2:17]>CO>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:15])(=[O:1])=[O:17])=[C:10]([F:16])[CH:9]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Br)cc1F
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(Br)cc1F

Procedure:
According to the procedure described for 54d the use of oxone® (1.48 g, 1.57 mmol) in 15 mL water and 4-bromo-2-fluoro-1-methylsulfanyl-benzene (347 mg, 1.57 mmol) in 30 mL methanol after 22 h reaction time gives crude title compound as a white solid. Purify by column chromatography, eluting with a gradient from 100:0 to 20:80 hexanes:ethyl acetate to obtain 4-bromo-2-fluoro-1-methanesulfonyl-benzene (220 mg) as a white solid. 1H-NMR (CDCl3) δ=3.21 (s, 3 H), 7.44-7.53 (m, 2H), 7.84 (mc, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.[CH3:15][N:16]1[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[N:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:15][N:16]1[C:20]([C:21]([NH:10][NH:9][C:7](=[O:8])[C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=[N:17]1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1C(=O)NNC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 19 h
Yield: 80.5 %

Procedure:
4-(Trifluoromethyl)benzohydrazide (583 mg) was added to a dimethylformamide (6.8 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (300 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.09 g) and diisopropylethylamine (830 μL) at a room temperature, and the obtained solution was then stirred for 19 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The obtained solid was washed with ethyl acetate/hexane (1:1), so as to obtain the title compound (598 mg) in the form of a colorless solid. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, chloroform:methanol=10:0 to 9:1), so as to further obtain the title compound (109 mg) in the form of a colorless solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][CH:8]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=1.ClC1C=C(S(Cl)(=O)=O)C=CC=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[N:29]=1.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C.N1C=CC=CC=1>[Cl:34][C:30]1[N:29]=[C:28]([NH:27][C:2]([NH:3][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH3:15])[CH:6]=2)(=[O:13])=[O:12])=[O:1])[CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(Cl)n1
Reactant: N#C[O-]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(S(=O)(=O)NC(=O)Nc2cccc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.128 g sodium cyanate in 3.0 ml acetonitrile was added 0.11 ml pyridine and 0.19 ml m-toluenesulfonyl chloride and the mixture was sonicated in a ultrasound bath at ca 40° C. for 1.5 h. HPLC showed disappearance of 3-Chloro-benzenesulfonyl chloride. The resulting suspension was added with stirring to a solution of 0.169 g 2-amino-6-chloropyridine in 1.0 ml of acetonitrile and the mixture was stirred at room temperature for 2 h. The reaction mixture was partioned between 0.1N sodium hydroxide and ethyl acetate (pH 10). The phases were separated and the aqueous phase was washed twice with ethyl acetate. The aqueous phase was acidified by addition of 25% hydrochloric acid and extracted with ethyl acetate, the organic phase was evaporated under reduced pressure. The residue was purified by silica column chromatography and crystallisation to yield 0.0995 g of a off-white solid. MS (ISN) M−H+=324.4
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][C:18]1([CH2:24][C:25](=O)[NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:13])([CH3:12])[CH3:11].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:10]([O:14][C:15](=[O:28])[NH:16][CH2:17][C:18]1([CH2:24][C:25]#[N:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC1(CC(N)=O)CCCCC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1(CC#N)CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
Cyanuric chloride (39.5 g, 0.214 mol) was added to (1-carbamoylmethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (3) (116 g, 0.429 mol) in 400 mL DMF. An ice-water bath was used to moderate the exotherm, and the reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water containing 120 g (1.43 mol) NaHCO3 and was extracted 4×EtOAc. The extracts were washed 1×water, 2× brine and dried over Na2SO4. Evaporation yielded an oil which was taken up in 3:1 hexane/EtOAc and filtered through silica gel. Evaporation yielded white crystals (86.5 g, 80%); mp 54-58° C.