Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.C1COCC1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CO>[CH:27]1([NH:31][C:2]2[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=[C:6]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:7]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: NC1CCC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccncc1F)c1cnc2c(NC3CCC3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A 1 dram vial was charged with 8A (25 mg, 0.077 mmol) and THF (1 mL). Cyclobutylamine (8.54 μL, 0.100 mmol) was added and the reaction was heated to 80° C. After 4 hours at 80° C., the reaction was cooled to room temperature and the solvent was removed under a stream of nitrogen. Trans-4-aminocyclohexanol (400 mg, 3.47 mmol) was added and the mixture was heated to 130° C. and then cooled to room temperature after 4 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 40 min gradient, monitored at 220 nm). The product (retention time=39.317 minutes) was isolated and lyophilized to dryness to afford 8-(cyclobutylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-hydroxycyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (5 mg, 11.78%). HPLC Rt=3.971 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=440.28.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]C=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3=NC=CC=C3CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3=[N:27][CH:17]=[CH:16][CH:15]=[C:14]3[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCc3cccnc32)n1
Product: CCc1nc(NC2CCc3cccnc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 8.47, 7.61, 7.18, 5.30, 3.05, 2.81, 2.78, 1.98, 1.33–1.19; (MS/CI) calcd for C16H19N4Br+H 348.3, found 347.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:15])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: C1CCNC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N2CCCC2)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (100 mg) and pyrrolidine (2 ml) was heated at 120° C. for 3 h to obtain 39 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyrrolidin-1-yl)propan-1-one after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THE.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[F:21][C:22]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(F)cc1F)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,4-difluorobenzoyl chloride, there is obtained ethyl N-(2,4-difluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 406 (8), 377 (22), 194 (100), 141 (74);
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[C:3](=[O:14])[NH:2]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[C:4]([C:3](=[O:14])[N:2]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:1]=4)=[CH:5][NH:6][C:7]=3[CH:8]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=c1[nH][nH]c2c1cnc1ccccc12
Product: CN1CCN(c2ccc3c4nn(-c5ccccc5)c(=O)c-4c[nH]c3c2)CC1

Procedure:
The title compound was prepared following the procedure in Step 5 using 13a and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.44 (3H, s), 2.74 (4H, brm), 3.44 (4H, brm), 7.03 (1H, d, J=2.20 Hz), 7.27 (1H, ddd, J=7.41, 1.64, 1.10 Hz), 7.35 (1H, dd, J=9.07, 2.47 Hz), 7.65 (2H, m), 7.99 (2H, m), 8.17 (1H, d, J=9.07 Hz), 8.53 (1H, s). m/z 360.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:14]1(=O)[O:19][CH2:18][CH2:17][CH2:16][CH2:15]1>Cl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[N:12]=[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[NH:13][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: O=C1CCCCO1
Agent: Cl
Product: OCCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1
Temperature: 135 °C
Yield: 84.6 %

Procedure:
4-chloro-5-(trifluoromethyl)benzene-1,2-diamine (5.00 g, 23.74 mmol) was dissolved in HCl solution (4 M solution) (18.85 ml) at r.t. and delta-valerolactone (2.62 g, 26.12 mmol) was added slowly. The reaction was heated to 135° C. for 2 hrs then slowly cooled to r.t. The reaction was quenched by the addition of sat. NaHCO3 solution (200 ml) to pH 8. The mixture was extracted with EtOAc (3×150 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml) to give the pure product (5.88 g, 84%): MS (ESI+) for C12H12ClF3N2O m/z 293.4 [M+H]+; LC purity 90% (ret. time, 1.49 min); 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.39-1.72 (2H, m), 1.71-1.94 (2H, m), 2.87 (2H, t, J=7.61 Hz), 3.58 (2H, t, J=6.09 Hz), 7.42-7.96 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.[OH-].[Na+].CO.Cl>O.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A stirred mixture of methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (245 g, 0.45 mol), NaOH (36 g, 0.90 mol) dissolved in water (225 mL), methanol (0.5 L) and THF (1.2 L) was heated at 65° C. for 90 min. The mixture was cooled to room temperature, treated with 6 N HCl (150 mL) and stirred at room temperature for 30 min. The resulting precipitate was collected by filtering, washed with water (2×1 L) and dried overnight at 45° C. in a vacuum oven to yield 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (162 g, 68%). A second crop of material was similarly obtained (27.2 g, 11%). 1H NMR (400 MHz, DMSO-d6): 8.48 (d, J=9 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 8.17 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 7.72 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (m, 1H), 6.92 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.46 (m, 1H), 1.32 (d, J=7 Hz, 6H). ES-LCMS m/z 533 (M+H)+.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][NH:20][CH:21]([CH3:23])[CH3:22]>C(#N)C>[CH:21]([N:20]([CH3:19])[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:23])[CH3:22]
Reactant: CNC(C)C
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CC#N
Product: COc1ccc(-c2c(N(C)C(C)C)c(=O)c2=O)cc1
Yield: 63.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and methyl-isopropylamine (0.07 mL, 0.670 mmol) in acetonitrile (3 mL) were converted to the title compound (0.10 g, 63%) m.p.: 109-115° C.; 1H NMR (DMSO-d6) δ7.60(m,2H), 7.07(m,2H), 4.91(m,1H), 3.81(s,3H), 1.23(br d, 6H); MS (m/z) 259 [M+].
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[F:7][CH:8]([F:49])[C:9]1[N:13]([C:14]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:17]=[C:16]([N:26]3[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][N:37]4[CH2:42][CH2:41]S[CH2:39][CH2:38]4)(=O)=[O:33])[CH2:28][CH2:27]3)[N:15]=2)[C:12]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:11]=2[N:10]=1.[O-:50][S:51]([O-:53])=O.[Na+].[Na+].[OH2:56]>CC(C)=O.C(O)(=O)C.C(Cl)Cl>[F:49][CH:8]([F:7])[C:9]1[N:13]([C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][S:51](=[O:53])(=[O:50])[CH2:41][CH2:42]4)(=[O:33])=[O:56])[CH2:28][CH2:27]3)[N:17]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:19]=2)[C:12]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:11]=2[N:10]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCSCC3)CC2)n1
Reactant: O=S([O-])[O-]
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCS(=O)(=O)CC3)CC2)n1
Yield: 65 %

Procedure:
A solution of KMnO4 (88 mg, 0.559 mmol) in water (6 mL) was added dropwise to a stirred solution of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[2-(4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (170 mg, 0.266 mmol) in acetone (50 mL) and acetic acid (7.5 mL) at room temperature. After 2.5 hrs the reaction was diluted with water, decolourized with Na2SO3 and the acetone removed under vacuum. The mixture was neutralized with conc. aq. NH3 to give a precipitate, which was dissolved in CH2Cl2 and dried (Na2SO4). The solvent was then removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98.5:1.5) gave 117 mg (65% yield) of 2-(difluoromethyl)-1-[4-(4-{[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole: mp 258-261° C.; 1H NMR (CDCl3) δ7.85 (d, J=8.3 Hz, 1H), 7.42 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 4.01 (br s, 4H), 3.88 (br s, 4H), 3.79 (m, 4H), 3.37 (t, J=5.0 Hz, 4H), 3.07 (m, 4H), 3.05 (s, 8H); HRMS Calcd. for C26H36F2N9O6S2: MH+ m/z 672.2198. Found: m/z 672.2184.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].C(OC([N:22]1[C:30]2[C:25](=[C:26]([CH2:31]Cl)[CH:27]=[CH:28][N:29]=2)[CH:24]=[CH:23]1)=O)(C)(C)C>C1COCC1>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:31][C:26]1[CH:27]=[CH:28][N:29]=[C:30]2[NH:22][CH:23]=[CH:24][C:25]=12)([O-:5])=[O:4]
Reactant: CC(C)(C)OC(=O)n1ccc2c(CCl)ccnc21
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1ccn2Cc1ccnc2[nH]ccc12
Reaction time: 4 h
Yield: 15.8 %

Procedure:
The title compound was also prepared according to the following method. Specifically, sodium hydride (144 mg, 6 mmol) was added to a solution of 4-nitroindole (973 mg, 6 mmol) in THF and the resulting mixture was stirred for 4 h. 1-(t-butyloxycarbonyl)-4-chloromethyl-7-azaindole (Int-11, 1.5 g, 5.5 mmol) was then added. After the reaction was complete (by TLC), the mixture was quenched with saturated aqueous ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to provide 4-[(4-nitro-1H-indol-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (254 mg, 16%).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:20])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5](=[O:20])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: CO[C@H]1CC[C@@H](Cn2ccc(C)c([N+](=O)[O-])c2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CO[C@H]1CC[C@@H](Cn2ccc(C)c(N)c2=O)CC1
Reaction time: 22 h

Procedure:
A mixture of cis-3-nitro-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone (0.16 g, 0.57 mmol) and 10% Pd/C (0.06 g) in ethanol was hydrogenated at 50 psi in a Parr apparatus for 22 hours. The catalyst was removed by filtration, and the solvent was evaporated to give cis-3-amino-1-(4-methoxycyclohexylmethyl)-4-methyl-2-pyridone (0.13 g, 0.52 mmol, 91%).
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[C:14]2[NH:13][S:12](=[O:16])(=[O:15])[N:11]([CH:17]([CH3:19])[CH3:18])[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCCl>[Cl:4][C:5]1[C:14]2[N:13]([C:2]#[N:1])[S:12](=[O:16])(=[O:15])[N:11]([CH:17]([CH3:18])[CH3:19])[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: CC(C)N1C(=O)c2cccc(Cl)c2NS1(=O)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)N1C(=O)c2cccc(Cl)c2N(C#N)S1(=O)=O
Temperature: 20 °C
Reaction time: 48 h

Procedure:
127 parts of cyanogen bromide are added to 274.5 parts of 8-chloro-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide dissolved in 1,500 parts of 1,2-dichloroethane at 5°-10° C. and 121 parts of triethylamine are then added dropwise at the same temperature. The reaction mixture is then stirred for 48 hours at room temperature (20° C.), after which it is washed twice with water and three times with normal aqueous sodium hydroxide solution and dried, and the solvent is evaporated off under reduced pressure. The residue is recrystallized twice from isopropanol and gives 90 parts of 8-chloro-1-cyano-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide of melting point 123°-124° C.
Reaction SMILES: [CH2:1]([C:15](=[CH2:19])[C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].B(F)(F)F.[CH3:24]O>>[CH2:1]([C:15](=[CH2:19])[C:16]([O:18][CH3:24])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CO
Reactant: C=C(CCCCCCCCCCCCCC)C(=O)O
Agent: FB(F)F
Product: C=C(CCCCCCCCCCCCCC)C(=O)OC

Procedure:
14.6 Grams of 2-tetradecylacrylic acid (0.052 mole) are combined with 65 ml of absolute methanol and 15 ml of 51% BF3 in methanol in a 200 ml flask equipped with a condenser and drying tube. The system is heated under reflux for six hours (two layers appear when cooled). The mixture is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over anhydrous MgSO4. The ether solvent is removed under reduced pressure. The oily residue of methyl 2-tetradecylacrylate (14.70 g) is not purified further (>95% pure by GC) and used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:12][C:13]([C:16]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][O:17]1)([CH3:15])[CH3:14]>CN(C)C=O>[CH3:14][C:13]([CH3:15])([C:16]([CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([OH:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:12]
Reactant: CC(C)(C)C1(CCCOc2ccccc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(CCCOc1ccccc1)Cn1cncn1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
5.6 g (0.082 mol) of 1,2,4-triazole are added to a suspension of 11.3 g (0.082 mol) of potassium carbonate in 50 ml of dimethylformamide. 8.8 g (0.038 mol) of 2-(1,1-dimethyl-ethyl)-2-(3-phenoxypropyl)-oxirane are then added dropwise to the mixture, and the mixture is heated at 130° to 140° C. for 12 hours. After cooling to room temperature, the reaction mixture is filtered. The filtrate is concentrated under reduced pressure and the residue which remains is dissolved in methylene chloride. The organic phase is washed three times with water and, after drying, is concentrated. The residue is recrystallized from n-hexane. 8.1 g (70.3% of theory) of 2,2-dimethyl-6-phenoxy-3-(1,2,4-triazol-1-yl-methyl)-hexan-3-ol of melting point 106° C. are obtained in this manner.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[CH3:16])=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[C:28]([C:29]#[N:30])[CH:27]=1)=[O:25])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)c1

Procedure:
Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G47) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light red solid (100 mg).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C>O1CCOCC1.Cl>[NH:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](Nc2nc3ccccc3[nH]2)CC1

Procedure:
A solution of trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (500 mg, 1.7 mmol) in dioxane (4 mL) and HCl (6 N, 8 mL) was heated to 60° C. for 16 h. After cooling, concentration of the reaction mixture gave trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid as a white solid (M) (420 mg): 1H NMR (300 MHz, CD3OD) δ 7.39 (m, 2H), 7.28 (m, 2H), 3.57 (m, 1H), 2.35 (m, 1H), 2.18 (br t, 4H), 1.65-1.40 (m, 4H); mass spectrum m/z 260 [(M+H)+; calcd for C14H18N3O2: 260].
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[C:9]1([CH3:19])[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1>>[C:1]([O:5][CH2:6][CH2:7][O:8][CH2:3][CH2:2][CH:1]1[O:4][CH2:14][C:9]([CH3:10])([CH3:19])[CH2:6][O:5]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC(=O)OCCO
Product: C=CC(=O)OCCOCCC1OCC(C)(C)CO1

Procedure:
A mixture of hydroxyethyl acrylate (11.6 g), an equivalent amount of 2-ethylenyl-5,5-dimethyl-1,3-dioxane (EDD) (14.2 g), and a catalytic amount of p-toluenesulfonic acid (100 mg) was heated at 65° C. overnight. Gas chromatography showed that reaction occurred. The unreacted starting materials were removed at 40° C. under 0.05 mm Hg.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH:11](C)[CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].C1(B(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP(=O)(CC)CC(C)CN
Agent: c1ccc(B(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCCN
Yield: 216.6 %

Procedure:
207 g (1 mol) of butyl ethyl(3-aminopropyl)phosphinate (produced as in Example 15) and 242 g (1 mol) of triphenylborane are stirred in 400 ml of toluene at room temperature for 1 hour. Toluene is distilled off at reduced pressure to leave 449 g (100% of theory) of butyl ethyl(3-aminopropyl)phosphinate as triphenylborane adduct.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C>>[C:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])(=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NC(=O)C1CCCc2c(Cc3ccccc3)cccc21
Product: NC(=O)C1CCCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 100 ml. of acetic acid is added 6.6 g. of 5-benzyl-1,2,3,4-tetrahydro-1-naphthamide and, under cooling with ice, 3.4 g. of chromic anhydride is added. The mixture is stirred well. After stirring overnight, the reaction mixture is poured over 500 g. of ice and the resultant crystals are collected by filtration. This is subjected to column chromtography on silica gel using chloroform as the eluent and the eluate is recrystallized from cyclohexane. The procedure gives 5-benzoyl-1,2,3,4-tetrahydro-1-naphthamide, melting point: 145.5°-147.5°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:6](C=O)=[CH:5][C:4]=1[CH3:14].[OH:15]O>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([OH:15])=[CH:5][C:4]=1[CH3:14]
Reactant: OO
Reactant: COc1c(C)cc(C=O)c2c1CCC2
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1c(C)cc(O)c2c1CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
The stirred solution of 7-methoxy-6-methyl-indan-4-carbaldehyde (1.0 gm, 0.0060 mole) in Methanol (20 ml), Sulphuric acid (0.6 ml) was added at room temperature. To the reaction mixture, 30% Hydrogen peroxide (1.6 ml) was added and stirred for 1 hour at 0° C. Methanol was distilled under vacuum and the residue was dissolved in Ethylacetate (50 ml), further ethyl acetate layer was washed with water and evaporated to give a crude product, which upon triturating with Hexane give 600 mg title compound as a solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[OH:3][NH:2][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[NH:5]
Reactant: NO
Reactant: N#CN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(NO)N1CCCCC1

Procedure:
Amidine (e) is readily produced from nitrites. More specifically, hydroxylamine hydrochloride dissolved in a suitable solvent, such as water, is reacted with cyanopiperidine (g) in the presence of a base such as sodium carbonate in a suitable solvent, such as in methanol and exposed to heat to provide the hydroxycarbamimidoyl-piperidine (h). The hydroxycarbamimidoylpiperidine (h) in a suitable solvent, such as acetic acid, is then hydrogenated via palladium catalyst in the presence of acetic acid anhydride under pressure to provide amidine (e).