Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Na].Br[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO.O>[CH:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)CCC/C=C\CBr
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CCC/C=C\CC(C(=O)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
Dimethyl malonate (39.6 g) is added slowly with cooling and stirring to a solution of 6.9 g of sodium dissolved in 100 ml of absolute methanol and the mixture stirred for 15 min. The bromoester of formula 9, methyl cis-7-bromo-5-heptenoate (65.7 g) is added dropwise. The mixture is heated at reflux for 1 hr., cooled and diluted with water. The mixture is extracted with ether. The ether extracts are dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give the title compound, b.p. 140°-150° C/0.7 mm.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]1[CH:10]2[CH2:11][C:12]3([NH2:15])[CH2:14][CH:8]([CH2:9]2)[CH2:7][CH:6]1[CH2:13]3.[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:20]=2[O:19][CH2:18][CH2:17]1>O>[C:12]12([NH:15][C:26]([C:25]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[O:27])[CH2:14][CH:8]3[CH2:9][CH:10]([CH2:5][CH:6]([CH2:7]3)[CH2:13]1)[CH2:11]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1cccc2c1OCCO2
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cccc2c1OCCO2
Yield: 25.7 %

Procedure:
200 ml of chloroform and 37.5 g of adamantamine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4-benzodioxane-5-carbonyl chloride was added in portions at a temperature of from 5°-10° C. After agitation at ambient temperature 1500 ml of water was added and then chloroform was removed under vacuum. The base which was precipitated by ammonia was extracted by means of methylene chloride. After removal of the solvent the residue was dissolved in hydrochloric ethanol. The crystals formed by cooling were dried off, washed and then dried. 20 g of N-(1-adamantyl)-1,4-benzodioxane-5-carboxamide was produced (M.P.: 137° C.; yield: 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=2)[N+:12]#[C-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=C1C#C[Si](C)(C)C.IC1C=C(C(N[CH:68]=[O:69])S(C2C=CC(C)=CC=2)(=O)=O)C=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([N+:12]#[C-:13])[C:14]2[CH:19]=[CH:18][C:17]([O:69][CH3:68])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Reactant: [C-]#[N+]C(c1cccc(I)c1)S(=O)(=O)c1ccc(C)cc1
Agent: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Product: [C-]#[N+]C(c1ccc(OC)cc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 53 but using (4-methoxyphenyl)(phenylsulfonyl)methylformamide (Tetrahedron Lett., 1996, 37 (45), 8113) in place of {(3-iodophenyl)[(4-methylphenyl)sulfonyl]methyl}formamide (Intermediate 52). Tan solid (26.15 g, 97%)
Reaction SMILES: Cl.O1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:19]3[NH:24][CH2:23][CH2:22][NH:21][N:20]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2OC1.Cl.C1C2C(=CC=CC=2)C=CC=1CC1NCCNN=1.[Cl:43]C1C=CC(CC(C2NCCNN=2)S(C2C=CC(C)=CC=2)(=O)=O)=CC=1>>[ClH:43].[C:9]1([CH:11]([C:19]2[NH:24][CH2:23][CH2:22][NH:21][N:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CC(C2=NNCCN2)c2ccc3c(c2)OCO3)cc1
Reactant: Cc1ccc(S(=O)(=O)C(Cc2ccc(Cl)cc2)C2=NNCCN2)cc1
Agent: Cl
Agent: c1ccc2cc(CC3=NNCCN3)ccc2c1
Product: c1ccc(CC(C2=NNCCN2)c2ccccc2)cc1

Procedure:
In addition to the compounds listed above, compounds which do not fit the general formula of Table 1 were prepared using the process of the invention. The compounds include: 3-(1-(1,3-benzodioxol-5-yl)-2-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride; 1,4,5,6-tetrahydro-3-(2-naphthalenylmethyl)-1,2,4-triazine monohydrochloride; and 3-(2-(4-chlorophenyl)-1-((4-methylphenyl)sulfonyl)ethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: ClCCNCCCl
Reactant: COc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1c(Cl)cc(N2CCNCC2)cc1Cl
Yield: 29.8 %

Procedure:
A mixture of 3,5-dichloro-4-methoxyaniline (16.0g) and bis-(2-chloroethyl)amine hydrochloride (14.77g) in n-butanol (100 ml) was stirred under reflux for 48 hr. Anhydrous potassium carbonate (11.45g) was added and the resulting mixture was stirred under reflux for a further 24 hr., then filtered hot. The solid which precipitated on cooling was crystallised from ethanol-ether to give 1-(3,5-dichloro-4-methoxyphenyl)piperazine hydrochloride (3.7g) m.p. 252°-255°.
Reaction SMILES: C1(C2[C:13]([C:14]3[NH:18][C:17](C)=[N:16][N:15]=3)=[CH:12]C(C(O)=O)=C(C)C=2)CCC1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:31])[CH:23]=1.C(NN)(=O)CC>>[CH2:13]([C:14]1[NH:18][C:17]([C:30]2[C:22]([F:21])=[CH:23][C:24]([CH3:31])=[C:25]([CH:29]=2)[C:26]([OH:28])=[O:27])=[N:16][N:15]=1)[CH3:12]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CCC(=O)NN
Product: CCc1nnc(-c2cc(C(=O)O)c(C)cc2F)[nH]1

Procedure:
The title compound was synthesized using standard chemical manipulations and procedures similar to those used for the preparation of compound 152.8 using 4-fluoro-2-methylbenzoic acid instead of 4-bromo-2-methylbenzoic acid and propionohydrazide instead of acetohydrazide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[S:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:30]2[S:31][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:9]
Reactant: COc1ccc(NC(=O)c2cc(Br)cnc2N)cn1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: COc1ccc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(6-methoxy-3-pyridyl)pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A40”; HPLC/MS: 1.29 min, [M+H]=426;
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43]Cl)=[CH:35][CH:34]=1.CCO>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][N:15]2[C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]=3[N:8]=[CH:16]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(OCCOCCl)cc1
Reactant: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(OCCOCn2cnc3nc(N)[nH]c(=O)c32)cc1
Yield: 88.6 %

Procedure:
Compound 8 (2.72 g, 8.20 mmol) was prepared in 82% yield from 6 (3.64 g, 9.25 mmol) and (2-(p-methoxyphenyloxy)ethoxy)methyl chloride (2.18 g, 10.1 mmol) in DMF (100 mL) by the method used for the synthesis of 7: mp>250° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.18; UV (EtOH) λmax 290 (ε 16,500); 1H NMR (DMSO-d6) δ 3.70 (s, 3 H, OCH3), 4.02-4.10 (m, 4 H, O(CH2)2O), 5.74 (s, 2 H, H2C1′), 5.88 (s, 2 H, NH2), 6.67, 6.70 (AA′BB′, J=9.30 Hz, 4 H, C6H4), 7.50 (s, 1 H, NH), 8.85 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 56.12 (CH3), 68.74 (OCH2), 70.20 (CH2Oph), 75.31(C1′), 107.25 (C5), 144.02 (C8), 153.25 (C4), 154.48 (C2), 159.26 (C6), 115.55, 116.38, 153.51, 155.56 (C6H4); MS m/z 331 (M+). Anal (C15H17N5O4) C, H, N; calcd (%): 54.37, 5.17, 21.13; found (%): 54.26, 5.20, 21.19.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH3:10].[C:11]([C:17](OC)=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:16][O:15][C:13]([C:12]1[CH2:11][C:17](=[O:18])[C:6]2[C:7](=[C:2]([Cl:1])[C:3]([CH3:10])=[C:4]([Cl:9])[CH:5]=2)[N:8]=1)=[O:14]
Reactant: Cc1c(Cl)ccc(N)c1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C1=Nc2c(cc(Cl)c(C)c2Cl)C(=O)C1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
To a solution of 2,6-dichloro-3-aminotoluene (20.5 g, 0.11 mol) in methanol (300 mL) was added dimethyl acetylenedicarboxylate (15 mL, 0.12 mol) and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to a yellow solid. Diphenyl ether (350 mL) was heated to 230–240° C., and the yellow solid was added to it. The temperature was maintained at 230–240° C. for 20 minutes and the reaction mixture was cooled slowly to ambient temperature and diluted with petroleum ether (1L). The solid was filtered and washed with hot ethyl acetate to afford a brown solid, 2-(methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 85%); NMR (CDCl3) 2.62 (s, 3), 4.04 (s, 3), 7.02 (s, 1), 8.24 (s, 1) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:27][C:28]([NH2:30])=[S:29])([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH:32]([CH3:36])[C:33](=O)[CH3:34]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:27][C:28]2[S:29][C:32]([CH3:36])=[C:33]([CH3:34])[N:30]=2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NC(=S)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: Cc1nc(N[C@@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(C(F)(F)F)c2)sc1C
Temperature: 90 °C
Yield: 99.2 %

Procedure:
The thiourea (28 mg, 0.064 mmol) in ethanol (0.3 mL) in a two drum vial was added 3-bromobutan-2-one (28 mg, 0.18 mmol). The vial was heated in a shaker at 90° C. for 1 hour. The reaction was concentrated and crude mixture was purified by prep HPLC to give the (S)-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)4,5-dimethylthiazol-2-amine as a white solid (31 mg, 99% yield). LCMS: 3.63 min [M+1] 498.34 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.22 (s, 3H), 3.62-3.73 (m, 1H), 3.74-3.85 (m, 1H), 6.57 (d, J=7.58 Hz, 2H), 7.06-7.16 (m, 4H), 7.17-7.23 (m, 2H), 7.24-7.31 (m, 1H), 7.39 (dd, J=8.59, 5.05 Hz, 2H) 11.25(s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17].Cl.[NH2:44][OH:45]>O.C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[N:33][NH:44][OH:45])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H](n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](n1cnc2cc(-c3ccc(C=NNO)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.1 %

Procedure:
To a solution of Na2CO3 (0.84 g, 7.92 mmol) in a mixture of H2O (8 mL) and THF (30 mL) was added (1R,2R)-4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (0.5 g, 0.99 mmol, obtained in example 32) and hydroxylamine hydrochloride (0.35 g, 1.95 mmol). The mixture was stirred at reflux overnight, concentrated and the aqueous residue was extracted with CHCl3. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated to a solid which was purified by flash chromatography to give the title compound as a pale yellow solid (325 mg, 61%): mp 246°-247° C.; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.60 (s, 1H, N=CH--N), 8.18 (s, 1H, triazole), 7.86 (d, J=8.5, 2H, arom), 7.78 (d, J=8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.66 (s, 1H, thiophene), 7.43 (dt, Jt =6.5, Jd =9, 1H, arom), 7.06 (ddd, Jd =2.5, Jd =8.5, Jd =14, 1H, arom), 6.89 (dt, Jd =2.5, Jt =8.5, 1H, arom), 6.09 (q, J=7.3, 1H, MeCH), 5.09 (d, J=14.2, 1H, CH(H)), 4.19 (d, J=14.2, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); MS 314 (N-ethylheterocycle, C15H14N4O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =+74.9° (c 1, MeOH). Analysis calculated for C25H21F2N7O3S: C 55.86; H 3.94; N 18.24; S 5.96. Found: C 55.10; H 3.84; N 17.72; S 5.69.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC1Cc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)CN1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2,3-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C:16]([C:17]3[C:22]([O:23]C)=[CH:21][CH:20]=[CH:19][C:18]=3[O:25]C)=[CH:15][C:14]([C:27]([NH:29][CH:30]([CH2:34][CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32])=[O:28])=[N:13]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[C:16]([C:17]3[C:18]([OH:25])=[CH:19][CH:20]=[CH:21][C:22]=3[OH:23])=[CH:15][C:14]([C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32])=[O:28])=[N:13]2)=[CH:4][CH:3]=1
Reactant: CCCCC(NC(=O)c1cc(-c2c(OC)cccc2OC)n(-c2ccc(Cl)c3ccccc23)n1)C(=O)O
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCC[C@H](NC(=O)c1cc(-c2c(O)cccc2O)n(-c2ccc(Cl)c3ccccc23)n1)C(=O)O
Temperature: -70 °C

Procedure:
0.3 g of 2-{[1-(4-chloro-1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolyl]carbonylamino}hexanoic acid is dissolved in 6.7 ml of dichloromethane and the mixtureis cooled to -70° C. 5.7 ml of boron tribromide, dissolved in 20 ml of dichlormethane, are added dropwise and the reaction mixture is left for2 hours at -70° C. It is allowed to return to room temperature, and 12 ml of water are then added while cooling. Concentrated NaOH is added topH 14. The aqueous phase is washed with ether and brought to pH 2, the product is extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and evaporated. The residue is crystallisedfrom diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[CH:51]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:57][CH2:56][C:52]3[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccnc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (365 mg, 0.920 mmol), 1-hydroxybenzotriazole (249 mg, 1.839 mmol) and EDCI (353 mg, 1.839 mmol) were dissolved in DCM (Volume: 3.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.321 ml, 1.839 mmol) and pyridin-3-ylmethanamine (199 mg, 1.839 mmol) were added. The reaction was stirred at room temperature overnight. Solid precipitate formed overnight. The reaction was concentrated and triturated with ethyl acetate to afford product as a white solid. (Yield: 315 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.46, 8.40, 7.70-7.60, 7.54, 7.40-7.29, 7.21, 7.13-7.05, 6.73, 5.49, 4.38, 4.30, 4.04, 2.95, 2.47-2.39, 1.71, 1.42
Reaction SMILES: [N:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (0.28 g, 1.00 mmol) in DMF (10 mL) was added sodium hydride (0.056 g, 60% in oil, 1.40 mmol) at 0° C. under argon. The mixture was stirred at 0° C. for 10 min at room temperature for 20 minutes, and then treated with 1 -bromohexane (0.198 g, 1.2 mmol). The resulted mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The desired compound, 11-(4-hexyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine, was obtained in 0.167 g (46%) as a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:18][C:19]2([OH:36])[C:23](=[O:24])[O:22][C@H:21]3[C:25]4[C@@:30]([CH3:33])([CH2:31][CH2:32][C:20]23[OH:35])[CH2:29][CH2:28][CH2:27][C:26]=4[CH3:34])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:36][C:19]1([CH2:18][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:23](=[O:24])[O:22][C@H:21]2[C:25]3[C@@:30]([CH3:33])([CH2:31][CH2:32][C:20]12[OH:35])[CH2:29][CH2:28][CH2:27][C:26]=3[CH3:34]
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN4CCCCC4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 24 h

Procedure:
Piperidine (70.59 mg, 0.829 mmol) was added to compound of example 5 (180 mg, 0.412 mmol) dissolved in ethanol (5 mL) and reaction mixture was stirred for 24 hours. Saturated sodium bicarbonate solution was added, and reaction mixture was extracted with dichloromethane (3×50 mL). Dichloromethane layer was washed with water and brine and was dried over sodium sulfate. Solvent was removed and the crude product was purified by column chromatography (silica gel, 5-10% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]2[CH2:25][CH2:24][S:23][CH2:22]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:21]2[CH2:25][CH2:24][S:23][CH2:22]2)[C:33](=[O:35])[CH3:34])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCSC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3ccccc3c2n1CCCCN(C(C)=O)C1CCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]-(tetrahydro-thiophen-3-yl)-amine in dichloromethane was added triethyl amine (1.5 eq.) and acetic anhydride (1.5 eq.) and stirred at ambient temperature for 4 hrs. Reaction mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford N-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-(tetrahydro-3-thienyl) acetamide.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30]N>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=358.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:12](O)(=[O:23])[CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])(=[O:23])[CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: CC(C)CCCCCCCO
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COc1cc(CC(=O)OCCCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 81.8 %

Procedure:
8-Methyl-1-nonanol (752 mg, 4.74 mmol), homovanillic acid (907 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl homovanillate (1.25 g, yield 81.5%) as a colorless oil.
Reaction SMILES: C1(=O)CCCCC1.O=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.[NH2:23]O>>[CH2:21]1[C:16]2[CH:17]([NH:23][CH:9]3[C:10]([CH:15]=2)=[CH:11][CH:12]=[CH:13][CH2:14]3)[CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CCCCC1CC1CCCCC1=O
Reactant: NO
Solvent: O=C1CCCCC1
Product: C1=CCC2NC3CCCCC3=CC2=C1

Procedure:
Sym. octahydroacridine was prepared by converting cyclohexanone to di-(2-oxo-cyclohex-1-yl)-methane and further reacting with hydroxylamine according to the method of Gill et al. (JACS 1952, 74, 4923) and was isolated as a colourless oil b.p. 110-15°/0.5 mm. in 40% overall yield.