Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C(O[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15]CCCCCCCCCCCCCCC)[CH:8]=1)C.[NH3:48]>C(O)C>[CH2:31]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:47])=[NH:48])[CH2:15][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)N)c1
Reaction time: 3 h
Yield: 74 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-benzimidate dihydrochloride (35.0 g., 0.05 mole) was dissolved in ethanol (150 ml.) and the mixture saturated with ammonia gas at 20° C. The mixture was held for three hours at 20° C., resaturated with ammonia gas at 20° C., and then stoppered and held overnight at room temperature. The mixture was evaporated in vacuo to a solid which was triturated with acetone (200 ml.), filtered, washed with water (4 × 100 ml.), triturated again with acetone (2 × 100 ml.), filtered and dried in vacuo overnight [22.0 g., 74% yield, Rf 0.42 (4:1, benzene:ethanol on silicic acid)]. The crude product was recrystallized from hot acetone (20.9 g., 70% yield, m.p.-forms a gel at 84° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethyisulphoxide (70 ml) was added over 10 minutes to a mixture of sodi-m cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesinm sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18](C(F)(F)F)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4].[Br:35]C1C2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=C(C=O)C=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18]([Br:35])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Product: COC(=O)C1CN(Cc2cc(Br)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde as starting material. ESI-MS(M+H+): 489.20/491.20.
Reaction SMILES: [N:1]1[C:8]([F:9])=[N:7][C:5](F)=[N:4][C:2]=1[F:3].[NH2:10][C:11]1[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:24][NH:25][C:26]2[CH:31]=[C:30]([S:32]([OH:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=2[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[OH-].[Na+]>>[F:9][C:8]1[N:1]=[C:2]([F:3])[N:4]=[C:5]([NH:10][C:11]2[C:12]([OH:45])=[C:13]([N:21]=[N:22][C:23]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[N:24][NH:25][C:26]3[CH:31]=[C:30]([S:32]([OH:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:27]=3[C:36]([OH:38])=[O:37])[CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=2)[N:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Reactant: Fc1nc(F)nc(F)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(F)nc(F)n2)c1O)c1ccccc1

Procedure:
14 parts of cyanuric fluoride are added dropwise to a neutral solution of 60 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxy-benzenesulfonic acid and 5 parts of disodium hydrogen phosphate in 500 parts of at a temperature below 2° C., the pH being kept constant by addition of sodium hydroxide solution. A solution of 5-[4,6-difluoro-1,3,5-triazin-2-ylamino]-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][N:53]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-(−)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at room temperature for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
A suspension of Example A1 (0.125 g, 0.497 mmol), Pd(PPh3)4 (0.029 g, 0.025 mmol), K2CO3 (0.275 g, 1.987 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid (0.104 g, 0.546 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3 and EtOAc and the solids were removed via filtration through diatomaceous earth. The layers of the filtrate were separated, the aqueous layer extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 4-((6-nitropyridin-3-yl)oxy)-2′-(trifluoromethyl)-2,4′-bipyridine (139 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (d, J=5.2 Hz, 1H), 8.78 (m, 1H), 8.64 (m, 1H), 8.53 (s, 1H), 8.44-8.38 (m, 2H), 8.17 (d, J=2.3 Hz, 1H), 8.03 (m, 1H), 7.36 (dd, J=5.5, 2.3 Hz, 1H); MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:22]([O:24][CH3:25])=[O:23])[CH:2]=C.[O:26]=[O+][O-]>C(Cl)Cl.CO>[CH2:15]([O:14][C:13]1[C:4]([CH2:1][CH:2]=[O:26])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)c(CC=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 4-allyl-5-(benzyloxy)isophthalate (3.5 g, 10.28 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil which was purified by column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the aldehyde (3.0g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 3.95 (s, 3 H) 4.29 (s, 2 H) 5.14 (s, 2 H) 7.31-7.56 (m, 5 H) 7.81 (d, J=1.32 Hz, 1 H) 8.29 (d, J=1.51 Hz, 1 H) 9.75 (s, 1 H); MS (ESI, pos): 343.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH:24]([Mg]Cl)([CH3:26])[CH3:25]>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:23])([CH:24]([CH3:26])[CH3:25])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(C)[Mg]Cl
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The above-mentioned ethanone (120.0 g, 0.34 mol) was added to a solution of MgBr diethyl etherate (195.8 g, 0.76 mol) in dichloromethane (DCM, 2.5 L) and the mixture stirred at room temperature for about 90 min. This mixture was then cooled to about 0° C. and isopropyl magnesium chloride (344.5 mL of a 2 M solution in THF, 0.69 mol) was added dropwise. The mixture was allowed to warm to room temperature and was then quenched by addition of a saturated ammonium chloride solution. The organic components were extracted three times with DCM, the organic phases combined, dried and the solvents evaporated. Addition of MTBE resulted in precipitation of the unreacted starting material, which was filtered off. The filtrate was then purified using reverse phase chromatography to give 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol as a brown oil (31.1 g, 23%, HPLC Rt=1.305 min, masse=392).
Reaction SMILES: [Al].[C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9](=[O:16])[C:8](O[Si](CC)(CC)CC)([C:17]([F:20])([F:19])[F:18])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O>[C:12]([C:10]1[CH:11]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[CH:7]=[C:8]([C:17]([F:19])([F:20])[F:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=C(C(C)(C)C)C=C(C(C)(C)C)C1=O
Agent: [Al]
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
A strip of aluminum foil weighing 267 mg (9.9 mmol) was amalgmated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ethanol followed by diethyl ether, cut into small pieces, and added to a solution of 400 mg (0.99 mmol) of 4,6-di-tert-butyl-2-triethylsiloxy-2-trifluoromethyl-3,5-cyclohexadien-1-one in 25 mL of 10% water 90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with 10 mL of tetrahydrofuran. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with petroleum ether), affording 226 mg (83% yield) of 2,4-di-tert-butyl-6-trifluoromethylphenol as a colorless liquid: 1H NMR (CDCl3)δ1.31 (s, 9H), 1.45 (s, 9H), 5.56 (q, 1H, JHF =4Hz), 7.39 (d, 1H, J=2Hz), 7.54 (d, 1H, J=2Hz); IR (neat) 3624, 2959, 2906, 2868, 1481, 1458, 1448, 1363, 1340, 1263, 1251, 1170, 1126, 1097, 887, 694 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 274 (20, M+), 259 (100), 239 (68), 98 (20), 57 (22), 41 (34).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)nc(Oc2ccccc2)n1
Yield: 45 %

Procedure:
2,4-Dichloro-6-phenoxy-s-triazine (C) was prepared in 45% yield via the condensation of one equivalent of phenol with cyanuric chloride in chloroform at 50° which also contained one equivalent of sodium hydroxide. The product C, obtained as a white crystalline solid (mp. 110°-112°), was condensed in a second step with B in a manner similar to that described in Example 6. During the course of the reaction a solid appeared which was filtered, air-dried and identified as 7.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5].[C:17]1([CH2:27]Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:8]([CH2:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1[nH]ncc1C(=O)CC(C)C
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C

Procedure:
Ethyl 4-(3-methyl-1-oxobutyl)-1H-pyrazole-5-carboxylate (Example 32, step c; 0.62 g), 1-naphthalenylmethyl chloride (0.53 g), and cesium carbonate (1.1 g) were stirred in dry dimethylformamide (8 ml) for 48 hours, and then dilute hydrochloric acid was added. The mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to give ethyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-3-carboxylate as a gum. (0.15 g)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][OH:45])=[O:37])[CH2:32][CH2:31]1>ClCCl>[CH3:29][N:30]1[CH2:31][CH2:32][N:33]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][O:45][N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:27]=[O:28])=[O:37])[CH2:34][CH2:35]1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CN1CCN(C(=O)c2ccccc2CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(C=O)OCc1ccccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
Triethylamine (6.50 ml) and octadecyl isocyanate (14.40 ml) were added to a solution of the syrup containing 2-(hydroxymethyl)phenyl 4-methylpiperazinyl ketone (9.83 g) in dichloromethane (100 ml). After being stirred for 14.5 hours at room temperature, the insoluble material was filtrated out under a vacuum. The filtrate was concentrated. The residue was purified by silica gel column chromatography (silica gel 225 g, chloroform:methanol=80:1), thereby yielding 12.00 g of the aimed compound as white solid.
Reaction SMILES: C(N)C1C=CC=CC=1.C([O:12][CH:13]1[S:30][CH2:29][C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C>CCOCC>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[CH2:29][S:30][C@@H:13]1[OH:12])(=[O:18])[CH3:17]
Reactant: CC(=O)OC1SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: NCc1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)SC[C@H]1OC(C)=O
Reaction time: 7 h
Yield: 47.3 %

Procedure:
22 ml (0.2 mol) of benzylamine are added under an inert atmosphere to a solution of 15 g (44.8.10-3 mol) of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 450 ml of ether. After 7 hours at room temperature (15°-25° C.), the reaction mixture is concentrated under reduced pressure and the residue is dissolved in methylene chloride and washed with a 1N solution of hydrochloric acid, a saturated solution of ammonium chloride and then water. The solution obtained is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 6.2 g (yield: 47%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (3/2 v/v) as the eluent, and crystallization from an ethyl acetate/hexane mixture, said product having the following physical characteristics:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 2 h

Procedure:
4.04 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid are suspended in 25 ml of toluene, and a 3-fold molar amount of a 20% strength solution of diisobutylaluminum hydride in toluene is added dropwise, under N2 and with stirring, the mixture is boiled for 2 hours and cooled and is decomposed with water, and the product is worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-formylindole, m.p. 131°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=3)=[O:20])=[C:13]([F:21])[CH:12]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)O)c(F)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cccc(C(F)(F)F)c2)c(F)c1
Yield: 11.6 %

Procedure:
A solution of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol), 3-(trifluoromethyl)aniline (44.3 mg, 0.275 mmol), HATU (125 mg, 0.330 mmol) and DIEA (0.048 mL, 0.275 mmol) in DMF (10 mL) was stirred at rt for 5 h. After LCMS analysis showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give crude product which was purified by preparative HPLC to give pure product 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(trifluoromethyl)phenyl)acetamide (14.56 mg, 0.032 mmol, 12% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.03 (br. s., 1H), 7.77 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.46-7.36 (m, 2H), 7.31-7.24 (m, 2H), 6.28 (s, 1H), 4.24-4.19 (m, 2H), 3.84 (s, 2H), 1.41 (t, J=6.8 Hz, 3H); ES-LCMS: m/z 435.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[S:34]1[CH:38]=[C:37]([CH2:39]Cl)[N:36]2[CH2:41][CH2:42][N:43]=[C:35]12>>[S:34]1[CH:38]=[C:37]([CH2:39][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][CH2:15][CH2:14][CH:13]3[C:11]([N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)=[O:12])[N:36]2[CH2:41][CH2:42][N:43]=[C:35]12
Reactant: ClCC1=CSC2=NCCN12
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCC4=CSC5=NCCN45)cccc32)cc1
Yield: 18.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and (5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl chloride (0.38 g) as starting materials, 5-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([C:26]([O:28]C)=[O:27])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:31])([CH3:30])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].CCO>CO>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([C:26]([OH:28])=[O:27])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:31])([CH3:30])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC1(C)Oc2ncnc(N)c2N=C1c1ccc(C23CCC(C(=O)O)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 724.2 %

Procedure:
To a solution of methyl 4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]octane-1-carboxylate (Intermediate 27; 140 mg, 0.33 mmol) in MeOH (10 mL) was added 2M NaOH (0.82 mL, 1.66 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then after the addition of EtOH (˜5 mL) and 1M NaOH (2 mL) the reaction mixture was heated to 50° C. for 5.5 hrs. The organic solvent was removed by evaporation under reduced pressure and the residue was acidified to pH 2 with 2M HCl. EtOAc was added and the suspension was filtered and dried to provide the title compound (97 mg, 2.39 mmol, 72%); 1H NMR δ 1.60 (s, 6H), 1.82 (s, 12H), 6.97 (s, 1H), 7.40 (d, 2H), 7.65 (d, 2H), 7.95 (s, 1H), NH2 not seen; MS m/e MH+ 407.