Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:11](#[N:13])C.[C-]#N.[K+].CCCCCC>C1OCCOCCOCCOCCOCCOC1.O.C(OCC)(=O)C>[CH:1]([CH:3]([C:11]#[N:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of vinylbenzyl chloride in acetonitrile (5.0 g, 0.033 mol, in 10 mL of ACN) was added to a mixture of potassium cyanide (1.5 ME, 0.0495 mol, 3.2 g), 18-Crown-6 ether (0.52 g) and acetonitrile (15 mL). The resulting mixture was stirred overnight at room temperature. TLC analysis (hexane:ethyl acetate, 8:2) indicated that the reaction had gone to completion. The reaction was worked up by adding water to the reaction mixture (50 mL) and extracting the product into ethyl acetate. The organic layer was washed twice with water followed by brine solution. The organic layer was dried on Na2SO4 and recovered under reduced pressure to obtain the required vinylbenzyl cyanide as a light brown coloured oil (4.2 g, 87.8%) which was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ3.7 (s, 2H), δ 5.3 (d, 1H, ethylene —CH trans), δ5.8 (d, 1H, ethylene-CH cis), δ 6.7 (m, 1H), δ 7.3 (Ar 2H, dd), δ 7.4 (Ar 2H, dd).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:20]>CN1C(=O)CCC1>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][C:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:30][CH2:31]1)[CH3:20]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Fc1ccccc1-c1nc(Cl)nc2ccccc12
Solvent: CN1CCCC1=O
Product: CCOc1cc(CN2CCC(Nc3nc(-c4ccccc4F)c4ccccc4n3)CC2)ccc1OC
Yield: 20.4 %

Procedure:
A solution of 2-chloro-4-(2-fluoro-phenyl)-quinazoline (38.8 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in NMP (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 14.9 mg (20%) of the title compound. MS (ISP): 487.5 [M+H]+.
Reaction SMILES: [C:1]12([C:11]3[C:19]4[O:18][CH2:17][O:16][C:15]=4[CH:14]=[C:13](Br)[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[CH:12]=[C:13]([B:37]([OH:38])[OH:36])[CH:14]=[C:15]4[O:16][CH2:17][O:18][C:19]=34)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: OB(O)c1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
To a solution of 4-(1-adamantyl)-6-bromobenzo[1,3]dioxole (2.10 g, 6.26 mmol) in THF (11 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (10.0 mmol) in hexane (6.26 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl)borate (4.30 mL, 18.8 mmol) was added, and the resulting solution was stirred at −78° C. for 20 min more before being allowed to warm to room temperature with stirring overnight. The mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 40 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane and dried to give 1.23 g (65%) of 3-(1-adamantyl)-4,5-methylenedioxyphenylboronic acid as a cream solid, mp 258-261° C. IR 3231, 2903, 2849, 1343, 1164 cm−1; 1H NMR δ (CDCl3) 1.81 (bs, 6H, AdCH2), 2.13 (bs, 9H, AdCH2 and AdCH), 6.02 (s, 2H, CH2), 7.48 (s, 1H, 6-ArH), 7.75 ppm (s, 1H, 2-ArH).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([C:37](OC)=[O:38])=[CH:27]1)[CH:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].CCCCCC>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:28]([CH2:37][OH:38])=[CH:27]1)[CH:19]=[CH:18]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OCc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Lithium aluminium hydride (0.258 g) was added to a solution of methyl 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carboxylate (3.04 g) in tetrahydrofuran (30 ml) at 0° C., and the mixture was stirred at room temperature for one hour. Sodium sulfate decahydrate (2.19 g) and hexane (30 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was concentrated. The colorless crystals obtained were collected by filtration to yield [1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]methanol (2.54 g, yield: 89%). This was recrystallized from ethyl acetate-hexane. Melting point: 116–117° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccc(NC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccc(N)cc2)cc1

Procedure:
The mixture of 1 g of 4-(4-acetamidophenylamino)-3-benzylamino-5-(4-acetamidophenylsulfamoyl)-benzoic acid and 10 ml of 2 N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5, the precipitate collected and recrystallized from 30 ml of 50% aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-benzylamino-5-(4-aminophenylsulfamoyl)-benzoic acid melting at 238° with decomposition.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]4=[O:20])=[CH:8][N:7]3[C:21]=2[CH3:22])[CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([CH2:18][O:19][C:27]5[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:20])=[CH:8][N:7]3[C:21]=2[CH3:22])[CH2:2][CH2:3]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cn12
Reactant: Oc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(F)cc4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 12.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-fluorophenol (85 mg) and tributylphosphine (307 mg) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (386 mg), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (24 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1>>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:24])[CH:13]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccco4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Furan-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 6.1c from 50 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-2-ylmethoxy)-1H-pyridin-2-one (example 6.1b) and 73 mg (0.52 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][O:39][CH3:40])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][O:39][CH3:40])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3N(CC)CCOC)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (205 mg) is dissolved in ethanol (2 ml) and thereto is added 2N-aqueous sodium hydroxide solution (418 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (155 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (110 μl) and the reaction solution is concentrated under reduced pressure to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid sodium salt (159 mg). MS (m/z): 706 [M−Na]−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)N.N([O-])=O.[Na+].Cl>CN(C)C=O.[Cu]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([S:22][C:32]3[CH:31]=[CH:29][CH:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[CH:33]=3)[NH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3cccc(C(F)(F)F)c3)[nH]c2-c2ccc(OC)cc2)cc1
Yield: 35.8 %

Procedure:
Under the conditions of Example 85, 6.25 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole is reacted in 150 ml of dimethylformamide in the presence of a pinch of powdered copper with 0.60 g of sodium hydride (80% in oil) and a diazonium salt solution prepared from 3.26 g of 3-trifluoromethylaniline (99%), 1.38 g of sodium nitrite, as well as 10 ml of 6 N hydrochloric acid. Chromatography according to Example 85 yields 3.27 g of 4,5-bis(4-methoxyphenyl)-2-(3-trifluoromethylphenylthio)imidazole as an amorphous foam.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:18][C:19]1[CH:20]=[C:21]([O:26][C:27]2[C:32]([F:33])=[C:31](F)[CH:30]=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:22]=[C:23]([Cl:25])[CH:24]=1.OS([O-])(=O)=O.[Na+]>C1COCC1>[Br:18][C:19]1[CH:20]=[C:21]([O:26][C:27]2[C:32]([F:33])=[C:31]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:30]=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 3.95 g, 98.6 mmol) was added to anhydrous THF (100 mL) and cooled to 0° C. under nitrogen. A solution of di-tert-butyl malonate (9.79 g, 45.3 mmol) in THF (20 mL) was added dropwise and the reaction mixture was stirred 30 min. A solution of 2-[(3-bromo-5-chlorophenyl)oxy]-3,4-difluoro-1-nitrobenzene (15.0 g, 41.1 mmol) was added dropwise in THF (50 mL) was added dropwise, the reaction was allowed to warm to RT and stirred for 90 min. The reaction was cooled to 0° C., a solution of saturated aqueous NaHSO4 (200 mL) was added and the aqueous mixture was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound a brown solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.05 (d, 1H), 7.58 (d, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 3.82-3.80 (m, 1H), 1.35 (s, 18H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: ClCc1ccccn1
Agent: Cl
Product: N#Cc1ccc(OCc2ccccn2)cc1F
Yield: 72.1 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (1.0 g) and 2-chloromethylpyridine hydrochloride (1.2 g) were processed in the same manner as in Production Example 1-1 to obtain the entitled compound (1.2 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][N:14]=2)[CH2:9]1.[CH2:25](B(CC)CC)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.C(OCC)(=O)C>[Cl:3][C:4]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:25][CH3:26])=[CH:15][N:14]=2)[CH2:9]1
Reactant: Clc1ccc(CNC2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Reactant: CCB(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 65 °C

Procedure:
Add (2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine dihydrochloride (272 mg, 0.61 mmol), triethylborane (1 mL, 1 mmol, 1.0 M in hexanes), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.031 mmol), and potassium carbonate (253 mg, 1.83 mmol) to anhydrous N,N-dimethylformamide (10 mL). Heat at 65° C. overnight. Dilute with water and extract twice with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 1:1 ethyl acetate:hexanes, to give the title compound. Combine the title compound and ethyl acetate, add 1 N hydrochloric acid in methanol (1 mL), and concentrate to give the title compound as the hydrochloride salt (35 mg, 13%). 1H NMR (400 MHz, MeOH-d4) δ 7.98 (d, 1H, J=8.8 Hz), 7.80 (s, 1H), 7.69-7.67 (m, 2H), 7.49 (dd, 1H, J=8.0, 2.2 Hz), 7.09 (d, 1H, J=8.8 Hz), 4.50-4.42 (m, 2H), 4.25-4.22 (m, 1H), 4.10-4.05 (m, 1H), 3.90-3.84 (m, 2H), 3.74-3.68 (m, 1H), 2.71-2.61 (m, 1H), 2.64 (q, 2H, J=7.2 Hz), 2.47-2.41 (m, 1H), 1.24 (t, 3H, J=7.2 Hz); MS (ES): m/z=350 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:29]C(OC(C)(C)C)=O)([C:14](=[O:28])[NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:29][C:11]1([C:14]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19][OH:20])=[O:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCNCC1
Yield: 84.9 %

Procedure:
Tert-butyl-4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)piperidine-1-carboxylate (Intermediate 71) (1.98 g, 3.76 mmol) was stirred in THF (18.82 mL) and 4M hydrogen chloride (14.11 mL, 56.46 mmol) in dioxane was added with stirring. The resulting solution was stirred at ambient temperature overnight. The crude mixture was purified by SCX chromatography (eluent 20% 7N ammonia/MeOH in DCM). Pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)piperidine-4-carboxamide (1.04 g, 85%), as a colourless, transparent gum.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][CH2:22][C:23]3([CH3:28])OCC[O:24]3)[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-].[Na+].ClCCl>O>[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][CH2:22][C:23](=[O:24])[CH3:28])[N:15]([CH2:16][C:17]([OH:19])([CH3:18])[CH3:20])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)CCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
Concentrated hydrochloric acid (0.20 mL, 2.4 mmol) was added to a stirred suspension of 1-{4-amino-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (0.30 g, 0.81 mmol) in water (5 mL). A solution resulted and was stirred at room temperature for 3 hours. The solution was adjusted to pH 13 with 20% aqueous sodium hydroxide. A gummy solid formed. Dichloromethane was added, but the solid did not dissolved. The mixture was poured into a separatory funnel, then the contents of the funnel were filtered. The white solid isolated by filtration was washed with water and dried to yield 0.17 g of 4-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]butan-2-one as a white powder, mp 181-184° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH:9]2[CH:7]([C:8]2([CH3:12])[CH3:11])[CH:6]([O:13]C)[O:5]1)(=[O:3])[CH3:2].O.S(=O)(=O)(O)O>CC(C)=O>[OH:5][CH:4]([C:1](=[O:3])[CH3:2])[CH2:10][C@@H:9]1[C:8]([CH3:12])([CH3:11])[C@@H:7]1[CH:6]=[O:13]
Reactant: COC1OC(C(C)=O)CC2C1C2(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(O)C[C@H]1[C@@H](C=O)C1(C)C

Procedure:
A 50-ml flask was charged with 4-acetyl-2-methoxy-7,7-dimethyl-3-oxabicyclo[4.1.0]heptane (10.1 mmol, 100% (1R,cis), a 1:1 (v) mixture (20 ml) of water and acetone and concentrated sulphuric acid (1.5 mmol), sp. gr. 1.84. After stirring the contents of the flask for one hour at 20° C. the majority of acetone was distilled off at 1.3 kPa. The residue was extracted with two 10-ml portions of dichloromethane. The combined extract phases were washed with two 20-ml portions of a saturated aqueous solutions of sodium hydrogen carbonate and then with a 10%w aqueous solution (20 ml) of sodium chloride. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried organic phase at 1.3 kPa to leave a residue (1.6 g) containing 2-(2-hydroxy-3-oxobutyl)-3,3-dimethylcyclopropanecarbaldehyde (100% (1R,cis), yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][OH:26])[N:24]=1)=[CH:16][CH:15]=3.I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][O:26][CH3:33])[N:24]=1)=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21
Product: COCc1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 101 above, with the compound from Example 95 above, 3-(2,4-dichlorophenyl)-6-(4-hydroxymethylthiazol-2-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: [F:1][C:2]([CH:4](O)[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3].S(Cl)([Cl:14])=O>CCCCCC.CN(C)C=O>[F:1][C:2]([CH:4]([Cl:14])[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3]
Reactant: C=C(F)C(O)C#CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=C(F)C(Cl)C#CC(C)(C)C
Yield: 90.4 %

Procedure:
Ten grams (0.064 mole) of 2-fluoro-3-hydroxy-6,6-dimethylhept-1-ene-4-yne was dissolved in 100 ml of hexane, and to 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 11.42 g (0.095 mole) of thionyl chloride were added to the resulting solution. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 10.1 g of 2-fluoro-3-chloro-6,6-dimethylhept-1-ene-4-yne.