Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[Mg].[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:25](=[O:26])[C:20]3[NH:21][CH2:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][C:16]=2[CH:27]=1)#[N:11].[Cl-].[NH4+]>O1CCCC1>[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:25]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)([OH:26])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]=2[CH:27]=1)#[N:11]
Reactant: CN1CCC(Cl)CC1
Reactant: N#Cc1ccc2c(c1)CCC1=C(NCC=C1)C2=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(C#N)cc3CCc3cccnc32)CC1
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
Into a tetrahydrofuran (THF) solution of a Grignard reagent prepared from 6.7 g of N-methyl-4-chloropiperidine and 1.2 g of magnesium, 4.68 g of 8-cyano5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (the compound prepared in Referential Example 1) were added under ice cooling. After the resultant mixture was stirred for 3 hours at room temperature, a saturated aqueous solution of ammonium chloride was added, followed by stirring for 15 minutes. The reaction mixture was then extracted with chloroform. The Extract was dried over anhydrous Na2SO4 and then filtered. The filtrate so obtained was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (50:1), 3.1 g of 8-cyano-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol were obtained (yield: 47%).
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34]([O:36][C:37]1[C:44]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:43][C:40]([CH:41]=O)=[C:39]([N+:52]([O-:54])=[O:53])[CH:38]=1)[CH3:35].O>C1COCC1>[C:1]([C:3](=[CH:41][C:40]1[CH:43]=[C:44]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37]([O:36][CH2:34][CH3:35])=[CH:38][C:39]=1[N+:52]([O-:54])=[O:53])[CH:4]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)C(CCC(=O)O)C1CCOCC1
Reactant: CCOc1cc([N+](=O)[O-])c(C=O)cc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)O)C2CCOCC2)cc1Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic acid (174 mg, 0.5 mmol) prepared as described in Example 3 above, in THF (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol). The resulting mixture was stirred for 30 min at −78° C. and then warmed to room temperature. 4-Ethoxy-2-nitro-5-phenoxy-benzaldehyde (137 mg, 0.5 mmol) was added and the resulting mixture stirred for 4 h at room temperature. Water was added, and the resulting solution was extracted with methylene chloride (3×), washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 0-2% methanol in methylene chloride) to yield a yellow foam.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:36])[C:4]([N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:35])[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][NH:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:19](=[O:35])[C:20]=1[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:36]
Reactant: CNC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNC(=O)c1c(CC2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
The compound prepared in Example 319 (0.121 g) was suspended in methanol (10 mL) and potassium carbonate (0.051 g) added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the crude material, which was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography to furnish the title compound (0.005 g) having the following physical properties.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Cl[CH2:15][O:16][CH3:17].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:15][O:16][CH3:17])[CH:5]=[O:6]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)cc(C=O)cc1C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
A solution of 9.0 g of 3,5-dimethyl-4-hydroxybenzaldehyde in 20 ml of dimethylformamide was added dropwise and whilst ice-cooling to a suspension of 3.14 g of a 55% w/w dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture was then stirred for 20 minutes, after which 5.8 g of methyl chloromethyl ether were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 11.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19](=[O:29])[NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:30])[N:10]1[CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C.Cl.C(OCC)(=O)C>>[NH2:33][CH2:32][CH2:31][N:10]1[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:18]([C:19]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:30]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)c2ccccc2C(C(=O)NCCc2ccccc2)C1c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCN1C(=O)c2ccccc2C(C(=O)NCCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To 410 mg of tert-butyl {2-[3-(2,4-dichlorophenyl)-1-oxo-4-[(2-phenylethyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}carbamate was added 4 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and chloroform and a 1 M aqueous sodium hydroxide solution were then added to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 192 mg of 2-(2-aminoethyl)-3-(2,4-dichlorophenyl)-1-oxo-N-(2-phenylethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[NH:19][N:18]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>C(#N)C>[Cl:15][C:13]1[CH:12]=[C:11]([NH:16][C:17]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:3](=[O:5])[CH3:2])[CH2:25][CH2:24]3)[NH:19][N:18]=2)[CH:10]=[C:9]([Cl:8])[CH:14]=1
Reactant: Clc1cc(Cl)cc(Nc2n[nH]c(NC3CCNCC3)n2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred suspension of N3-(3,5-dichlorophenyl)-N5-(piperidin-4-yl)-1H-1,2,4-triazole-3,5-diamine 2,2,2-trifluoroacetate (50 mg, 0.113 mmol) in acetonitrile (5 mL), was added saturated sodium bicarbonate solution (5 mL) and acetic anhydride (14 mg, 0.136 mmol). The reaction mixture was stirred overnight at rt. The solution was extracted with EtOAc (3×10 mL) and dried with sodium sulfate. Removal of solvent gave the crude product, which was purified by flash chromatography to give 35 mg (84%) desired product as a white solid. MS +m/z: 369.0 (M+H)+
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.30-7.35 (3H, m) 7.41-7.43 (1H, m), 7.47 (1H, s), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11ClN4O, 311; Found, 311.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>O1CCCC1>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:13]
Reactant: OCCNCCO
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)N(CCO)CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
2.1 g of diethanolamine are dissolved in 30 ml of tetrahydrofuran, and 2.1 g of 2-chloroethyl isocyanate is added dropwise thereto at 0° to 5° C. The solution is stirred at room temperature for 2 hours. Then, the reaction solution is condensed under reduced pressure. 4.2 g of 1-(2-chloroethyl)-3,3-bis(2-hydroxyethyl)urea are obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[C:31]=2[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:27]1[C:36]2[C:31](=[C:32]([C:2]3[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5cnccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 130 °C
Yield: 49.7 %

Procedure:
A sealable tube was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.630 g, 1.59 mmol), isoquinoline-5-boronic acid (0.331 g, 1.91 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.056 g, 0.08 mmol), 1 N aqueous sodium carbonate solution (2.5 mL) and acetonitrile (7.5 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in methanol and filtered through celite. The filtrates were concentrated then purified by chromatography (C-18 reverse phase column, 5 to 95% acetonitrile in water containing 0.1% TFA). The fractions containing the desired product were concentrated then dissolved in MeOH/dichloromethane, basified with solid sodium carbonate then filtered and concentrated to furnish 109 (0.386 g, 50%) as a white foam. MS m/e 489 [M+H]; 1H NMR (300 MHz, MeOH-d4) δ ppm 1.61-1.91 (m, 2 H) 1.99-2.15 (m, 2 H) 2.17-2.36 (m, 2 H) 2.88 (s, 6 H) 3.04-3.28 (m, 3 H) 3.73-3.87 (m, 4 H) 3.91 (s, 2 H) 3.96-4.07 (m, 4 H) 7.33 (s, 1 H) 7.69-7.83 (m, 1 H) 8.18 (d, J=8.3 Hz, 1 H) 8.30 (d, J=7.2 Hz, 1 H) 8.43 (d, J=6.4 Hz, 1 H) 8.57 (d, J=6.0 Hz, 1 H) 9.28 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:40])[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:40]=[C:29]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=4)[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COc1cc(OC)cc(C(N)=NO)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2noc(-c3ccc(-n4nc(-c5c(F)cccc5Cl)[nH]c4=O)cc3OC)n2)c1
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using Methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-20, 0.077 g, 0.529 mmol), sodium hydride (0.006 g, 0.39 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1H NMR (DMSO-d6): δ 3.84 (s, 611), 3.99 (s, 3H), 6.73 (s, 1H), 7.19 (s, 2H), 7.47 (t, J=8.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.67 (t, J=8.7 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 12.61 (br s, 1H); MS (m/z): 523.89 [M+]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2,2-dimethyl-propyl)-benzenesulfonamide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 598.1 [(M−H−]; mp 231° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([Si](CC)(CC)CC)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C(Cl)(Cl)(Cl)Cl.[I:28]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([I:28])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: ClI
Reactant: CC[Si](CC)(CC)c1cc(C(=O)OC)cc2c1OC(F)(F)O2
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(I)c2c(c1)OC(F)(F)O2
Temperature: 77 °C
Reaction time: 3 h

Procedure:
17.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 100 ml of CCl4 and 2.9 ml of ICl added. The mixture was then stirred for 3 h at 77° C., 1.5 ml of ICl added and stirred for 2 h at 77° C. The mixture was then allowed to cool to room temperature, 200 ml of CH2Cl2 added, and washed three times using 300 ml of a saturated aqueous Na2SO3-solution each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:20 yielded 10.2 g of the title compound, colorless oil. Rf (EA/HEP 1:20)=0.30
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].Br[CH:12]1[CH2:16][CH2:15][O:14][CH:13]1[O:17][CH3:18].[I-].[Na+]>CN(C=O)C.O>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[CH:12]1[CH2:16][CH2:15][O:14][CH:13]1[O:17][CH3:18])[CH3:10]
Reactant: COC1OCCC1Br
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C#N)C1CCOC1OC
Reaction time: 1 h
Yield: 15.2 %

Procedure:
Sodium hydride (95%, 30.32 g, 1.2 mol) was suspended in anhydrous DMF (350 ml) in a 2 L, 3-necked flask and ethyl cyanoacetate (136 ml, 1.2 mol) was added dropwise with stirring under argon over 1 h. After a further 15 min, 3-bromo-2-methoxytetrahydrofuran (75 g, 0.41 mol) was added, followed by sodium iodide (2 g) and then the solution was heated with vigorous stirring at 140° C. for 20 h under argon. After cooling, water (200 ml) was added and the solution was concentrated on a rotary evaporator to about 300 ml. More water (200 ml) was added and the crude product was extracted into diethylether (4×500 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. Distillation of the residue under reduced pressure through a Vigreaux column afforded a colourless liquid (13.28 g, 15%). The cut b. p. 90-110° C./0.4 mmHg was taken; Rf (in A), 0.45, 0.36; stains yellow with anisaldehyde/H+; δH(d6-DMSO) 5.00 (0.75 H, m, mixt. of trans-2-H), 4.89 (0.25 H, d J2.1, cis-2-H), 4.29-4.19 (2 H, 2 q, cis/trans-CH2), 4.06-3.83 (2 H, 2 m, cis/trans-5-H), 3.39 (0.75 H, s, MeO), 3.36 (0.75 H, s, MeO), 3.35 (0.75 H, s, MeO), 3.31 (0.75 H, s, MeO), 2.78-2.70 (1 H, m, cis/trans-3-H), 2.30-1.71 (2 H, 2 m, 2×cis/trans-4-H) ppm; m/z (EI) 213.1002 (M+; Calc. for C10H15NO4, 213.1023).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13]1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:14]1[CH:15]=[CH:16][O:12][CH:13]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccoc1
Agent: Cl
Product: O=C(/C=C/c1ccoc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-furyl)propenoicacid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 247 (MH+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:30][C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)(=[O:21])=[O:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=480.1 (M+H)+
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(OCC3CCNC3)cccc2c1
Yield: 72.2 %

Procedure:
A solution of 0.42 g (1.28 mmol) of 1,1-dimethylethyl 3-[(1-naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate, prepared in Step 12.1., in 10 ml of 1,4-dioxane and 6 ml of a 2N solution of aqueous hydrochloric acid is stirred for 6 hours. It is evaporated to dryness and then coevaporation is carried out twice with toluene. The solid residue is washed with diethyl ether. The solid is taken up in dichloromethane and concentrated ammonia solution is added until a basic pH is obtained. The system is filtered on a Whatman PTFE cartridge and the organic phase is concentrated, to give 0.21 g of oily product, which is used as it is in the following step.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N+:16]([O-:9])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Cl)ccnc2c1C
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Yield: 18.3 %

Procedure:
Metachloroperbenzoic acid (90.2 g, 366.0 mmol) was added portion wise over 3 h to a solution of 4-chloro-7-methoxy-8-methylquinoline (60, 15.2 g, 73.2 mmol) in CHCl3 (1 L). Then, the solution was partitioned between ice-cooled NaOH 1N and CH2Cl2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient of AcOEt/CH2Cl2, 1:2 to 1:0) to give 3.0 g (18.3%) of the title product 61 as a pale yellow powder: m/z=224 (M+H)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30]2([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:40][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30]3([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(C(N)=O)CCCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(C(N)=O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (953 mg of 77% pure material, 4.25 mmol) was added to a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxamide (1.30 g, 3.54 mmol) in chloroform (15 mL); the reaction was stirred for one hour at ambient temperature. Ammonium hydroxide (15 mL) and p-toluenesulfonyl chloride (742 mg, 3.89 mmol) were added, and the mixture was stirred vigorously for two hours. The aqueous fraction was separated and extracted several times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 2-7% methanol in dichloromethane) followed by recrystallization from acetonitrile to provide 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanecarboxamide as a tan crystalline solid, mp 221-223° C.