Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:18][CH2:17]1
Reactant: NCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056 g), (tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) and N,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide (15 mL) solution was heated at 90° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:40]=C(O)[CH:42]=[CH:43][CH:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[CH:42]=[CH:43][CH:44]=[C:39]([O:38][CH3:37])[CH:40]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)c1
Yield: 31.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-methoxyphenol (29 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (23 mg, yield 30%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23]C4N=CN(C)N=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1.[CH3:30][N:31]1[C:35](CO)=[N:34][CH:33]=[N:32]1>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23][C:35]4[N:31]([CH3:30])[N:32]=[CH:33][N:34]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1
Reactant: Cn1ncnc1CO
Reactant: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)no1
Product: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4C)nn23)no1

Procedure:
The title-compound was prepared from the product of Example 116 part a and 1-methyl-1,2,4-triazole-5-methanol (prepared using the conditions of Itoh and Okongi, EP-A-421210) in a similar manner to Example 98, mp 206-207.5° C.; 1H NMR (360 MHz, CDCl3) δ 3.53 (3H, s, CH3), 4.12 (3H, s, CH3), 4.73 (2H, s, CH2), 5.87 (2H, s, CH2), 7.20 (1H, s, ArH), 7.42 (1H, s, ArH), 7.93 (1H, m, ArH), 8.06 (1H, m, ArH), 8.30 (1H, d, J=7.7 Hz, ArH), 8.70 (1H, d, J=7.2 Hz, ArH); MS (ES30) m/e 393 [MH]+.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[C:43](=[O:44])[CH2:42][C:36]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35][C:34]=2[OH:45])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:14][CH:13]=1)#[N:11].C(N(CC)C(C)C)(C)C>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:33]2[C:34](=[O:45])[CH2:35][C:36]3([CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH2:42][C:43]=2[O:44][CH3:6])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC3(CCOCC3)CC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyloxonium tetrafluoroborate (320 mg, 2.16 mmol) is added to a solution of 1-((4-cyanophenyl)(8-hydroxy-10-oxo-3-oxaspiro[5.5]undec-8-en-9-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 10, 712 mg, 1.43 mmol) and N,N-diisopropylethylamine (490 μL, 2.81 mmol) in dichloromethane (20 mL). The mixture is stirred at room temperature for 30 min and washed with water. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 380 mg; ESI mass spectrum [M+H]+=514, Retention time HPLC: 1.18 min (V012_S01).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:44]=[C:43]([CH3:45])[N:42]([CH3:46])[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:44]=[C:43]([CH3:45])[N:42]([CH3:46])[N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2cc(C)n(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2cc(C)n(C)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogen carbonate (2.89 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:25]1(NC2CCCCC2)[CH2:30]CCC[CH2:26]1.[OH2:38]>CN(C)C=O>[O:38]=[C:25]([CH3:30])[CH2:26][O:20][C:19](=[O:21])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22]
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O
Solvent: CN(C)C=O
Product: CC(=O)COC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyl-oxy)phenoxy) propionic acid (3.62 g) was dissolved in dimethylformamide (50 ml) and the solution was stirred with an addition of dicyclohexylamine (2.2 ml). The mixture was further stirred at a temperature of 60° C. for 3 hours. To the reaction mixture, 100 ml of water was added, followed by extracting with toluene. After washing with water, the mixture was dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and the resultant oily product was subjected to silica gel medium pressure column chromatography (n-hexane/ethyl acetate=9/1 v/v%) to obtain 4.00 g of the title compound in the form of a colorless oily product (yield=96%).
Reaction SMILES: [C:1](=[S:3])=[S:2].[CH2:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH3:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:1](=[S:3])[S-:2])[CH:16]=[CH:17][CH:18]=1.[CH2:4]([NH+:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH3:5]
Reactant: S=C=S
Reactant: Nc1cccc(Cl)c1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC[NH+](CC)CC
Product: S=C([S-])Nc1cccc(Cl)c1
Reaction time: 24 h

Procedure:
5.7 g of carbon disulphide and 22 ml of triethylamine are mixed in keeping a temperature below 10° C. by an ice-bath. 10 g of 3-chloroaniline dissolved in 10 ml of absolute ethanol are added and the reaction mixture is stirred and left to return to ambient temperature. After 24 h, the yellow precipitate obtained is filtered off, washed with ethanol then with pentane.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:9]=1[CH3:19].[OH2:20]>>[Cl:7][C:8]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:9]=1[C:19]([OH:2])=[O:20]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Cl)c(S(C)(=O)=O)c1Cl
Agent: [K+]
Product: CS(=O)(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Temperature: 0 °C

Procedure:
Potassium permanganate (33.66 g) was added in portions to a stirred heated suspension of 2,4-dichloro-3-(methylsulphonyl)toluene (16.88 g) in water at 95°-100° C. The mixture was stirred and heated at reflux for one and a half hours. The hot suspension was filtered and the filtrate was cooled to 0° C. and acidified. It was filtered to give 2,4-dichloro-3-(methylsulphonyl)benzoic acid (5.35 g) as an orange solid, m.p. 157.5°-158.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[C:15](=O)(O)[O-:16].[Na+]>CN(C=O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2ncccc12
Temperature: 5 °C

Procedure:
Phosphorus oxychloride (36.5 mL) was added dropwise to cooled solution of DMF (40 mL) while maintaining the temperature below 10° C. The resulting solution was further cooled to 5° C. and a solution of 7-azaindole in DMF (40 mL) was added slowly over 30-40 min, maintaining the temperature below 25° C. The mixture was heated at 95° C. for 48 h then cooled to 35° C. and added cautiously with stirring over an hour to a cooled solution of saturated aqueous sodium bicarbonate solution (800 mL). The mixture was extracted with ethyl acetate (4×500 mL) and the combined extracts washed with water (500 mL) and brine (500 mL), then dried (MgSO4), filtered and concentrated in vacuo to afford a dark brown semi-solid. This crude product was purified using column chromatography eluting with a 50:50 mixture of ethyl acetate:hexane, gradually increasing to 90:10 mixture. 1H-NMR (400 MHz/D6-DMSO): δ=7.25 (m, 1H), 8.38 (m, 2H), 8.42 (s, 1H), 9.92 (s, 1H), 12.62 (br.s, 1H). MS (ES+): 147 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH:27]=3)=C[C:17]=2F)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(#[N:41])C.CS(O[CH2:47][C:48]1([C:51]([F:54])([F:53])[F:52])[CH2:50][CH2:49]1)(=O)=O>ClCCl.O>[CH3:31][S:28]([N:25]1[CH2:26][CH:27]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:47][C:48]4([C:51]([F:52])([F:53])[F:54])[CH2:49][CH2:50]4)[CH2:9][CH2:10]3)=[CH:17][N:41]=2)[CH2:23][CH2:24]1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCN(CC4(C(F)(F)F)CC4)CC3)cn2)CC1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To Preparation 6 (206 mg, 0.586 mmol), potassium carbonate (243 mg, 1.76 mmol) and acetonitrile (2.93 mL, 56 mmol) in a microwave vial is added (1-(trifluoromethyl)cyclopropyl)methyl methanesulfonate (256 mg, 1.17 mmol). The microwave vial is sealed and heated at 140° C. for 2 h then 150° C. for 30 min in the Biotage microwave. The reaction is diluted with dichloromethane and water. The organic layer is separated and washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is triturated with diethylether and the title product is collected via vacuum filtration to obtain 0.181 g of the title compound. MS (m/z) 474 (M+1).
Reaction SMILES: [F:1][C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH2:18][OH:19])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29]C)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[F:1][C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH2:18][OH:19])[N+:9]=2[CH3:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH2:7]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: OCc1cc2ccccc2c(C2(F)C=CC=CC2)n1
Product: C[n+]1c(CO)cc2ccccc2c1C1(F)C=CC=CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 145.1 %

Procedure:
1-(1-Fluorophenyl)-3-isoquinolinecarboxylic acid was converted into its ethylester and then reduced using lithium aluminum hydride to obtain 1-(1-fluorophenyl)-3-isoquinolinemethanol. 1.26 g of the obtained 1-(1-fluorophenyl)-3-isoquinolinemethanol was reacted with 930 mg of methyl p-toluenesulfonate in the same manner as in Reference Example 10 to give 1.6 g of the desired compound as a pale orange-colored solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5](N)=[C:4]([CH2:11][CH3:12])[CH:3]=1.Cl.N([O-])=O.[Na+].[OH:18][PH2]=O.[CH3:21][CH2:22][OH:23]>O.C(O)(=O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([CH2:21][C:22]([OH:18])=[O:23])[CH:8]=[C:7]([CH2:9][CH3:10])[CH:5]=1)[CH3:12]
Reactant: CCO
Reactant: O=[PH2]O
Reactant: CCc1cc(Br)cc(CC)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CC)cc(CC(=O)O)c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of 4-bromo-2,6-diethylaniline, 160 ml of acetic acid, 100 ml of a concentrated HCl solution, 30 ml of water and 100 ml of EtOH is cooled to −5° C., a solution of 6.6 g of sodium nitrite in 25 ml of water is added dropwise and the mixture is left stirring for 30 minutes at RT. The reaction mixture is poured over 170 ml of 50% H3PO2 cooled to 0° C., the mixture is left stirring for 2 hours at 0° C. and then for 48 hours at RT. The reaction mixture is extracted with ether, the organic phase washed with water, with a 1N NaOH solution, with water, dried over Na2SO4 and the solvent evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with cyclohexane. 18 g of the expected product are obtained.
Reaction SMILES: N[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC[N:36](CC)CC>C(Cl)Cl.CCOC(C)=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:32]([NH2:36])=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCN(CC)CC
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C(N)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (247 μL, 2.28 mmol) and Et3N (0.64 mL, 4.56 mmol) and allowed to warm slowly to room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to yield a yellow solid. The yellow solid was dissolved in a minimum amount of CH2Cl2 and EtOAc was added until the solution became turbid. The mixture was placed in a freezer overnight and white crystal formed. The crystals were isolated by filtration and were dried under vacuum to give 126 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-phenylurea. mp 171.0-174.0° C.;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:29].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH:28]=[CH2:29])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Yield: 21298.1 %

Procedure:
A solution of Intermediate 1 (250 mg) obtained in Example 1, Step A, 2,6-di(tert-butyl)-4-methylphenol (0.5 mg, Tokyo Kasei Kogyo), and tri(n-butyl)vinyltin (0.25 ml, Tokyo Kasei Kogyo) in toluene (8 ml) is added with tetrakis(triphenylphosphine)palladium(0) (13 mg, Kanto Chemicals) under a nitrogen gas atmosphere, and the mixture is refluxed by heating for 12 hours. The reaction mixture is cooled to room temperature, and then the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (195 mg (predictive yield)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH2:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=2)[CH2:14][CH2:15]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 140 °C

Procedure:
To a solution of 4-chloropicolinic acid (0.8 gm, 0.0051 mol) in DMSO (4 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (2.5 gm, 0.010 mol) and the mixture warmed to 140° C. for 18 h. The reaction was cooled and diluted with 10% sodium bicarbonate (100 mL) and washed with ether (2×25 mL). The aqueous extract was washed with dichloromethane (3×50 mL), and the dichloromethane extract dried over sodium sulfate and concentrated to an oil (2.4 gm). The oil was chromatographed on silica using dichloromethane/methanol/acetic acid/water-90/10/1/1 to give 4-[(1-benzyloxycarbonyl-piperidin-4-ylmethyl)-amino]-pyridine-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1.[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:18]([CH3:20])[CH3:19])[CH:6]=2
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: COC(=O)c1cc(Br)cc2nn(C(C)C)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %
Yield: 40 %

Procedure:
To a cooled (0° C.) solution of methyl 6-bromo-1H-indazole-4-carboxylate (1.25 g, 4.90 mmol) in N,N-dimethylformamide (25 mL) was added sodium hydride (0.216 g, 5.39 mmol). The reaction mixture was stirred for 15 min, then 2-bromopropane (0.920 mL, 9.80 mmol) was added and the reaction allowed to warm to RT. The reaction was maintained at RT overnight. The contents were concentrated to about ½ volume, then poured into saturated NH4Cl (200 mL) with stirring. The contents were extracted with ether (2×) and the combined organics washed with brine, dried (MgSO4), filtered, and concentrated to give an orange residue (1.55 g crude). Purification by silica gel chromatography (eluent: 5-25% ethyl acetate in hexanes) gave methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (0.60 g, 40% yield) and methyl 6-bromo-2-(1-methylethyl)-2H-indazole-4-carboxylate (0.65 g, 43% yield). Both products were isolated and methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate was taken on to the next step. Data for 1-alkylated isomer: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H) 8.02 (d, J=1.52 Hz, 1H) 7.85 (s, 1H) 4.83 (dt, J=13.33, 6.60 Hz, 1H) 4.04 (s, 3H) 1.63 (s, 3H) 1.61 (s, 3H); LC-MS(ES) [M+H]+ 297.5/299.5. Data for 2-alkylated isomer: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.25 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 4.96 (m, 1H), 3.95 (s, 3H), 1.57 (d, J=6.6 Hz, 6H); LC-MS(ES) [M+H]+ 297.5/299.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(NCCO)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Intermediate 33 from 3.97-g (20 mmol) of 4-fluorobenzenesulfonyl chloride and 3.11 g (50 mmol) of ethanolamine, yielding 3.0 g of a white solid; m.p. 77-78° C.; MS (ES) m/z 219.8 (MH+); HRMS (EI) Calcd. for C8H10FNO3S (M+): 219.0366, Found: 219.0369.