Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[CH:12]=[N:11]2)=[CH:6][CH:5]=1
Reactant: Nc1ncnc2c1cnn2-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
Title compound 10A, 1-(4-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (1.0 g, 3.9 mmol) was added to 10% w/w palladium on carbon (0.1 g, 10% w/w) suspended in ethanol (300 ml). This was stirred for 42 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered to remove the palladium residues and the filtrate was concentrated to dryness in vacuo. The resultant residue was purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as an off-white solid. (0.53 g, 2.3 mmol, 60%). LCMS: [M+H]+=227, Rt=0.64 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)Cl>>[C:18]([O:17][C:9]1[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)OC1=C(c2ccc(C)cc2)C(=O)CC(C)(C)C1
Yield: 71 %

Procedure:
Using the procedure described in Example III and starting with 3.00 g (0.0130 mol) of 2-(4'-methylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 1.59 g (0.0098 mol) of octanoyl chloride, 2.63 g (0.0260 mol) of triethylamine, and 30 mol of methylene chloride, 2.5 g (71% yield) of a clear, colorless oil was obtained as the desired product.
Reaction SMILES: [Mg:1].Cl[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2C=1C=C[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1CCCC1>BrCCBr>[Mg:1].[CH2:12]([N:7]1[CH2:3][CH2:11][CH2:10][C:9](=[O:19])[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc2c1ccn2Cc1ccccc1
Reactant: C1CCOC1
Agent: [Mg]
Solvent: BrCCBr
Product: O=C1CCCN(Cc2ccccc2)C1
Temperature: 30 °C

Procedure:
A mixture of 113 g of magnesium in 200 ml of tetrahydrofuran was refluxed while a solution of 184 g of the product of Step A in 20 ml of 1,2-dibromoethane and 300 ml of tetrahydrofuran were added slowly thereto and the mixture was then refluxed for 3 hours and cooled to 30° C. to obtain a magnesium solution to which a solution of 128 g of N-benzyl-3-piperidone in 250 ml of tetrahydrofuran was added while keeping the temperature below 35° C. The mixture was refluxed for 2 hours and then was cooled to 20° C. Then one liter of an aqueous saturated ammonium chloride solution was slowly added thereto and 2 liters of ethyl acetate were added thereto. The mixture was filtered and the decanted ethyl acetate phase was washed with water, dried and evaporated to dryness. The 330 g of residue were chromatographed over silica gel and were eluted with a 9-1 cyclohexane-triethylamine mixture to obtain 218.4 g of product which was dissolved in ethyl acetate. The solution was extracted with 1 N hydrochloric acid and the aqueous phase was made alkaline by addition of ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic phase was dried. 100 ml of ethyl acetate saturated with gaseous hydrogen chloride were added to the organic phase and the mixture was filtered. The recovered product was washed with ethyl acetate, with ether and dried to obtain 194 g of 1-benzyl-3-[1-benzyl-1H-indole-4 -yl]-3-piperidinol hydrochloride melting at 185° C. Crystallization from ethyl acetate containing 10% methanol yielded the pure product melting at 190° C. The free base was obtained by treating the hydrochloride salt with sodium hydroxide, extracting the aqueous phase with ethyl acetate and evaporating the organic phase to dryness.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:26][C:27](=[CH2:30])[CH2:28]I>O.[OH-].[Li+].C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:27]([CH3:30])=[CH2:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: C=C(C)CI
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the solution of 3.81 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 25 ml of water and about 2 ml of 4 N aqueous lithium hydroxide (to adjust the pH to 7.2), the solution of 2 g of 2-methylallyliodide in 2 ml of ethanol is added at room temperature while stirring and maintaining the pH between 6.7 and 7.0 with lithium hydroxide, and diluting the mixture with 10 ml of ethanol. After 23 hours (and the consumption of about 65% of the theoretical amount of lithium hydroxide) the mixture is washed with diethyl ether and acidified with hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-(2-methylallylamino)-5-sulfamoylbenzoic acid melting at 193°-195°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14])[N:3]=[C:2]2[NH:28][C:25]1[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2cc(F)ccc2n1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccc(F)cc23)n[nH]1
Yield: 84.9 %

Procedure:
(6-Fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone was prepared from (4-chloro-6-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (306 mg, 1 mmol) and 5-methyl-1H-pyrazol-3-amine (194 mg, 2 mmol) using a procedure analogous to that described in Example 48 Step A. The crude product was triturated with MeOH to afford (6-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone (310 mg, 85%). 1H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.71 (s, 1H), 8.64 (d, J=9.6 Hz, 1H), 7.95-8.09 (m, 2H), 7.93-7.95 (m, 1H), 7.80-7.86 (m, 1H), 7.39 (t, J=8.6 Hz, 2H), 6.53 (s, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](F)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=C(NC(C)(C)C)[N:8](C)[C:7]2=[O:18].BrC1C(F)=CC=C2C=1N=C(Cl)N(C1CC1)C2=O.[Br:37][C:38]1[C:39]([F:57])=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[N:44]([CH:53]1[CH2:55][CH2:54]1)[C:43]2=[O:56]>>[Br:37][C:38]1[C:39]([F:57])=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45]([NH:48][C:49]([CH3:50])([CH3:51])[CH3:52])[N:44]([CH:53]1[CH2:54][CH2:55]1)[C:43]2=[O:56].[C:49]([NH:48][C:45]1[N:44]([CH:53]2[CH2:55][CH2:54]2)[C:43](=[O:56])[C:42]2[C:47](=[C:38]([C:4]3[NH:10][C:11]4[C@@H:2]([CH3:3])[NH:8][C:7](=[O:18])[C:6]=4[CH:5]=3)[C:39]([F:57])=[CH:40][CH:41]=2)[N:46]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: Cn1c(NC(C)(C)C)nc2c(Br)c(F)ccc2c1=O
Agent: CC(C)(C)Nc1nc2c(Br)c(F)ccc2c(=O)n1C1CC1
Agent: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C5CC5)c(NC(C)(C)C)nc34)[nH]c21
Yield: 51 %

Procedure:
8-Bromo-2-(tert-butylamino)-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (461a, 288 mg, 85%) as a brown foam was prepared according to the procedures described for Intermediate 405a, starting from 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721) (305 mg, 0.96 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (1H, dd, J=8.7, 6.4 Hz), 7.04 (1H, t, J=8.7 Hz), 6.25 (1H, s), 2.76-2.88 (1H, m), 1.57 (9H, s), 1.18-1.27 (2H, m), 0.69-0.81 (2H, m). m/z (ESI, +ve ion) 354.0/356.0 (M+H)+. (R)-2-(tert-butylamino)-3-cyclopropyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (461) (171 mg, 51%) as a white solid was prepared according to the procedures described for Example 407, starting from 8-bromo-2-(tert-butylamino)-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (461a, 288 mg, 0.81 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (1H, s), 7.90 (1H, dd, J=8.8, 6.5 Hz), 7.59 (1H, s), 7.04 (1H, dd, J=10.1, 8.9 Hz), 6.35 (1H, t, J=1.8 Hz), 6.15 (1H, s), 4.49 (1H, q, J=6.5 Hz), 2.76-2.88 (1H, m), 1.40 (9H, s), 1.34 (3H, d, J=6.5 Hz), 1.19-1.28 (2H, m), 0.70-0.78 (2H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −105.25 (s). m/z (ESI, +ve ion) 410.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccccc1)N1CCN(C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 7.3 g (66.0 mmol) of 1-methylpiperazine. The reaction mixture was refluxed for three hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropano/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with bane, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent. A second purification was performed using methanol/chloroform as eluent and was concentrated to dryness to yield 5.21 g (95%) of the desired mixture of isomers as a yellow oil. MS (ion spray) 249.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=[O:19])=[O:18].[OH-].[Na+].C(OCC)C>O1CCCC1.C([Li])CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:17]([OH:19])=[O:18])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ncsc2C1
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (845 mg) in absolute tetrahydrofuran (20 ml), n-butyllithium (1.65N hexane solution, 2.13 ml) was added dropwise at −78° C., and the mixture was stirred for 30 minutes with ice cooling. After passing carbon dioxide gas into the reaction mixture at −78° C. for 1 hour, the reaction mixture was warmed to room temperature. A 5N aqueous solution of sodium hydroxide and diethyl ether were added to the reaction mixture to separate a water layer. 6N Hydrochloric acid was added to the water layer to adjust the pH thereof to 1 to 2. After addition of dichloromethane, an organic layer separated was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (562 mg) as a pale yellow foamy substance.
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16](/[C:17](/[NH2:18])=[CH:6]/[C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:15][CH:14]=1
Reactant: Cc1nccs1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N/C(=C\c1nccs1)c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 31 %

Procedure:
A 2.5M solution of N-butyllithium (8.00 mL, 20.00 mmol) in hexanes, was added dropwise to 2-methylthiazole (1.983 g, 20 mmol) dissolved in THF (35.00 mL) over a period of 5 minutes under argon at −70° C. The resulting pale yellow slurry was stirred at −70° C. for 2.5 hour. 4-chlorobenzonitrile (2.75 g, 20.00 mmol) in THF (35.00 mL) was added dropwise to the suspension, which was stirred at −70° C. for 90 minutes after the end of the addition. The reaction mixture was allowed to warm to room temperature under stirring and darkened. The crude was concentrated to dryness and diluted with ethyl acetate then washed with water, dried over magnesium sulphate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 100% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford (Z)-1-(4-chlorophenyl)-2-(thiazol-2-yl)ethenamine (1.466 g, 31.0%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(O)=[O:2].[CH3:23][NH:24][CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[C:1]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2]
Reactant: O=C(O)c1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O

Procedure:
8.0 grams (0.0275 mole) of the acid chloride of the product of Example 2 was reacted with excess dimethylamine in 200 mls of toluene. This solution was heated on a steam bath for 2 hours. The solution was filtered and the filtrate distilled at reduced pressure. The residual solid was filtered, washed with petroleum ether and air dried. There was isolated 5.0 grams of a solid which when recrystallized from absolute ethyl alcohol gave 2.5 grams of a white solid that melted at 278° C. The infrared spectrum showed two carbonyl bands one at 6.0μ, the other a 6.1μ. Analysis calculated for C19H17N3O2.1H2O, C, 70.4; H, 5.4; N, 12.9. Found: C, 70.1; H, 5.5; N, 12.9.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:19]=[CH:20][S:21][CH:22]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1cscn1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cscn2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (491 mg, 3.4 mmol) was dissolved in anhydrous DMF (25 mL), then potassium carbonate (1.43 g, 10.3 mmol) and 4-(bromomethyl)-1,3-thiazole (922 mg, 5.2 mmol) were added. The mixture was stirred for 4 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM in MeOH to afford to 6-methyl-2-[(1,3-thiazol-4-ylmethyl)sulfanyl]pyrimidin-4-ol (268 mg, 32% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.53 (s, 2H), 6.00 (bs, 1H), 7.63 (d, J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[NH2:40].N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:40][C:39]1[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:37]([O:36][CH3:35])[CH:38]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COc1ccc(N)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3,4-dimethoxy aniline (248 mg, 1.62 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl>N1C=CC=CC=1>[C:32]1([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]3[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=3)=[CH:4][C:3]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccccc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.995 g, 0.00181 mol) and phenylsulfonyl chloride (0.484 g, 0.00274 mol) 40 mL of methylene chloride was added 5 mL of pyridine. The reaction mixture was stirred overnight at room temperature, washed with 1N HCl and 1N NaOH, dried over Na2SO4 and concentrated. A crystallization from ethyl acetate-hexanes gave an oil. It was solidified under standing. Yield 1.043 g (83%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]1[C:30]([O:32]C)=[O:31])=[CH:11][C:10]([O:34][CH3:35])=[CH:9][CH:8]=2.C(OCC)C.O>O1CCOCC1>[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]1[C:30]([OH:32])=[O:31])=[CH:11][C:10]([O:34][CH3:35])=[CH:9][CH:8]=2
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCc1c(Cl)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncc(Cl)c(CCCC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Temperature: 60 °C
Yield: 80.4 %

Procedure:
60 cm3 of a 1 N aqueous sodium hydroxide solution are added to 7.05 g of methyl (3RS,4RS)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate in 100 cm3 of dioxane. The reaction medium is then heated at 60° C. for 2 hours and then concentrated to dryness under reduced pressure (45° C.; 5 kPa). The residue obtained is taken up with 300 cm3 of diethyl ether and 500 cm3 of distilled water. The aqueous phase is then washed with 200 cm3 of diethyl ether and then acidified with 55 cm3 of a 1 N aqueous hydrochloric acid solution. Re-extraction is then carried out with 2 times 250 cm3 of ethyl acetate. The pooled organic phases are dried over magnesium sulfate for 1 hour, then filtration is carried out through a sintered glass funnel and evaporation is carried out under reduced pressure (45° C.; 5 kPa). 5.5 g of (3RS,4RS)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid, in the form of a white solid, are obtained.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9](B(O)O)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:18]1[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1.C1COCC1.O.O.O.O.O.O.O.O.O.O.B(O)([O-])[O-].B(O)(O)O.B(O)(O)O.B(O)(O)O.[Na+].[Na+]>O>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:18]2[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=2)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCCCc1cc(F)c(B(O)O)c(F)c1
Agent: OB(O)O
Agent: [Na+]
Agent: [O-]B([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(-c2cnc(Cl)nc2)c(F)c1

Procedure:
A mixture of 0.22 mol of 4-pentyl-2,6-difluorophenylboronic acid (prepared from 5-pentyl-1,3-difluorobenzene and trimethyl borate using n-butyllithium), 0.18 mol of 5-bromo-2-chloropyrimidine, 550 ml of THF, 75 ml of an aqueous buffer solution (pH=8), 230 ml of an aqueous disodium tetraborate decahydrate solution (4%), 200 ml of water and 2 g of tetrakis[triphenylphosphine]palladium (0) is heated at the boil for 20 hours. Customary work-up gives the product, which can be further processed without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:5]3[C:6]([C:7]([F:8])([F:9])[F:10])=[C:2]([Cl:1])[C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)=[N:4]3)[CH2:29][CH2:30]2)=[CH:35][C:36]=1[O:41][CH3:42]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Fc1cccc(-c2n[nH]c(C(F)(F)F)c2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4cccc(F)c4)c(Cl)c3C(F)(F)F)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-[3-Fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.51) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.44-7.52 (m, 1H), 7.18-7.28 (m, 4H), 6.38-6.48 (m, 2H), 4.94 (s, 2H), 3.84 (s, 3H), 3.52-3.78 (m, 4H), 3.12 (s, 4H).