Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>N1C=CC=CC=1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1C

Procedure:
The product from Example 2B (0.03 g, 0.1 mmoles) in pyridine (2 mL) at 0° C. was treated with ethanesulfonyl chloride (0.01 g, 0.12 mmoles). The reaction mixture was quenched after 1 hour with water (2 mL), extracted with diethyl ether (5 mL), washed with water (2×2 mL), rinsed with brine (2 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TFA in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ1.22 (t, 3H, J=7.3 Hz), 2.40 (s, 3H), 3.02 (dd, 2H, J=14.6, 7.5 Hz), 4.05 (s, 4H), 6.94 (m, 2H), 7.01 (m, 1H), 7.20 (m, 2H), 7.27 (m, 7H), 8.92 (s, 1H); MS (APCI+) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:23]3[C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[CH:30][C:22]=3[O:21][CH2:20][CH:16]3[CH2:17][CH2:18][CH2:19]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2c(OCC3CCC3)ccc3c2OCO3)OC1(C)C
Product: CCOC(=O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-cyclobutylmethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A30) the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O>N1C=CC=CC=1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: Nc1nncs1
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-butylbenzenesulfonyl chloride (4.89 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.46 g, 11.6 mmol, 59% yield) as a solid, mp 120-121° C.; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, 3H, J=7 Hz), 1.29-1.37 (m, 2H), 1.56-1.61 (m, 2H), 2.65 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.84 (d, 2H, J=8 Hz), 8.25 (s, 1H); 13C NMR (75 MHz, CDCl3) 13.9, 22.3, 33.2, 33.6, 126.5, 129.1, 138.1, 142.7, 148.6, 167.4; MS (Q-TOF) Calcd for C12H16N3O2S2 298.0684, found 298.0695 (M+H)+; Calcd for C12H15N3N3O2S2 320.0503, found 320.0361 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15]
Reactant: COc1ccc2c(c1)NC(=O)C(Cl)(Cl)CC2
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(=O)C(Cl)CC2
Reaction time: 1 h

Procedure:
A solution of 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (20 g) and anhydrous sodium acetate (13.2 g) in glacial acetic acid (250 ml) was hydrogenated at atmospheric pressure using 10% Pd/C (1 g) as catalyst, until the uptake of hydrogen ceased. The catalyst was filtered off and the acetic acid was evaporated under reduced pressure. Water (100 ml) was added to the residue and the suspension stirred for 1 hour. The solid was filtered, washed with water (50 ml), and dried to give 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 162°-163°.
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3C=C[C@H]([CH:4]2C=[CH:2]1)C3.[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2)=[O:16]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1CC2C=CC1C2
Temperature: 180 °C
Yield: 85 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 256.5 ml, 1.9 mol), methylacrylate (Aldrich, 405 ml, 4.5 mol) and hydroquinone (3.2 g, 0.03 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 180° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 50° C. (yield: 85%, exo/endo=41/59).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Clc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(Cl)cccc32)nc(N2CCOCC2)cc1=O
Yield: 21.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 84 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a slightly pinkish powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH:17]2[CH2:19][CH2:18]2)([OH:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[CH2:20](Cl)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([C:9]([CH:17]2[CH2:19][CH2:18]2)([OH:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: ClCCc1ccccc1
Reactant: Oc1ccc(Cl)cc1C(O)(Cn1ccnc1)C1CC1
Product: OC(Cn1ccnc1)(c1cc(Cl)ccc1OCCc1ccccc1)C1CC1
Yield: 26.4 %

Procedure:
The general procedure of Example 6 was repeated using 4-chloro-2-(1-cyclopropyl-1-hydroxy-2-(1H-1-imidazolyl)ethyl)phenol [compound (2-3)] and phenethyl chloride, to thereby yield 1-(5-chloro-2-(phenethyloxy)phenyl)-1-cyclopropyl-2-(1H-1-imidazolyl)-1-ethanol as colorless crystals (yield: 26.4%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]=O)[CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]([O:22][CH3:23])=[N:20][C:19]2[C:14]1=[N:15][C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:17][C:18]=2[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:26]([O:25][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[C:21]([O:22][CH3:23])[N:13]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)=[C:18]([NH2:24])[N:17]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: O=CC1CCCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCOC3)c2n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
Tetrahydro-2H-pyran-3-carbaldehyde (19.39 mg, 0.17 mmol) was added to 9-(3-aminopropyl)-2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine (50 mg, 0.17 mmol) in DCM (1 ml). Sodium triacetoxyborohydride (72.0 mg, 0.34 mmol) and DCM (1 ml) was added followed by acetic acid (0.024 ml, 0.425 mmol). The mixture was stirred at 20° C. under nitrogen for 5 hours. The mixture was quenched with NaHCO3 (5 ml) and diluted with DCM (2 ml). The organic layer was separated using a hydrophobic frit and the solvent removed in vacuo. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen to give the title compound as white solid (47 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[C:3]([C:11]([NH:33][CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23]3[O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]=3)[CH2:31][CH2:30]2)=[O:13])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1ccc(N)c(C(=O)O)n1
Product: CCOc1ccc(N)c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)n1

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 282 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1CCCCl.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>C(#N)C.C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:36][CH2:37][CH2:38][O:39][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenyl)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6-fluoro-3-[1-[3-(2-methoxyphenoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1)[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCc1cccc(C)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH3:20])[C:14]3[N:15]([CH:17]=[N:18][N:19]=3)[N:16]=2)[CH2:7][CH:6]1[Se:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:20][C:13]1[C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([OH:4])[CH:6]([Se:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:7]2)[CH:12]=1
Reactant: CC(=O)OC1CCN(c2cc(C)c3nncn3n2)CC1[Se]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N2CCC(O)C([Se]c3ccccc3)C2)nn2cnnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.6 g of 4-acetoxy-1-(8-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)-3-(phenylselenyl)piperidine in 25 ml of ethanol was stirred at room temperature while 10 ml of 1N sodium hydroxide was added. After stirring an additional 30 minutes at room temperature, the reaction was partitioned in water/dichloromethane. The layers were separated, the aqueous phase was washed with fresh dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and evaporated to give a colorless glass. When this material was boiled in 50 ml of ethyl acetate, a crystalline material formed. After cooling to room temperature, the product was collected and dried to give 1-(8-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-3-(phenylselenyl)-4-piperidinol melting at about 157°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][CH2:18][O:19][CH3:20].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1.C([O-])(=O)C.[NH4+].C(#N)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1
Reactant: COCCNc1cnccc1-c1c(F)cccc1OC
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COCCN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to example 223, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) and using preparative HPLC (ammonium acetate/acetonitrile) for purification. Yellow solid (17%). MS (ESI): m/z=527.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:25]O>>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:25])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F

Procedure:
5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl2 in appropriate solvent. The reaction normally completes within several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[F:12]C(F)(F)C(OC(=O)C(F)(F)F)=O.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([F:12])=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nccc2n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)n2ncc(F)c2n1
Temperature: 0 °C

Procedure:
A mixture of 5,7-dimethyl pyrazolo[1,5-a]pyrimidine [1.47g (10 mmoles)], trifluoroacetic anhydride (2.0 ml), and boron trifluoride etherate (2.0 ml) in CH2Cl2 (30 ml) was heated at reflux for 24 hours. At the end of this time the red solution was cooled and added to an ice cold solution of NaOH (30 ml, 2N). The organic layer was separated and the alkaline layer extracted with CH2Cl2 3(20 ml). The combined CH2Cl2 extracts were washed with water 2(20 ml) and dried over Na2SO4. The CH2Cl2 extract was evaporated and the residue covered with n-petane qnd chilled. The yellow white crystalline plates were separated by filtration, and recrystallized from n-heptane to yield an analytically pure product; mp 129°-30°.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]([O:41]C(C)(C)C)=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1>>[C:12]([C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:8]3[C:7]4[CH:9]=[C:10]([N:14]5[C:15](=[O:24])[C:16]6=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]6[C:18]5=[O:19])[CH:11]=[C:12]([CH3:13])[C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])=[CH:32][CH:31]=2)[C:34]=1[C:39]([OH:41])=[O:40])([CH3:13])([CH3:6])[CH3:11]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2cccc(C(C)(C)C)c2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.C[Si](C)(C)[O-].[K+]>C1COCC1.CCOC(C)=O>[C:18]([O:17][C:15]([N:5]([CH2:4][C:3]([OH:22])=[O:2])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CN(Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of methyl[(tert-butoxycarbonyl)(3,5-difluorobenzyl)amino]acetate from Step B (1.89 g, 5.99 mmol) in THF (60 mL) was added potassium trimethylsilanolate (1.00 g, 7.79 mmol). The reaction mixture was allowed to stir at ambient temperature for 72 hours. The bulk of the THF was then removed in vacuo, and the residue was diluted with water. The aqueous layer was extracted three times with diethyl ether, discarding ether extracts. The aqueous layer was placed under reduce pressure to remove residual ether and then was brought to an acidic pH with aqueous 1 M HCl to obtain an oil. The oil was dissolved in EtOAc and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound. MS: m/z=319 (M+18 (NH4+)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)O
Reactant: Fc1cccc(S)c1
Solvent: CCOCC
Product: O=C(O)CCSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 20.2 h
Yield: 80.3 %

Procedure:
3-Fluorothiophenol (5.39 g, 42 mmol) was placed in a flask with acrylic acid (3.73 g, 52 mmol) and stirred at room temperature for 20.2 hours. The reaction mixture solidified, was dissolved in ether and extracted with 10% Na2Cl3. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(3-fluorophenylthio)propanoic acid (6.75 g), contaminated with some acrylic acid, as a white solid which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[CH3:9]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Oc1ccncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1ccc(=O)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a solution of 3-bromo-4-pyridinol (308.2 mg, 1.771 mmol) in N,N-dimethylformamide (10 mL, 100 mmol) was added potassium carbonate (371.0 mg, 2.684 mmol) and methyl iodide (133 uL, 2.14 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-20% methanol in dichloromethane) to yield 269.9 mg (81%) of 3-bromo-1-methylpyridin-4(1H)-one. LCMS (ESI): M+H=188.2; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J=2.1 Hz, 1H), 7.68 (dd, J=7.4, 2.1 Hz, 1H), 6.21 (d, J=7.4 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with benzoyl chloride (9.1 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:18]=[C:17]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34]Br)(=[O:29])[CH3:28].[H-].[Na+]>>[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][O:16][CH2:15][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:20][C:19]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:18][C:17]=2[Cl:26])[O:14][N:13]=1)(=[O:29])[CH3:28]
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Reactant: CC(=O)OCCOCBr
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOCOCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl}-3-isoxazolylmethoxymethoxyethyl acetate [XXIV; n=5, R1 and R2 =Cl] was prepared from 4.0 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 116) and 2.0 g of 2-acetoxyethoxymethyl bromide [CH3COCH2CH2OCH2Br] in the presence of sodium hydride according to the procedure of Example 117, and was obtained in the form of a colorless oil (2.4 g).