Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1CC(C)N(Cc2ccc(F)cc2)CC1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: [Cl:1][C:2]([O:5]C=O)(Cl)Cl.[CH2:8]([NH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:9]=[CH2:10].C(N(CC)CC)C>ClCCl>[CH2:8]([N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]([Cl:1])=[O:5])[CH:9]=[CH2:10]
Reactant: C=CCNC1CCCC1
Reactant: O=COC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)Cl)C1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
790 mg (0.48 ml, 3.99 mmol) of trichloromethylformate (“diphosgene”) are dissolved in 15 ml of dichloromethane and cooled to 0° C. To this are slowly added dropwise 1.00 g (1.17 ml, 7.986 mmol) of allyl(cyclopentyl)amine and 1.21 g (1.67 ml, 12.0 mmol) of triethylamine, and the mixture is left to stir at room temperature overnight. For workup, the reaction solution is poured into ice-water, extracted three times with dichloromethane, dried over MgSO4 and concentrated. The crude product is employed directly in the next stage.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:16])[C:7]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:10][C:9]=2[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][NH:24]1>>[O:12]1[C:13]2[CH:14]=[CH:15][C:7]([CH2:6][NH:16][C:3](=[O:4])[CH2:2][N:24]3[CH2:25][CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[CH:30][C:29]=4[CH:23]3[CH2:22][C:21]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:8][C:9]=2[O:10][CH2:11]1
Reactant: O=C(Br)CBr
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NCc2ccc3c(c2)OCO3)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with piperonylamine and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O.O>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-hydroxyphenethyl alcohol (15.02 g), benzyl bromide (13.6 ml), and potassium carbonate (75.1 g) in acetone (250 ml) is heated at reflux for about 4 hours. The mixture is cooled and poured into ether and water. The organic layer is washed with water, 1N sodium hydroxide solution, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-benzyloxyphenethyl alcohol.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3].C1(O)C=CC=CC=1.Cl.Br[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH2:1]([N:4]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3]
Reactant: Brc1ccncc1
Reactant: CCCNN1C(=O)Cc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CCCN(c1ccncc1)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1,3-dihydro-1-(propylamino)-2H-indol-2-one (10.4 g) and phenol (30.8 g), preheated to 150° C. under nitrogen, was added 4-bromopyridine hydrochloride (11.04 g) over 5 min. Heating was continued for 7 hours at which time the reaction mixture was cooled to room temperature and made basic by slow addition of dilute aqueous sodium hydroxide. The product was extracted four times with ethyl acetate and the combined organic layers back-extracted with dilute aqueous sodium hydroxide, washed with brine, and dried (K2CO3). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, EtOAc), preparative high performance liquid chromatography (HPLC) (silica gel, EtOAc→2% Et3N/0-7% MeOH/EtOAc), and a third column (alumina, EtOAc) followed. Recrystallization from ethyl acetate-pentane afforded 2.10 g (14%) of 1,3-dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one, as a solid, m.p. 140°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH2:12]([NH:19][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyridine E-2.1″ (10.000 g; 51.817 mmol) and benzylamine (5.552 g; 51.817 mmol) in NMP is added DIPEA (20.053 g; 155.451 mmol) at 0° C. The mixture is stirred at RT for 1 h. Water is added, precipitation of the product occurs. Product is filtered off and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1([S:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[S:29][C:30]([CH3:40])=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:23]=23)(=[O:20])=[O:19])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.CO.C(O)(=O)C.[H][H]>CCO.[Pd]>[Cl:1][C:2]1([S:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[S:29][C:30]([CH3:40])=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:23]=23)(=[O:20])=[O:19])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4(Cl)CCN(C(=O)OCc5ccccc5)CC4)c23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4(Cl)CCNCC4)c23)c1
Yield: 11.3 %

Procedure:
Phenylmethyl 4-chloro-4-[({2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}amino)sulfonyl]-1-piperidinecarboxylate (Example 10) (80 mg, 0.133 mmol) was taken-up in EtOH (5 mL), MeOH (5 mL) and acetic acid (1 mL). 10% Palladium on carbon (14.19 mg, 0.013 mmol) was then added and the reaction mixture was stirred at RT under 2 Bar of hydrogen for 48 h. The reaction mixture was then filtered through celite and the celite was washed with 50 mL of MeOH. The solvent was concentrated to give a residue which was purified by normal phase chromatography, eluting with a gradient from 0-10% 2N NH3 in MeOH in DCM and then further purified by MDAP (basic conditions), to afford the title compound (7 mg). LCMS (A) m/z: 466 [M+1]+, Rt 0.81 min (basic).
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C=O)C>[Si:13]([O:6][CH:3]1[CH2:4][CH2:5][CH:1]([OH:7])[CH2:2]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a solution of 1,3-cyclopentanediol (5 g, 49 mmol) and imidazole (5 g, 74 mmol) in DMF (20 mL) added tert-butyldimethylsilyl chloride (5.9 g, 39 mmol). The reaction stirred for 3 h at room temperature and was then poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (10% diethyl ether:hexanes) to afford 3.5 g (33%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 4.3-4.5 (m, 2H), 1.9-2.15 (m, 2H), 1.65-1.8 (m, 2H), 1.4-1.6 (m, 2H), 1.32-1.41 (m, 1H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 1-methylsulfonylpiperazine (HCl salt), using 2.8 equiv of triethylamine, via General Procedure C to give crude 5-chloro-2-(4-methylsulfonylpiperazin-1-yl)-7-morpholinothiazolo[4,5-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 135 after purification by reverse HPLC. MS (Q1) 478 (M+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][N:22]([S:25](Cl)(=[O:27])=[O:26])[CH2:21][CH2:20]1>C(#N)C>[O:19]1[CH2:24][CH2:23][N:22]([S:25]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:27])=[O:26])[CH2:21][CH2:20]1
Reactant: Nc1cccc2c(O)cccc12
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1cccc2c(O)cccc12)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 4.8 g. of 5-amino-1-naphthol in 210 ml. of acetonitrile were added 2.5 ml. of pyridine and a mixture of 75 ml. of acetonitrile and 5.6 g. of morpholinosulfonyl chloride was added dropwise thereto under stirring and ice-cooling. Stirring was continued at room temperature for 2 hours and reaction was conducted at 40° C. for 1 hour. The mixture was concentrated and the residue was added to about 150 ml. of water containing 3 ml. of conc. hydrochloric acid. The precipitate thus separated was recovered by filtration, washed with water and then dried to give 6.7 g. of the desired product with m.p. 220°-223° C. (with dec.).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]2[C@H:16]([CH2:25][NH:26][C@@H:10]1[CH:11]([O:14]2)[O:12][CH3:13])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[CH2:32]([O:39][C:40]([N:26]1[CH2:25][C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]2[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:10]1[CH:11]([O:14]2)[O:12][CH3:13])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1NC[C@@H]2OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2OCc1ccccc1
Reaction time: 2 h

Procedure:
To the crude amine (15), in a solution of diethyl ether:saturated sodium bicarbonate (3:2, 20 ml), was added benzylchloroformate (0.2 ml, 1.2 mmol). The reaction was then stirred, at such a rate as to make it one phase, for 2 hours. The aqueous phase was then separated and washed with diethyl ether (3×10 ml). The combined ethereal layers were then dried (sodium sulphate) and the solvent removed in vacuo. Purification by flash chromatography (0-50%, diethyl ether/hexane) then yielded methyl N-benzyloxycarbonyl-3,5-di-O-benzyl-2,6-deoxy-2,6-imino-L-gulofuranoside (16), as a colorless oil (200 mg, 67% from azidotriflate). νmax (CHCl3): 1685, 750, 700 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:8]1=[O:29].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(OCC)(=O)C.CCCCCC>[CH3:36][O:35][C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([CH2:12][CH2:13][OH:14])[C:8]1=[O:29]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3ccccc3)C2=O)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCC(CCO)(Cc3ccccc3)C2=O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.0 g, 1.95 mmol) and tetrahydrofuran (5 mL). Cool to 0° C. using a ice bath. Add a solution of tetrabutylammonium fluoride (3.90 mL, 1 M in THF, 3.90 mmol). After the addition is complete, warm to ambient temperature. After 1.5 hours, add aqueous 1 M hydrochloric acid solution (20 mL). Extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound: Rf=0.27 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH3:25][I:26]>CC(C)=O>[I-:26].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[CH3:25])=[O:20])=[CH:13][CH:14]=1
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2ccccc2Cc2ccccn2)cc1
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2Cc2cccc[n+]2C)cc1
Product: [I-]
Reaction time: 64 h
Yield: 93 %

Procedure:
2'-(2-Pyridylmethyl)-p-anisanilide (9.5 g., 0.03 mole) and 0.3 mole of methyl iodide in 100 ml. of acetone is refluxed with stirring for a period of 64 hr. The reaction mixture filtered and the filter cake washed with acetone provides a 93% yield of 2-[2-(p-methoxybenzamido)-benzyl]-1-methylpyridinium iodide, m.p. 184° -186° C. (corr.).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13].[ClH:21]>C(#N)C>[Cl:21][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Temperature: 60 °C

Procedure:
9.3 g of anhydrous cuprous chloride and 8.8 g of tert-butyl nitrite were added to 150 ml of acetonitrile and under stirring and heating at 60° C. 11 g of 3-amino-2,4,5-trifluorobenzoic acid 26 (a commercial product) was added. The mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Finally the residue was subjected to silica gel (100 g) column chromatography using chloroform as an eluent. The procedure gave 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[C:34]1([C:43]2[CH:48]=[CH:47]C=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:37](C(O)=O)=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20]([C:21]4[CH:45]=[CH:44][C:43]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:48][CH:47]=4)=[O:22])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), [1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate and isopropyl ether (1:5), to give the titled compound (36.8 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][N:44]([CH:40]3[CH2:43][CH2:42][CH2:41]3)[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 1-cyclobutylpiperazine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (62%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:28][O:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[N:8]([CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:7]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3ccccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:15]2[C:11](=[CH:12][O:13][N:14]=2)[CH:10]=[CH:9][CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:14]1[O:13][CH:12]=[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:6])[C:15]=12
Reactant: COc1cccc2conc12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cccc2conc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
18.5 ml of a 1M solution of boron tribromide in dichloromethane are added to a solution of 1.38 g (9.25 mM) of 7-methoxy-2,1-benzisoxazole in 50 ml of dichloromethane cooled to −78° C., and the mixture is then stirred at ambient temperature overnight. The reaction medium is poured into water and the mixture is brought to pH=7-8 by adding a solution of sodium carbonate, and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude product obtained is purified by silica gel chromatography, elution being carried out with a methylcyclohexane/ethyl acetate mixture (gradient of 100/0 to 50/50; v/v). The expected product is obtained in the form of a yellow solid with a yield of 10%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:25])[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([CH3:18])[C:16]=1[CH3:17])=[O:11].CC([O-])(C)C.[K+].[Cl:32][C:33]1[C:34]([C:40]([NH2:42])=[O:41])=[N:35][CH:36]=[CH:37][C:38]=1Cl.CCOC(C)=O>CN(C=O)C.O>[Cl:32][C:33]1[C:34]([C:40]([NH2:42])=[O:41])=[N:35][CH:36]=[CH:37][C:38]=1[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.879 mmol) and t-BuOK (118 mg, 1.05 mmol) in DMF (3 mL) was stirred at rt for 30 minutes, then 3,4-dichloropicolinamide (201 mg, 1.05 mmol) was added. The reaction mixture was heated to 120° C. and stirred for 12 hours. EtOAc (1 mL) and H2O (20 mL) were added, and the resulted mixture was stirred at rt overnight. Filtered to give the title compound as a brown solid (379 mg, 87.0%).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:11]1[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[S:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>O.C1COCC1.CO>[CH2:4]([C:11]1[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCc1csc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A solution of lithium hydroxide hydrate (1.20 g, 28.3 mmol) in water (50 mL) was added to a solution of compound 1017 (2.4 g, 9.4 mmol) in THF (50 mL) and methanol (30 mL). The reaction mixture was stirred at room temperature for 12 hours. After removal of organic solvent, the aqueous solution was acidified to pH 4.0 with 6 N hydrochloric acid solution and extracted with EtOAc. The organic layer was dried and concentrated to give 4-heptylthiophene-2-carboxylic acid (1018, 2.1 g) which was directly used in the next step without further purification. Rf=0.03 (10% EtOAc in hexane).