Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:3][C@@H:4]([OH:6])[CH3:5].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][C@H:4]([CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[CH2:10])[CH3:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C=CCCC(C)C[C@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCCC(C)C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
To a solution of (2S)-4-methyloct-7-en-2-ol (39 g, 0.274 moles) in pyridine (400 mL) was added 4-(dimethylamino)pyridine (DMAP, 1.67 g, 0.013 moles) and the solution was stirred for 10 min. P-toluenesulfonyl chloride (60 g, 0.315 moles) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred overnight. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated aq. bicarbonate solution, brine solution, dried over anhydrous Na2SO4, filter, and concentrated under reduced pressure to get crude compound (2S)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 61%). The crude compound was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In methanol (6.6 ml) and THF (4.4 ml) was dissolved methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (2.2 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18 g) as colorless amorphous.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][C:14]=2[F:23])[N:5](S(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:23])[NH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
50 mg (0.11 mml) of N-[4-({3-ethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}oxy)-3-fluorophenyl]acetamide are dissolved in 3 ml of ethanol. 1 ml of 1N aqueous sodium hydroxide solution is added, and the mixture is stirred at 90° C. overnight. The reaction solution is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The crude product obtained is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[N+:11]([O-])=O.O.[NH2:15]N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[NH:11][NH2:15]
Reactant: NN
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc(Cl)c1Cl
Solvent: O
Product: NNc1c(Cl)c(Cl)cc(Cl)c1Cl

Procedure:
Process of claim 1 wherein 2,3,5,6-tetrachlorophenylhydrazine is prepared by reacting 2,3,5,6-tetrachloronitrobenzene with hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:40])=[CH:27][C:28]([O:31][CH2:32][C:33]3([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34]3)=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(F)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
In trifluoroacetic acid (3.0 mL) and water (0.3 mL) was dissolved 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (299 mg), and the solution was stirred at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was made a pH=4 with a saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with a saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and isopropyl ether was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1-{[(5-{3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (200 mg).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13]>[Cu]>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(OC)c(I)c(OC)c1
Agent: [Cu]
Product: COc1cc(OC)c(-c2c(OC)cc(OC)cc2OC)c(OC)c1
Temperature: 235 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Compound 6 (7.0 g, 0.024 mol) and copper powder (2.0 g, 0.03 1 mol) were mixed thoroughly and transferred to a heavy wall, pressure vessel. The vessel was placed into a sand-bath at the initial temperature of 120° C. Once the vessel was secured, the temperature of the bath was raised to 235° C. in 15 min and kept at 235° C. for 1 h. The vessel was allowed to cool and the contents removed and powdered. The product was extracted with methanol for 18 h in a soxhlet. The resultant solution was concentrated in vacuo. Purification of the crude reaction mixture via column chromatography (1:5 ethyl acetate/hexane) yielded 7 (3.1 g, 78%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16](OC)=[O:17])[N:10]=[CH:9]2)#[N:2].CO.[BH4-].[Na+]>C(Cl)Cl>[F:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[C:3]([CH:23]=1)[C:1]#[N:2]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A flask was charged with methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate (100.0 g, 307.4 mmol) and MeOH (620 mL, 0.5M) and purged with nitrogen, Sodium borohydride (40.00 g, 1057 mmol) was added portionwise to the reaction mixture over 2.5 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. To the residue were added 1000 mL of saturated aqueous NH4Cl solution and 1000 mL of EtOAc. The mixture was stirred for 1 hour at ambient temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with saturated NH4Cl and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to provide 91.1 g of the crude product. The crude solid was dissolved in CH2Cl2 (1500 mL). Hexanes (2500 mL) were added to the solution with stirring. The light brown solid which crashed out of solution was filtered, washed with 1:2 CH2Cl2:hexanes and dried under high vacuum to provide 84.8 g (92.8%) of the title product. 1H NMR (400 MHz, CdCl3) δ 7.98 (s, 1H), 7.50 (d, J=8.98 Hz, 1H), 7.39-7.35 (m, 2H), 7.21-7.15 (m, 2H), 6.80 (dd, J=4.29 Hz. 9.37 Hz, 1H), 4.49 (t, J=5.00 Hz, 2H), 4.19-4.10 (m, 2H), 2.90 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:16][CH2:17][C:12]([F:11])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: FC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: FC1(c2ccccc2)CCN(c2ccnc(Cl)c2Cl)CC1
Temperature: 110 °C

Procedure:
A mixture of D10 (2 g, 7.302 mmol), 4-fluoro-4-phenylpiperidine hydrochloride (2.048 g, 9.493 mmol) [C.A.S. 1056382-25-2] and DIPEA (5.055 ml, 29.209 mmol) in CH3CN (10 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM from 4:1 up to 1:4 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D18 (0.88 g, 37%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl.O>[N:12]1([C:10]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][CH:2]([O:1][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)=[O:24])[CH2:3][CH2:4]2)=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccccn1
Reactant: O=C(OCC1CCC(O)CC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCC(COC(=O)N2CCCC2)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-hydroxy-cyclohexylmethyl ester (1 mmol) in methylene chloride (5 mL) were added picolinoyl chloride (1.1 mmol) and triethylamine (1.5 mmol) and the resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (233 mg, 70% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[Br:18]Br>C(Cl)Cl.CO>[Br:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH:12]=1
Reactant: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Reactant: BrBr
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Temperature: 25 °C

Procedure:
1-Ethyl-3-(6-methoxy-1,3-benzothiazol-2-yl)urea (1.10 g, 4.38 mmol) was suspended in DCM (50 mL) and MeOH (5 mL). Bromine (0.34 mL, 6.60 mmol) was added and the mixture stirred at rt. The mixture was stirred for a total of 1.5 h then concentrated to dryness under reduced pressure. The desired compound was obtained as an orange solid, 2.17 g, and used without further purification, stating purity as 66 mass % in further reactions. m/z: 329.94/331.91 [M+H]+.
Reaction SMILES: [P:1]([O:35]C(C)(C)C)([O:30]C(C)(C)C)([O:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([NH2:18])=[N:12][C:11]=2[N:10]([CH2:19][C:20]2[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=2)[CH:9]=1)=[O:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[P:1]([OH:30])([OH:35])([O:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([NH2:18])=[N:12][C:11]=2[N:10]([CH2:19][C:20]2[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=2)[CH:9]=1)=[O:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCCOP(=O)(O)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 4-(2-amino-4-chloro-7-((4-methoxy-3 5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-ynyl di-tert-butyl phosphate (see example 43) in DCM ( ) was treated with TFA ( ) at rt for x h. Evaporation gave the title compound as a TFA salt (5 g). The crude was dissolved in a mixture of Et3N (0.7 mL and MeOH (60 mL), loaded on Dowex 50Wx2-400 (20 g, pre-washed with MeOH), and the resin was washed with MeOH (200 mL) to remove the excess TFA. The desired phosphate was released from the resin with Et3N:MeOH 1:10 (200 mL) The solution was concentrated to give the phosphate as an oily triethylamine salt (2.75 g). Crystallization was induced with EtOH (60 mL). The mixture was left at rt for 1.5 h and at −20° C. overnight to give a first crop of crystals (0.64 g). The mixture was concentrated and the crystallization procedure was repeated to give a second crop (0.74 g). The combined triethylamine salts (1274 mg) were dissolved in MeOH (50 mL) with the help of Et3N (326 μL) and treated with a 1.0 M solution of NaGH in MeOH (4.68 mL). Evaporation and drying on high vacuum overnight gave the title compound as a solid sodium salt. HPLC Rt=4.21 mm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:30]=[CH:29][C:21]2[S:22][C:23]([C:26]([NH2:28])=O)=[C:24]([CH3:25])[C:20]=2[CH:19]=1.CS(Cl)(=O)=O.O.C(OCC)(=O)C>N1C=CC=CC=1>[C:26]([C:23]1[S:22][C:21]2[CH:29]=[CH:30][C:18]([O:17][CH2:16][C:15]3[CH:31]=[CH:32][CH:33]=[C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH:14]=3)=[CH:19][C:20]=2[C:24]=1[CH3:25])#[N:28]
Reactant: Cc1c(C(N)=O)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C#N)sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc12
Reaction time: 16 h

Procedure:
To a stirred solution of 5-[3-(2-quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophene-2-carboxamide (454.5 mg, 1 mmol) in pyridine (10 ml) at room temperature is added methanesulfonyl chloride (387 μL, 5 mmol). The solution is stirred for 16 hours and water (50 ml) and ethyl acetate (100 ml) are added. Extraction with ethyl acetate, washing with water and brine, drying (MgSO4) and concentration affords a crude product which is chromatographed over silica gel. Elution with 25% ethyl acetate in hexane provides 2-cyano-5-[3-(2-quinolinylmethyloxy)benzyloxy]-3-methylbenzo(b)thiophene.
Reaction SMILES: ClC1C=C(Cl)C=CC=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH3:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1B(O)O>>[CH2:28]([C:11]1[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:32]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=2[CH3:30])[N:10]=1)[CH3:29]
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-methyl-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a peach colored foam. IR (diffuse reflectance) 3439, 2968, 2933, 2875, 1608, 1564, 1482, 1391, 1294, 1279, 1242, 1204, 1175, 1050, 742 cm−1; OAMS supporting ions at: ESI+ 404.0 & ESI− 402.1; MS (EI) m/z 403 (M+); HRMS (FAB) calcd for C25H29N3O2+H1 404.2338, found 404.2324. Anal. Calcd for C25H29N3O2: C, 74.41; H, 7.24; N, 10.41. Found: C, 74.05; H, 7.44; N, 10.28.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11].[Cl:18][C:19]1[CH:24]=[C:23](I)[C:22]([F:26])=[CH:21][N:20]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[C:23]([NH:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([NH:12][CH3:13])=[O:11])[C:22]([F:26])=[CH:21][N:20]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CNC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1F
Temperature: 80 °C
Yield: 82.6 %

Procedure:
Cesium carbonate (651 mg, 2.00 mmol) was added to a mixture of 2-amino-N-methylbenzamide (150 mg, 1.00 mmol), 2-chloro-5-fluoro-4-iodopyridine (257 mg, 1.00 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (35 mg, 0.06 mmol) and palladium(II) acetate (9 mg, 0.04 mmol) in dioxane (10 mL) under an atmosphere of nitrogen and the resulting suspension was heated at 80° C. for 24 hours. The mixture was filtered through Celite and the residue washed with CH2Cl2 (20 mL). The filtrate was evaporated and the residue was then dissolved in CH2Cl2 (40 mL) and washed sequentially with a saturated solution of NaHCO3 (25 mL), water (25 mL), and finally with a saturated solution of NaCl (25 mL). The organic layer was dried over MgSO4 and then evaporated to leave a solid. The solid was triturated in CH2Cl2 to afford 2-(2-chloro-5-fluoropyridin-4-ylamino)-N-methylbenzamide (231 mg, 83% yield); 1H NMR spectrum (300.132 MHz, d6 DMSO+d4 Acetic acid): δ 2.76 (3H, s), 7.19 (1H, m), 7.22 (1H, d), 7.50-7.58 (2H, m), 7.71 (1H, dd), 8.19 (1H, d); Mass spectrum: m/z (ESI+) (M+H)+=280.0 and 282.0.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].C(O)C>ClC(Cl)Cl.C1CCN2C(=NCCC2)CC1>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: CC(C)(C)N
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3cc(Cl)c(F)cc3cc2c1=O

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine is prepared under the conditions of Example 17 but starting from 8.86 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 4.03 g of tert.-butylamine in 45 cm3 of trichloromethane and then in 4.53 g of DBU and 45 cm3 of ethanol 5 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 239° C.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:24]([CH3:23])[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C1CN(C(c2ccccc2)c2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (WO 96/05193) (1.4 g) in dioxane (25 mL) were added N-methyl benzenesulphonamide (1.2 g) and caesium carbonate (2.6 g). The reaction mixture was heated to reflux for 3 h, then cooled to room temperature. Water (20 mL) was added to the resulting slurry, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and dried in vacuo to yield crude product. Chromatography on silica gel eluting with ethyl acetate:hexanes (2:3 by volume) yielded the title compound as a white foam (1.31 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@:10]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]2)=[O:31])([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@:10]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]2)=[O:31])([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][CH:9]=1
Reactant: O=C1CCC(C(=O)N[C@@](Cc2ccccc2)(c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C1CCC(O)C1
Reaction time: 16 h
Yield: 71 %

Procedure:
NaBH4 (600 μg, 0.015 mmol) was added to a solution of N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-oxocyclopentanecarboxamide (prepared as described in Example 7, Procedure 12) (7.7 mg, 0.015 mmol) in THF (1 mL) at room temperature. The reaction was monitored by HPLC and after 16 h, the solution was diluted with H2O and extracted with EtOAc (3×). The combined EtOAc layers was further washed with 6N HCl and sat'd aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 0-100% EtOAc/hexanes) gave 5.4 mg of N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-hydroxycyclopentanecarboxamide as a film. 1H NMR (500 MHz, CDCl3, mixture of isomers) δ 8.54 (s, 1H), 8.52 (s, 1H), 8.35-8.29 (m, 2H), 7.72-7.66 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.32 (m, 2H), 7.25-7.06 (m, 10H), 6.56-6.50 (m, 4H), 4.48-4.38 (m, 2H), 4.30-4.22 (m, 2H), 3.64-3.53 (m, 2H), 2.89-2.80 (m, 2H), 2.10-0.80 (m, 12H); LC/MS (MeOH/H2O/NH4OAc mobile phase) rt=3.91 min; [M+H]=507.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.N1CCCC[CH2:20]1.FC1C=CC=CC=1[N+]([O-])=O.NC1C=CC=CC=1>>[NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:20]1
Reactant: c1ccc(N2CCCC2)c(NCC2=NCCN2)c1
Reactant: C1CCNCC1
Agent: O=[N+]([O-])c1ccccc1F
Solvent: Nc1ccccc1
Product: c1ccc(N2CCCCC2)c(NCC2=NCCN2)c1

Procedure:
Under conditions similar to those used for the preparation of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-pyrrolidinyl)aniline (Example 64), piperidine was reacted with 2-fluoronitrobenzene, the nitro group was reduced, and the aniline was coupled, with CMI to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-piperidinyl) aniline.