Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[C:10]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-acetamido-3,5-bis(trifluoromethyl)benzene (400 mg, 1.37 mmol) in concentrated H2SO4 (3 mL) at 0° C. was added dropwise 70% HNO3 (0.4 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (10 g). The precipitate was collected by filtration, affording 400 mg of crude product which contained two compounds by 1H NMR. It was separated on a column of silica gel, eluted with chloroform, to afford 134 mg of pure 1-acetamido-2-nitro-3,5-bis(trifluoromethyl)benzene as white long needles. mp: 190°-2° C., 1H NMR (CDCl3): δ2.226 (s, 3H), 7.765 (s, 1H), 7.978 (s, 1H); 8.918 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:11][C:10]([C:21]([O:23]CC)=O)=[N:9]1.[CH3:26][NH2:27].CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:11][C:10]([C:21]([NH:27][CH3:26])=[O:23])=[N:9]1
Reactant: CCOC(=O)c1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(Sc2ccc(Cl)nc2)n(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of ethyl 1-(2-chlorophenyl)-5-[(6-chloropyridin-3-yl)thio]-1H-pyrazole-3-carboxylate (2.06 g) in methanol (4 mL) was added 40% methylamine-methanol solution (6 mL) at room temperature and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-yellow amorphous form (yield 1.75 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:19](=O)[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N+]([O-])([O-])=O.[C:27]1([NH:33][C:34]([NH2:36])=[NH2+:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.CCOCC>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:19]3[CH:20]=[CH:21][N:36]=[C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:35]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=[NH2+])Nc1ccccc1
Reactant: C#CC(=O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: COc1cccc(-c2nc3c(Cl)cccn3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 140 °C
Yield: 49.2 %

Procedure:
To a solution of 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (58 mg, 0.19 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added N-phenylguanidinium nitrate (185 mg, 0.94 mmol) and potassium carbonate (129 mg, 0.94 mmol). The mixture was heated at 140° C. for 1.25 hours and then cooled to room temperature. Water was added then ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes-ethyl acetate) provided 4-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-N-phenylpyrimidin-2-amine (40 mg, 50%) as a yellow solid. 1H NMR (CDCl3 with 2 drops CD3OD): δ 9.45 (d, 1 H), 8.16 (d, 1 H), 7.60–7.58 (m, 2 H), 7.39 (d, 1 H), 7.34–7.29 (m, 3 H), 7.17–7.15 (m, 2 H), 7.07 (t, 1 H), 6.95 (m, 1 H), 6.75 (t, 1 H), 6.58 (d, 1 H), 3.79 (s, 3 H); MS m/z 428 (M+1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 72.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methylsulfonylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (101 mg, 0.23 mmol) in DMF (2.5 ml) was added hydrazine monohydrate (80%, 28 μl, 0.87 mmol, 3.8 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (72 mg, 72%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([P:19](=[O:36])(OCC2C=CC=CC=2)[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([P:19]([Cl:2])(=[O:36])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]
Reactant: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(P(=O)(Cl)OCc2ccccc2)cc(OC)c1OC
Temperature: 60 °C

Procedure:
Phosphorous pentachloride (1.15 mmol) is added to a mixture of diester 2 (1 mmol) in 5 mL of CHCl3. The mixture is heated at 60° C. until 1H NMR of an aliquot shows that no starting material remains (approximately 4 hours). The mixture is cooled to room temperature, and the volatile components are removed in vacuo overnight
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:29][C:30]1[C:31]([C:45](O)=[O:46])=[N:32][C:33]([C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])=[C:34]([F:36])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:31]3[C:30]([NH2:29])=[CH:35][C:34]([F:36])=[C:33]([C:37]4[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=4[F:43])[N:32]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.9 mg, 0.018 mmol), HATU (15 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4 mg, 41%). LCMS calc. for C32H36F3N6O5 (M+H)+: m/z=641.3. Found: 641.0.
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH2:23][C:24]([O:26]CCC(C)C)=[O:25])[CH:22]=3)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:7]1=[O:43])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].O.Cl>C(O)C.O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:32][CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=3)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:7]1=[O:43])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc3c(c2)n(CCC(C)C)c(=O)n3CCC(C)C)ccc1OCCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCOc1ccc(C(=O)c2ccc3c(c2)n(CCC(C)C)c(=O)n3CCC(C)C)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In a mixture of 3 ml of ethanol and 3 ml of tetrahydrofuran is dissolved 0.28 g of isopentyl 2-[5-[(1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbonyl]-2-(isopentyloxy)phenyl]acetate. After adding 1.4 ml of 1 mol/L sodium hydroxide solution, the mixture is stirred at ambient temperature for 3 hours. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 0.21 g of 2-[5-[(1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbonyl]-2-(isopentyloxy)phenyl]-acetic acid is obtained as a white foaming product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[C:19](=S)[C:4]2=[CH:3]1.C1COCC1>[Ni].CCO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:10][CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:19][C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
Raney nickel (0.012 g, 0.207 mmol) was added to s suspension of 5-methyl-7-(1,1-dioxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-1,6-dioxo-5H-pyrrolo[3,4-c]pyridine-3-thione (0.1 g, 0.207 mmol, see Example 12.1) in EtOH (5 ml)/THF (5 ml) and the reaction was allowed to stir under an hydrogen atmosphere (pressure of about 35 psi) at r.t. for 16 h. The reaction was filtered through a pad of celite and concentrated. The resulting mixture was purified by preparative HPLC (Waters system, eluent: MeCN/ammonium acetate buffer (gradient: 12:88 to 45:55 over 15 min), column: Boston Analytics, C-18, 10 μm, 10×250 mm) to afford the title compound (45 mg, 48.0% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]=1[CH3:25])=[O:19])=[CH:7]2.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:33][N:32]=[N:31][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:30])[C:18]([C:20]1[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]=1[CH3:25])=[O:19])=[CH:7]2
Reactant: Cc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 3-methyl-benzofuran-2-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.039 g, 4.40 mmol), prepared in the previous step, sodium azide (846 mg, 13.0 mmol) and ammonium chloride (695 mg, 13.0 mmol) in 60 mL of DMF was stirred under nitrogen at 100° C. for 6 h. The reaction was diluted with water, made basic by the addition of 1 N NaOH and extracted three times with ethyl acetate. The aqueous layer was acidified with 1 N HCl, which caused an oil to precipitate. The aqueous layer was decanted from the oil. Water was added to the oil, which caused it to solidify. The solid was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound as a white solid, mp 164-166° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1>>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH:30]=[C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(C3=CCN(C(=O)OC(C)(C)C)CC3)ccn2c1=O
Yield: 125.3 %

Procedure:
Methyl 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (467.0 mg, 1.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a brown oil (830 mg, 100%). ESI-MS m/z: 461 (M+Na)+, 439 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.[N:13](/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC.CCCCCC>[CH3:7][N:5]1[CH:6]=[C:2]([N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:3]=[N:4]1
Reactant: CC(C)(C)OC(=O)/N=N\C(=O)OC(C)(C)C
Reactant: Cn1cc(I)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 4-iodo-1-methyl-1H-pyrazole (21 g, 0.12 mol) in dry ether (200 mL) at −78° C. was added n-BuLi (84.5 mL of a 2.5 M solution in hexane, 0.18 mol) over a period of 30 min and the mixture stirred for a further 30 min. A solution of di-tert-butyl(Z)-diazene-1,2-dicarboxylate (30.4 g, 0.12 mol) in ether (100 ml) was added to the reaction mixture over a period of 10 min and the resultant mixture stirred at −78° C. for 1 hour. The reaction was warmed to 0° C. and quenched with ice-water and extracted with ether (3×100 mL). The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The crude material was washed with hexane and then dried under vacuum to give the title compound in 30% yield, 11.2 g.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:15]=[O:16].OC1C=CC2C(=CC=CC=2)C=1C=O.[BH4-].[Na+]>C(O)C.O>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH2:15][OH:16]
Reactant: O=Cc1c(OCCF)ccc2ccccc12
Agent: O=Cc1c(O)ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1c(OCCF)ccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.4 %

Procedure:
A solution of 2.5 grams (0.012 mole) of 2-(2-fluoroethoxy)-1-naphthaldehyde (prepared by the method of Example 1 from 2-hydroxy-1-naphthaldehyde) and 0.6 gram (0.015 mole) of sodium borohydride in 35 ml of ethanol was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 gram of 2-(2-fluoroethoxy)-1-hydroxymethylnaphthalene as a solid.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=O)[CH:4]2[CH2:3]1)=[O:7].[CH3:13][NH2:14]>>[CH3:13][N:14]1[C:9](=[O:8])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Reactant: CN
Product: CN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 150 °C
Yield: 95 %

Procedure:
An appropriately equipped glass reaction vessel was charged with 186.5 grams (1 mole) of 4-chlorotetrahydrophthalic anhydride and heated to 150° C. under nitrogen. Methylamine gas (32 grams, 1.03 mole) was then introduced to the reaction vessel subsurface over 30 minutes. The reaction mixture was then heated for 3 hours at 180° C. The product was then distilled to give N-methyl-4-chlorophthalimide in approximately 95% yield.
Reaction SMILES: ClC1C=CC=C(F)C=1C(NCC1(CC2CC2)CCNCC1)=O.[F:23][C:24]([F:30])([F:29])[S:25]([O-:28])(=[O:27])=[O:26].[CH3:31][C:32]1[N:33](S(N2C=CN=C2C)(=O)=O)[CH:34]=[CH:35][N+:36]=1[CH3:37].O(C)S(C(F)(F)F)(=O)=O>C(#N)C.C(Cl)Cl>[F:23][C:24]([F:30])([F:29])[S:25]([O-:28])(=[O:27])=[O:26].[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N+:36]=1[CH3:37]
Reactant: Cc1nccn1S(=O)(=O)n1cc[n+](C)c1C
Agent: COS(=O)(=O)C(F)(F)F
Agent: O=C(NCC1(CC2CC2)CCNCC1)c1c(F)cccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: Cc1[nH]cc[n+]1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-chloro-6-fluoro-N-{[4-cyclopropylmethylpiperidin-4-yl]methyl}benzamide (I-4) in acetonitrile (2.5 mL) was added to a solution of 2,3-dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (for synthesis see J. Org. Chem., 2003, 68, 115) (361 mg, 0.925 mmol) in acetonitrile (2 mL) The yellow solution was stirred at room temperature for 12 h then the solvent removed in vacuo. Biotage chromatography (2% methanol-DCM) afforded 2-chloro-N-{[4-cyclopropylmethyl)-1-[(2-methyl-1H-imidazol-1-ylsulfonyl)]-piperidin-4-yl]methyl}6-fluoro-benzamide (144 mg) that was directly methylated. A solution of methyl triflate (0.031 mL, 0.27 mmol) in DCM (1 mL) was added dropwise to a stirred solution of 2-chloro-N-{[4-cyclopropylmethyl)-1-[(2-methyl-1H-imidazol-1-ylsulfonyl)]-piperidin-4-yl]methyl}6-fluoro-benzamide (118 mg) in DCM (2 mL) cooled in an ice bath. The solution was stirred in an ice bath for 1.5 h then the volatile components removed in vacuo to leave 1-{[4-{[2-chloro-6-fluorobenzoyl)amino]methyl}-4-(cyclopropylmethyl)piperidin-1-yl]sulfonyl}-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (I-5) that was used in the next step without further purification. MS 483 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])=O.Cl.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17].C1(C)C=CC=CC=1.O>CCOCC>[CH3:15][N:16]([CH2:18][CH2:19][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:3][C:2]([F:13])([F:12])[F:1])[CH3:17]
Reactant: CN(C)CCCl
Reactant: O=C(c1ccccc1O)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)CCOc1ccccc1CC(F)(F)F
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of 2-trifluoroacetylphenol (380 mg, 2.0 mmol), 2-[N, N-dimethylamino]ethyl chloride, hydrochloride (432 mg, 6.0 mmol) potassium carbonate (1.38 g, 10 mmol) and toluene (5 ml) was refluxed for 3.5 h. After cooling to r.t., the mixture was treated with water and ether. The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (acetone/ether 1:1 to 1:0) to give the title compound (375 mg, 72%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:24][C:25]1[CH:30]=[C:29]([C:12]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:22])[C:7](=[O:23])[CH2:6]3)[CH:28]=[N:27][CH:26]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2C1CC1
Temperature: 120 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 40d (50 mg, 0.16 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 113 mg, 0.479 mmol), 1,2-dimethoxyethane (1.5 mL), and 2 M aqueous sodium carbonate (0.2 mL, 0.4 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (43.5 mg, 4.79 μmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 343.0451 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.18-0.26 (m, 2H), 0.78-0.88 (m, 2H), 1.87-1.99 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:20]2[CH:19]([C:21](O)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1COCC1.CO>CCOCC.O>[CH:7]1[C:20]2[CH:19]([CH2:21][OH:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Yield: 97.7 %

Procedure:
To a suspension of 7.5 g of lithium aluminum hydride in 360 mL of dry ether was added dropwise a solution of 30 g of xanthene-9-carboxylic acid in 90 mL of freshly distilled THF at 0° C. over a period of 30 minutes. The mixture was stirred at room temperature until the color had changed from grey to brownish red (ca. 1.5 hours) The excess LiAlH4 was decomposed by the slow addition, while stirring, of a mixture of 60 mL of methanol and 25 mL of water at room temperature. The milky white suspension was filtered (sintered glass funnel) and rinsed with ether (3×50 mL). The filtrate was washed with water (2×200 mL), dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure to give 27.5 g (100%) of the crude alcohol as an off-white solid. Recrystallization from Skelly F--ether (2:1) afforded 23.59 g (86.4%) of the pure 9-xanthenemethanol as white crystals, m.p. 66°-68° C.; IR (KBr): 3290 cm-1 (OH); 1H NMR (CDCl3): δ b 1.70 (t, 1H, OH), 3.71 (dt, 2H, CH2), 4.09 (t, 1H, CH), 6.95-7.40 (m, 8H, aryl).