Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10](C)=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[NH2:35][C:33]([C:32]1[CH:36]=[CH:37][C:29]([NH:28][C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[CH:10]=[N:9][N:8]([CH:12]([CH3:13])[CH3:14])[C:6]=3[N:7]=2)=[CH:30][CH:31]=1)=[O:34]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: NC(=O)c1ccc(N)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Nc3ccc(C(N)=O)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 4-aminobenzamide (29.5 mg, 0.217 mmol), cesium carbonate (88 mg, 0.271 mmol), N,N-dimethylacetamide (DMA) (1.5 mL), palladium(II) acetate (2.431 mg, 10.83 μmmol) and Xantphos (10.44 mg, 0.018 mmol) wherein the reaction temperature was 150° C. and reaction time was 1 h. The final product was collected as 12 mg (14%). LCMS E-S (M+H)=488.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 2.32 (s, 3 H), 4.35 (d, J=4.8 Hz, 2 H), 4.99 (quin, J=6.8 Hz, 1 H), 5.89 (s, 1 H), 6.65 (s, 1 H), 7.15 (br. s., 1 H), 7.75-7.82 (m, 1 H), 7.84-7.96 (m, 4 H), 8.56 (t, J=4.9 Hz, 1 H), 9.77 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:49]=[CH:48][C:43]3[NH:44][C:45](=[O:47])[NH:46][C:42]=3[CH:41]=2)O1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:49]=[CH:48][C:43]3[NH:44][C:45](=[O:47])[NH:46][C:42]=3[CH:41]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]c(=O)[nH]c2c1
Yield: 131.1 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.059 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.325 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-100%) in heptane furnished 0.273 g (85%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:36]2[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=2)[C:10]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:23]5[S:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[CH:17][CH:18]=4)[C:13]([CH2:34][CH3:35])([CH2:32][CH3:33])[C:12]=3[CH:11]=2)=[CH:5][CH:4]=1.NC1C=CC=CC=1S.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C1(C)C=CC=CC=1.C(O)(=O)C.O.O.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)[C:10]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:23]5[S:24][C:25]6[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=6[N:27]=5)=[CH:17][CH:18]=4)[C:13]([CH2:32][CH3:33])([CH2:34][CH3:35])[C:12]=3[CH:11]=2)=[CH:5][CH:4]=1
Reactant: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3ccc(OC)cc3)c3ccc(OC)cc3)cc21
Agent: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC1(CC)c2cc(-c3nc4ccccc4s3)ccc2-c2ccc(N(c3ccc(O)cc3)c3ccc(O)cc3)cc21
Temperature: 195 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of N,N-di(4-methoxyphenyl)-7-(benzothiazol-2-yl)-9,9-diethyl-fluoren-2-amine, (Example 9; 11.0 g, 18.9 mmol), 2-aminothiophenol (9.0 mL, 10.53 g, 84.0 mmol), potassium carbonate (0.58 g, 4.2 mmol) and 1-methylpyrrolidine-2-one (NMP, 50 mL) was heated to 195° C., and held at this temperature for 6 hours. After cooling, the mixture was poured into a mixture of acetic acid (100 mL) and water (750 mL). The separated solids were collected and reslurried in a mixture of ethanol (100 mL) and toluene (50 mL), and the insoluble solids, 7.44 g, m.p. 294-297° C. were collected. Additional 2.71 g, with the same melting point was obtained by concentration of the filtrate, and slurrying the crude product in toluene. Total product recovered was 10.15 g (97% yield). A sample for analysis was prepared by heating 1 g of the sample with 2:1 acetic-acid-water mixture (75 mL), 0.98 g, m.p. 294.2-294.5° C. Mass spec: m/z 554 (M+). Anal. Calcd for C36H30N2O2S: C, 77.95%; H, 5.45%; N, 5.05%; S, 5.78%. Found; C, 77.95%; H, 5.53%; N, 5.18%; S, 5.90%. 1H NMR (DMSO-d6) δ ppm: 0.30 (t, 6H, 7.3 Hz), 1.80-1.84 (m, 2H), 1.99-2.04 (m, 2H), 6.70-6.81 (m, 6H), 6.94-6.97 (m, 4H), 7.42-7.46 (m, 1H), 7.52-7.56 (m, 1H), 7.65 (d, 1H, 8.4 Hz), 7.78 (d, 1H, 7.92 Hz), 7.97-8.13 (m, 4H), 9.38 (s, 2H). 13C NMR (DMSO-d6) δ ppm: 8.96, 32.23, 56.01 (3 sp3C), 113.42, 116.71, 118.47, 119.66, 121.28, 121.77, 122.68, 123.02, 125.69, 127.06, 127.42, 127.59, 130.52, 131.90, 134.77, 139.22, 145.09, 150.09, 150.34, 151.87, 154.15, 154.50, and 169.38 (23 sp2C).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH2:10][CH:11]=[CH2:12])[C:3]=1[OH:13].[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH2:10][CH2:11][CH3:12])[C:3]=1[OH:13]
Reactant: [H][H]
Reactant: C=CCc1c(C#N)ccc(N)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(C#N)ccc(N)c1O
Yield: 283.7 %

Procedure:
A mixture of 2-amino-5-cyano-6-prop-1-ene-3-yl-phenol (0.5 g, 2.4 mmol) and 10% palladium on carbon (0.05 g) in ethyl acetate (50 mL) was stirred at rt under 1 atm of hydrogen for 2 hours. The mixture was filtered through Celite to remove the palladium and the filtrate was concentrated under reduced pressure to afford the title compound as a pinkish-white solid (1.2 g, 78%). MS(ES+) m/e 177 [M+H]+; MS(ES−) m/e 175[M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2F)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3F)CC2)cc1
Yield: 80.3 %

Procedure:
0.382 g (0.001825 mol) of 1-(2-fluoro-benzyl)-piperidin-4-ol and 0.512 ml (0.00365 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.483 ml (0.00365 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.48 g (80%) of 1-(2-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23 FN02+).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50]([CH2:52][O:53][CH3:54])[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][C@H:50]([CH2:52][O:53][CH3:54])[CH2:51][N:47]6[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(C(=O)COC(=O)[C@@H]3CC[C@H](C)N3C(=O)OC(C)(C)C)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Yield: 65.3 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs2CO3 (306 mg, 0.94 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:11][C:5]=2[CH:4]2[O:21][CH:3]12.[H-].[Na+].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>CS(C)=O>[CH3:22][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:13])=[O:14])=[CH:11][C:5]=2[C@@H:4]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[C@@H:3]1[OH:21]
Reactant: O=C1CCCN1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6.3 g (0.02 mole) of 3,4-dihydro-2,2-di-methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzo[b]pyran in 20 ml of DMSO is added dropwise, at 20°, to a suspension of 0.6 g (0.02 mole) of 80% NaH in 10 ml of DMSO. Then 2.3 ml (0.03 mole) of 2-pyrrolidinone are added, and the mixture is stirred at 45° for one hour. After it has stood at 20° overnight it is introduced into ice-water. The precipitate is filtered off with suction, washed to neutrality, dried and chromatographed on silica gel with methylene chloride/methanol 19:1. 30 ml fractions are collected. Fractions 12-22 are concentrated, and the residue is recrystallized from acetonitrile.
Reaction SMILES: C([O:4][CH:5]([CH2:30][O:31]C(=O)C)[CH2:6][N:7]1[C:27](=[O:28])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:22]=4[N:9]([C:10]=23)[C:8]1=[O:29])(=O)C.Cl>CO>[OH:4][CH:5]([CH2:30][OH:31])[CH2:6][N:7]1[C:27](=[O:28])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[S:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=4[N:9]([C:10]=23)[C:8]1=[O:29]
Reactant: CC(=O)OCC(Cn1c(=O)c2cccc3c2n(c1=O)-c1cc(C(F)(F)F)ccc1S3)OC(C)=O
Agent: Cl
Solvent: CO
Product: O=c1c2cccc3c2n(c(=O)n1CC(O)CO)-c1cc(C(F)(F)F)ccc1S3
Reaction time: 8 h

Procedure:
A mixture of 48.1 g. (0.0975 mol.) of 2-(2,3-diacetoxypropyl)-10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione in 200 ml. of methanol and 25 ml. of concentrated hydrochloric acid was heated under reflux for 0.5 hour, then allowed to stand overnight at ambient temperature. The white solid that precipitated was isolated by filtration and washed with water to give the title compound, m.p. 159°-162° (chloroform).
Reaction SMILES: C1CCCCC1.S(=O)(=O)(O)O.O=O.[N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([O-:16])=[O:15].[N+:24](C1CCCCC1)([O-:26])=[O:25]>C(Cl)(Cl)(Cl)Cl>[N+:24]([O-:26])([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([O-:16])=[O:15])=[O:25]
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: O=[N+]([O-])C1CCCCC1O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])OC1CCCCC1[N+](=O)[O-]
Yield: 30 %

Procedure:
A solution of 4.4 grams (50 mmoles) of cyclohexane in 50 milliliters of carbon tetrachloride containing 1 milliliter of concentrated sulfuric acid was treated with 6.9 grams of N2O4 and 21 grams of oxygen at about 5°C. Analysis of the isolated product (7.3 grams) showed it consisted of a mixture of 2-nitrocyclohexyl nitrate (30 percent yield), 2-nitrocyclohexanol, nitrocyclohexane and carboxylic acids.
Reaction SMILES: Cl.Cl.[OH:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:7][NH2:8])[CH2:5][NH2:6].[OH-].[Na+].[CH3:17][C:18]([CH3:20])=O>O>[CH3:17][C:18]1([CH3:20])[NH:8][CH2:7][C:4]([OH:3])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][NH:6]1
Reactant: NCC(O)(CN)c1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)NCC(O)(c2ccccc2)CN1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
4.4 g (0.01841 mol) of the dihydrochloride obtained in stage (c) above are dissolved in 50 ml of water. 2.2 g of sodium hydroxide pellets and 3 ml of acetone are added. The mixture is left to stand overnight at room temperature (15°-20° C.) and extracted with 3×100 ml of CHCl3, and the chloroform phase is washed with 30 ml of water, dried over MgSO4 and then filtered to remove MgSO4. The filtrate is evaporated to dryness; recrystallization from petroleum ether (fraction boiling at 45°-60° C.) gives 2.6 g (yield: 68.5%) of CRL 41 365. M.p.=108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH:29]=O)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH:33]1[CH2:36][CH:35]([N:37]2[CH2:42][CH2:41][CH:40]([F:43])[CH2:39][CH2:38]2)[CH2:34]1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH2:29][N:33]2[CH2:36][CH:35]([N:37]3[CH2:42][CH2:41][CH:40]([F:43])[CH2:39][CH2:38]3)[CH2:34]2)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC1CCN(C2CNC2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C[C@@H](CCN1CC(N2CCC(F)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
N-[(2S)-2-(4-Fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (see Method 20; 189 mg, 0.43 mmol), 1-azetidin-3-yl-4-fluoropiperidine dihydrochloride (see WO 97/27185; 139 mg, 0.56 mmol) and triethylamine (154 mg, 1.52 mmol) were dissolved in methanol (10 mL). A methanol solution (5 mL) of sodium cyanoborohydride (191 mg, 3.04 mmol) and zinc chloride (178 mg, 1.30 mmol) was added and the mixture stirred at room temperature for 20 minutes. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The organic solution was washed with aqueous NaHCO3 (1 M) and then brine. The solution was dried over Na2SO4 and then the solvent was removed by evaporation. The product was chromatographed on silica gel using a gradient of methanol and CH2Cl2 (0% MeOH-20% MeOH). There was obtained 120 mg (48%) of the title compound as a gum. 1H NMR (500 MHz, CDCl3): 1.4-1.9 (cm, 6H), 2.1-2.4 (cm, 6H), 2.6-3.5 (cm, 10H), 3.6-3.8 (m, 1H), 4.6-4.8 (bd, 1H), 6.8-7.5 (m, 6H), 7.8 (s, 1H); LCMS: m/z 578 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13][C:12]2=O)=[O:8]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][CH:13]=[C:12]2[Cl:3])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]ncc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nncc(Cl)c2c1
Reaction time: 1.15 h
Yield: 1.3 %

Procedure:
Thionyl chloride (5 mL, 68.5 mmol) and N,N-dimethylformamide (3 drops) were added to 4-oxo-1,4-dihydro-cinnoline-6-carboxylic acid methyl ester (212 mg, 1.04 mol), and the solution was stirred for 1.15 hours under reflux. Toluene was added to the reaction mixture, which was then evaporated in vacuo. Ethyl acetate was added to the residue the organic layer was washed with an ice water, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (192 mg, 0.862 mmol, 82.9%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li:16]CCCC>CCCCCC>[CH3:1][C:2]1[C:10]([Li:16])([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1=C(N2CCCC2)c2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1(N2CCCC2)C(C)=Cc2ccccc21
Reaction time: 8 h
Yield: 87 %

Procedure:
1-(2-Methyl-1H-3-indenyl)pyrrolidine (16.276 g, 81.67 mmol) was stirred in hexane (250 mL) as n-BuLi (98.0 mmol, 49.0 mL of 2.0 M solution in cyclohexane) was added dropwise. This mixture was allowed to stir overnight during which time a precipitate formed. After the reaction period the mixture was filtered. The desired product was isolated as a pale yellow solid following washing with hexane and drying under vacuum and was used without further purification or analysis (14.51 g, 87 percent yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1C=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC1C=CC=C(CC([O-])=[O:25])C=1CC([O-])=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Solvent: ClCCl
Product: O=CCCCCCOCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of alcohol (22, 6-(benzyloxy)hexan-1-01) dissolved in dry DCM, Tempo free radical (0.1 equiv), iodobenzenediacetate (1.1 equiv) were added and stirred at 25° C. On completion of the reaction (by checking TLC), it was quenched with dilute solution of Na2S2O3. The organic layer was extracted in DCM, washed with brine, dried over anhydrous Na2SO4. The solvent was removed in vacuum concentrated and subjected for chromatographic separation. The eluent was allowed to come in a solution of pet ether:EtOAC=95:5 as a colorless liquid. 1H NMR (CDCl3, 200 MHz): δ 9.8 (s, 1H), 7.2-7.4 (m, 5H), 4.5 (s, 2H), 3.5 (t, 2H), 2.4 (t, 2H), 1.6 (m, 4H), 1.4 (m, 4H); 13C NMR (CDCl3, 50 MHz): δ 202.75, 138.50, 128.40, 127.68, 127.50, 72.95, 70.03, 43.86, 29.53, 25.85, 21.91.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:6]=2[N:5]=1)[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C(=O)OC)cccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CCOc1nc2c(C(=O)OC)cc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
To a stirring solution of methyl 2-ethoxy-1H-benzimidazole-4-carboxylate (prepared as described in J. Med. Chem., 1993, 36, 2182) (500 mg) in conc. sulfuric acid (5 mL), potassium nitrate (275 mg) was added portion-wise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into ice, alkalified with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the titled compound (595 mg) as white powder.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]([Cl:15])=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)C.[OH-].[Li+]>CO>[Cl:15][C:14]1[N:6]([CH2:5][C:4]([OH:16])=[O:3])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[N:9]2
Reactant: CCOC(=O)Cn1nc2ncccc2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1nc2ncccc2c1Cl

Procedure:
(3-Chloro-pyrazolo[3,4-b]pyridin-2-yl)-acetic acid ethyl ester was treated with 1N lithium hydroxide (LiOH) (1 equiv) in 1 mL of MeOH to provide 2-(3-Chloro-pyrazolo[3,4-b]pyridine-2-yl)-acetic acid, which was used as directly in subsequent reactions without further purification: LCMS(ES) M+H 212.0, Rf 0.34 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water /94.9% acetonitrile).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([CH2:24][CH2:25][CH2:26][Br:27])[CH2:21][CH2:22][Br:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O[SiH](C1C=CC=CC=1)C1C=CC=CC=1)[C@@H](CCCO)CCO)(C)(C)C.BrN1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Si:1]([O:18][CH2:19][C@@H:20]([CH2:24][CH2:25][CH2:26][Br:27])[CH2:21][CH2:22][Br:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCC(CCBr)CCCBr)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(O[SiH](c1ccccc1)c1ccccc1)[C@H](CCO)CCCO
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](OC[C@H](CCBr)CCCBr)(c1ccccc1)c1ccccc1
Yield: 75 %

Procedure:
Following the same procedure described for the preparation of racemic dibromide, 3-(tert-butyldiphenylsilyloxymethyl)-1,6-dibromohexane, (S)-(-)-3-(tertbutyldiphenylsilyloxymethyl)-1,6-hexanediol (4.85 g, 12.53 mmol) was reacted with N-bromosuccinimide (5.35 g, 30.1 mmol) and triphenylphosphine (7.87 g, 30.1 mmol) CH2C12 (150 mL) at 0° C. to afford compound (S)-(-)-3-(tert-butyldiphenylsilyloxymethyl)-1,6-dibromohexane 4.81 (75%) as a clear, colorless oil which was homogenous by TLC (Rf =0.8, 10% EtOAc in hexanes. Both the TLC properties and 1H spectra of this compound were identical in all respects with racemic isomer. MS.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].[BH4-].[Na+]>C(O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:9]([O:10][CH3:11])=[C:8]([F:12])[CH:7]=1
Reactant: COc1c(F)cc(C=O)cc1F
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(F)cc(CNCC(OC)OC)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
3,5-Difluoro-4-methoxybenzaldehyde (3.38 g, 0.0196 mole) was added to aminoacetaldehyde dimethyl acetal (2.14 ml, 0.0196 mole) and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (35 ml), and sodium borohydride (0.743 g., 0.0196 mole) was added and the mixture was stirred overnight at 25° C. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed with water and brine and then dried with sodium sulfate. The mixture was filtered, and the solvent removed under reduced pressure to give N-(3,5-difluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an oil (4.94 g, 96%).