Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@H:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C@@H:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield (2R)-3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([OH:18])[C:6](=[CH:16][CH:17]=1)[CH:7]=[N:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].[OH:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([OH:18])[C:6](=[CH:16][CH:17]=1)[CH:7]=[N:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]=[CH:23][C:22]1[C:21](=[CH:28][C:27]([OH:29])=[CH:26][CH:25]=1)[OH:20]
Reactant: CN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N)c(O)c1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCO
Product: CN(C)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(O)cc2O)c(O)c1
Temperature: 60 °C

Procedure:
To a solution of 2.5 g (9.56 mmol) (R,R)-N-mono(4-dimethylaminosalicylidene)-1,2-cyclohexanediamine in 225 ml of ethanol is added dropwise at room temperature over the course of 45 minutes a solution of 1.321 g (9.56 mmol) 2,4-dihydroxybenzaldehyde in 225 ml ethanol. The reaction solution is heated at 60° C. for 4 h. After cooling to room temperature the resultant reddish brown solution is concentrated to dryness. The crude product (ca. 5 g) is resolved by column chromatography (ethyl acetate/methanol 9:1). Yield: 1,09 g (300%), yellowish orange solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccc(Br)cn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-6-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (342 mg, 66%) as a brown solid.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([N+:27]([O-])=O)[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>O.C(OCC)(=O)C>[NH2:27][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[CH:7]=3)([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Yield: 102.1 %

Procedure:
In a mixture of 10 mL of water, 2 mL of acetic acid and 0.52 g of reduced iron, a solution of 0.84 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-nitro benzoic acid amide in 10 mL of ethyl acetate was added dropwise at 75° C. with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2.5 hours. After the completion of the reaction, insoluble material was removed by hot filtration, 20 ml of water was added in the filtrate, and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 ml×2). The combined organic phases were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.80 g of the crude aimed product as yellow crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:5]2[C:6]([C:8]3[C:13]([CH3:14])=[CH:12][N:11]=[C:10]4[NH:15][CH:16]=[CH:17][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:19][CH:20]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2c(C)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2c(C)cnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate afforded the title compound. ESMS [M+H]+: 389.2
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:30]#[N:31])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([F:29])[F:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:32]=[CH:33][CH:34]=[N:35][C:11]2=3)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:29][CH:27]([F:28])[CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:32]=[CH:33][CH:34]=[N:35][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:30]#[N:31])[CH2:25][CH2:24]1
Reactant: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1ncc2[nH]c3ncccc3c2c1OC1CCN(CC(F)F)CC1
Yield: 72 %

Procedure:
To a solution of 9-benzenesulfonyl-5-[1-(2,2-difluoroethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (68 mg, 0.14 mmol) in methanol (5 mL) was added potassium carbonate (193 mg, 1.4 mmol) and the resultant suspension was heated to 40° C. for 4 hours. After this time, the reaction mixture was loaded directly onto a 5 g SPE NH2 cartridge, which was eluted with 1:1 methanol: dichloromethane. The appropriate fractions were concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, Si-SPE, 0-4% 2N NH3 in methanol in dichloromethane) to afford the title compound as a pale yellow solid (36 mg, 73%). LCMS (Method C): RT=6.07 min, M+H+=358. 1H NMR (300 MHz, CD3OD): 8.74 (s, 1H), 8.64-8.64 (m, 2H), 7.58 (s, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 5.94 (tt, J=55.8, 4.2 Hz, 1H), 4.93-4.92 (m, 1H), 3.11-2.99 (m, 2H), 2.82 (td, J=15.1, 4.3 Hz, 2H), 2.51-2.51 (m, 2H), 2.15-2.14 (m, 4H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[C:11]([NH:19][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:29][C@H:28]([C:30](OC)=O)[O:27][CH2:26][C@:24]2([C:34]2[CH:39]=[C:38]([Br:40])[CH:37]=[CH:36][C:35]=2[F:41])[N:25]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1>[Br:40][C:38]1[CH:37]=[CH:36][C:35]([F:41])=[C:34]([C@:24]23[CH2:26][O:27][C@@H:28]([C:30]4[O:5][N:4]=[C:2]([CH3:3])[CH:1]=4)[CH2:29][C@H:23]2[CH2:22][S:21][C:20]([NH:19][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:25]3)[CH:39]=1
Reactant: COC(=O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Reactant: CC(C)=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(Br)ccc3F)CO2)on1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of propan-2-one oxime (0.216 g, 2.96 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C. To this solution was added n-butyllithium (2.5 M in hexanes, 2.40 mL, 6.00 mmol) in a drop-wise manner. The resulting solution was allowed to warm to room temperature and left stirring at room temperature for 25 minutes. The resulting solution was cooled again to 0° C., followed by a drop-wise addition of methyl (4aR,6R,8aS)-2-(benzoylamino)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazine-6-carboxylate (C35) (1.09 g, 2.03 mmol) in tetrahydrofuran (3 mL). The reaction mixture was allowed to warm to room temperature and was left stirring for 25 minutes. The reaction mixture was cooled to 0° C. again, and sulfuric acid (0.840 mL, 15.8 mmol) was added in a drop-wise manner. The reaction mixture was allowed to warm up to room temperature and was left stirring for 16 hours at room temperature. The reaction mixture was basified to pH 12 with sodium hydroxide (5 N, ˜4 mL) and then extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oily residue. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield: 330 mg, 63%. LCMS m/z 532.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br s, 1H), 7.47-7.61 (m, 4H), 7.19 (dd, J=12.0, 8.9 Hz, 1H), 4.97 (br d, J=9.4 Hz, 1H), 4.31 (dd, J=11.8, 1.5 Hz, 1H), 4.00-4.14 (m, 2H), 3.00 (dd, J=13.2, 4.0 Hz, 1H), 2.83 (dd, J=13.1, 2.9 Hz, 1H), 2.10 (d, J=12.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH:3]=[CH:4][CH2:5][OH:6]>C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCC=CC(F)(F)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: OCCCC(F)(F)C(F)(F)F
Yield: 87 %

Procedure:
A solution of 25 g of 4,4,5,5,5-pentafluoropent-2-en-1-ol (Kitazume, T. and Ishikawa, N.J. Am. Chem. Soc., (1985), p. 5186) in 100 ml of ethyl acetate is shaken with 100 mg of platinum dioxide under a hydrogen atmosphere for 1 hour. Then, the catalyst is filtered off and distilled fractionating. At 133°-135° C., 22 g of 4,4,5,5,5-pentafluoropentanol is obtained with 1H-NMR (CDCl3) δ: 1.86 (m, H2), 2.18 (m, H1) and 3.75 (t, J=6.1 Hz, H1).
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[Na+:26]>ClC1C=CC=CC=1Cl>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[Na+:26]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 77.3 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), sodium trimethylsilanolate (5.6 g, 50 mmol), dry o-dichlorobenzene (200 mL), and 1 h at room temperature followed by rapid heating to 150°. Sodium perfluoro-2-methyl-3-oxahexanoate (13.6 g, 77% yield) was isolated as a white solid: The 19F NMR data were the same as reported in Example 15.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.O=P(Cl)(Cl)Cl.[NH2:13][C:14](=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15].[O-]CC.[Na+].Cl>ClCCCl>[OH:23][C:22]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:15])[N:13]=[C:3]2[N:2]([CH3:1])[CH2:6][CH2:5][C:4]=12
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1c(C)nc2c(c1O)CCN2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 1-methylpyrrolidin-2-one (14.81 ml, 154 mmol) in anhydrous 1,2-dichloroethane (DCE) (250 ml) under a nitrogen atmosphere was added drop wise POCl3 (28.5 ml, 307 mmol) over a 10 min period and the mixture was stirred at ambient temperature. After 1 h, a solution of diethyl 2-(1-aminoethylidene)malonate (30.9 g, 154 mmol) in DCE (10 mL) was added and the mixture was heated to 40° C. After 18 h, the reaction mixture was partitioned between sat. aq. NaHCO3 and DCM. The organic later was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, The residue was dissolved in N,N-dimethylformamide (DMF) (150 ml) and treated dropwise with sodium ethoxide (172 ml, 461 mmol) and heated to 100° C. After 3 h, the reaction mixture was cooled to ambient temperature and the pH was adjusted to pH 7 with 1M HCl. The mixture was partitioned between water and EtOAc and the organics washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 0-25%) to afford ethyl 4-hydroxy-1,6-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (11.0 g, 30.3% yield) as a white solid. 1H NMR (CHLOROFORM-d) δ: 11.89 (s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.54 (t, J=8.7 Hz, 2H), 2.87-3.05 (m, 5H), 2.64 (s, 3H), 1.41 (t, J=7.1 Hz, 3H); LC/MS (m/z) ES+=237.1 (M+1)+
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][CH2:5][NH:4]1)=[CH2:2].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:4]1[CH2:5][CH2:6][C:7](=[O:9])[CH2:8][CH:3]1[CH:1]=[CH2:2])([CH3:21])[CH3:20]
Reactant: C=CC1CC(=O)CCN1
Reactant: CC(C)Oc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CC1CC(=O)CCN1Cc1cccc(OC(C)C)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
2-vinylpiperidin-4-one (4.85 g, 38.7 mmol) in acetonitrile (40 ml) was added 1-(chloromethyl)-3-isopropoxybenzene (7.16 g, 38.7 mmol) and finely ground K2CO3 (16.1 g, 116 mmol). The mixture was stirred at 60° C. for 12 hrs. The solution was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 65i, eluting with 15% ethyl acetate/hexanes.
Reaction SMILES: C(N)CN.O1CCOCC1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@:18]2([CH3:33])[C@H:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)[NH:21]S(=O)(=O)[NH:19]2)=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:22]([NH2:21])[C@:18]([C:15]2[CH:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=2)([NH2:19])[CH3:33])=[CH:24][C:25]=1[F:30]
Reactant: C[C@]1(c2ccc(Cl)nc2)NS(=O)(=O)N[C@H]1c1ccc(Cl)c(F)c1
Solvent: ClC(Cl)Cl
Solvent: NCCN
Solvent: C1COCCO1
Product: C[C@](N)(c1ccc(Cl)nc1)[C@H](N)c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
Ethylenediamine (7.40 ml, 111 mmol) was added to a dioxane (80 ml) solution of the compound (4.15 g, 11.0 mmol) obtained in Step 8 above and the resulting mixture was stirred under heating at 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with chloroform, washed with 1 N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=93:7 (v/v)] to give the title compound (3.35 g, 97%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>C(Cl)Cl.CO.O1CCOCC1>[ClH:36].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[N:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCNCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.12 mmol) in DCM (0.5 mL) and methanol (0.3 mL) was treated with 4M HCl in dioxane (0.8 mL) and the reaction mixture stirred at RT for 1.5 h before being concentrated in vacuo. The resultant residue was triturated with diethyl ether to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene hydrochloride (66 mg, 100%). LCMS RT=1.68 min, [M+H]+=380
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH:25]=[CH:26]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:23][CH2:24][CH:25]=[CH:26][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: OCC=CB(O)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCO)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2 supra) in dimethoxyethane (5 mL) was added 3-hydroxy-1-propenyl-boronic acid (from Example 66 above) (42 mg, 0.418 mmol), tetrakis(triphenylphosphine) palladium(O) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(3-hydroxy-propenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 22 mg, 53%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH:6][C:7](=[O:15])[CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.Cl[Ti](Cl)(Cl)Cl>[CH:2]1([CH2:5][NH:6][C:7](=[O:15])[CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([CH:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]([F:23])([F:35])[F:34])[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C(C=C1CCNCC1)NCC1CC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(C=C1CCN(C(c2ccc(F)cc2)C(F)(F)F)CC1)NCC1CC1
Reaction time: 9 h
Yield: 25.9 %

Procedure:
A solution of TiCl4 (0.0299 ml, 0.271 mmol) in CH2Cl2 (0.5 ml) was added to a solution of N-(cyclopropylmethyl)-2-(piperidin-4-ylidene)acetamide hydrochloride (125 mg, 0.542 mmol) prepared in EXAMPLE 22e, triethylamine (0.225 ml, 1.63 mmol) and 2,2,2,4′-tetrafluoroacetophenone (0.0770 ml, 0.542 mmol) in CH2Cl2 (3.5 ml), and the whole was stirred for 9 hours. A solution of sodium cyanoborohydride (102 mg, 1.63 mmol) in methanol (1 ml) was added to the reaction mixture and the whole was stirred for 30 minutes. After the reaction was quenched with aqueous 2 N NaOH solution (15 ml), the aqueous phase was extracted with ethyl acetate (30 ml×2) and the combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/n-hexane: 35/65 to 55/45) to give N-(cyclopropylmethyl)-2-(1-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)piperidin-4-ylidene)acetamide (52 mg, 26%) as a yellow solid: LCMS: 371 {M+1}+. 1H NMR (DMSO-d6)□ δ: 0.11 (m, 2H), 0.37 (m, 2H), 0.85 (m, 1H), 2.17 (m, 2H), 2.43-2.68 (m, 4H), 2.91 (m, 4H), 4.70 (m, 1H), 5.57 (s, 1H), 7.26 (m, 2H), 7.45 (m, 2H), 7.87 (t, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC>CCOCC>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
Here 5 g (30 mmol) fluorene, dissolved in ether, was reacted for three hours with 18.8 ml of butyllithium (1.6M in hexane). The solvent was evaporated to yield yellow fluorenyl lithium. Then 11.4 g (45 mmol) of Ph2SiCl2, i.e. diphenyl dichloro silane, was dissolved in 200 ml of pentane and the solid fluorenyl lithium was added in one portion to the pentane solution. After stirring for one hour, the mixture was filtered, the precipitated LiCl was eluated with 50 ml of ether, and the solvent evaporated from the combined organic layers to yield a yellow powder characterized by GC/MS as FlSiPh2Cl, i.e. fluorenyl-diphenyl chlorosilane. Crystallization in pentane yields colorless crystals of the product, from which a H-NMR-spectra could be obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:39]([C:36]4[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:43])[F:44])=[CH:38][CH:37]=4)(=[O:41])=[O:40])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.300 g (0.925 mmol) of {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester, and 8 mL of dichloromethane was added 0.112 mL (1.39 mmol) of pyridine, 0.271 g (1.11 mmol) of 4-Trifluoromethyl-benzenesulfonyl chloride and 0.004 g (0.0277 mmol) DMAP. The dark orange solution was stirred at r.t. for 4 h. The mixture was extracted with dichloromethane, then washed with water, 1N HCl, and brine. Dried with Na2SO4. Purified on silica gel (EtOAc/Heptane, 9:1 to 6:4) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d6) 0.99-1.10 (m, 2 H) 1.34-1.46 (m, 2 H) 1.71-1.82 (m, 5 H) 2.14 (d, J=6.82 Hz, 2 H) 2.39 (tt, J=12.16, 3.25 Hz, 1 H) 3.57 (s, 3 H) 7.16 (d, J=8.34 Hz, 2 H) 7.54 (dd, J=2.53, 1.77 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.73 (d, J=8.34 Hz, 2 H) 7.78 (d, J=8.08 Hz, 2 H) 8.14 (dd, J=2.27, 1.01 Hz, 1 H).