Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](O)=[O:42]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:41]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)=[O:42])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1cccs1
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)c1cccs1)CC2
Yield: 51.4 %

Procedure:
The compound obtained in Example 3 (483 mg) and thiophen-2-carboxylic acid (158 mg) are treated in the same manner as in Example 5 to give methyl 2-n-butyl-5-(2-thienyl)carbonyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (306 mg).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][CH:30]=[CH:31][N:32]=2)=[CH:24][C:23]=1[F:33])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[CH3:34][Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:29][CH:30]=[CH:31][N:32]=3)=[CH:24][C:23]=2[F:33])[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[C:1]([OH:3])([CH3:34])[CH3:2])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 13 %

Procedure:
N-((1R,2R)-2-acetylcyclohexyl)-4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)benzenesulfonamide (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5.0 mL) and a solution of 1.4M methyl magnesiumbromide in 3:1 toluene/tetrahydrofuran (2.0 mL, 2.8 mmol) was added. After 1 h, TLC indicated conversion to a new product. The reaction mixture was quenched with methanol followed by saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give a mixture of starting material and product. The crude mixture was purified by flash chromatography on silica gel twice using a gradient of 15-50% ethyl acetate/hexanes followed by 10-35% ethyl acetate/hexanes to give 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(2-hydroxypropan-2-yl)cyclohexyl)benzenesulfonamide as a colorless oil (20 mg, 13% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66-7.78 (m, 4H), 7.62 (dd, J=10.83, 1.51 Hz, 1H), 7.52 (t, J=7.81 Hz, 1H), 7.35-7.45 (m, 2H), 7.21-7.28 (m, 3H), 4.44-4.56 (m, 2H), 3.87 (d, J=3.02 Hz, 1H), 3.06 (s, 1H), 1.85 (d, J=8.31 Hz, 2H), 1.62-1.69 (m, 2H), 1.52-1.61 (m, 3H), 1.49 (br. s., 1H), 1.18 (s, 3H), 1.05-1.16 (m, 7H). MS [M+H+Na]+=529.19.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:45]2[N:44]=[C:43]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[N:42]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:45]3[N:44]=[C:43]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[N:42]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCc1nc2c(CCl)cccc2n1COCC[Si](C)(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCc1nc2c(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Method D, 2.1 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.81 g of 4-chloromethyl-2-(3-methoxypropyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.37 (3:1 EtOAc-heptane); Rt=6.04.
Reaction SMILES: Cl[C:2]1[CH:3]=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[N:30]([CH:2]([CH3:3])[CH3:7])[N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2cccnc12
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Product: CC(C)n1nc(-c2cccc(Cl)c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 18A and substituting for 8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one with 5-(3- chlorophenyl) pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-chlorophenyl)-7-(2-propyl) pyrido[2,3-d]-pyridazin-8-one.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([S:24][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCC(Sc1ccc(C(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A mixture of 5.0 g (0.02 mole) ethyl 2-bromooctanoate, 3.37 g (0.02 mole) p-t-butylthiophenol and 3.31 g (0.24 mole) potassium carbonate in 70 ml acetone was refluxed under nitrogen overnight. The reaction mixture was cooled to room temperature and filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on 500 g silica gel, eluting with 6:4 methylene chloride/hexane to yield 3.8 g (57% yield) of the desired product as an oil.
Reaction SMILES: C=O.[CH:3](C1C=C(C=CC=1)C(OC)=O)=O.Cl.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C@H:26]3[CH2:27][NH:28][CH2:29][C@@H:25]3[CH2:24][N:23]([CH3:30])[C:22](=[O:31])[C:21]=2[CH:32]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C@H:26]3[CH2:27][N:28]([CH3:3])[CH2:29][C@@H:25]3[CH2:24][N:23]([CH3:30])[C:22](=[O:31])[C:21]=2[CH:32]=1
Reactant: CN1C[C@H]2CNC[C@@H]2c2ccc(F)cc2C1=O
Reactant: COC(=O)c1cccc(C=O)c1
Agent: C=O
Agent: Cl
Product: CN1C[C@@H]2CN(C)C(=O)c3cc(F)ccc3[C@H]2C1

Procedure:
The title compound was prepared according to the procedure outlined in Example 68 substituting formaldehyde for methyl 3-formylbenzoate and substituting (3aR,10bS)-8-fluoro-5-methyl-1,2,3,3a,4,5-hexahydrobenzo[c]pyrrolo[3,4-e]azepin-6(10bH)-one hydrochloride (Example 225B) for Example 2. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dt, J=16.6, 8.3, 1H), 7.27 (td, J=8.5, 2.8, 1H), 7.18 (dd, J=8.5, 5.6, 1H), 3.36 (ddd, J=19.2, 14.5, 5.7, 3H), 3.15-2.92 (m, 5H), 2.71 (dt, J=25.9, 9.0, 2H), 2.41 (d, J=6.1, 3H), 2.24-2.07 (m, 1H); MS (ESI+) m/z 249.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([OH:19])=O.CN(C)C=O.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([Cl:27])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (40.0 g) described in Reference Example 8 in toluene (147 ml) were added N,N-dimethylformamide (catalyst quantity) and thionyl chloride (52.6 g) at room temperature, and stirred at 80° C. for 4.5 hours. After completion of the reaction, the solvent and excessive thionyl chloride were evaporated, azeotropy was performed with toluene twice, and then dried in vacuo to give the titled compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:19]#[N:20])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:27]#[N:28].[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33].O>C1COCC1>[C:19]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([OH:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([NH:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:3]([C:27]#[N:28])[C:4]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: NC[C@@H](O)CO
Reactant: N#Cc1c(Cl)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61.5 mg (0.15 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}benzenecarboxylic acid (Example 72A) were initially charged in 1.6 ml of THF. After addition of 27.6 mg (0.30 mmol) of (2R)-3-aminopropane-1,2-diol, the mixture was stirred at RT overnight. 2 ml of water were added, and the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14](O)([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH2:22]([C:14]([C:5]1[CH:4]=[C:3]([OH:2])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:7]([OH:12])[CH:6]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(C(O)(Cc2ccccc2)Cc2ccccc2)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1c(O)cc(C(=Cc2ccccc2)Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2-(3,5-dimethoxy-4-i-propylphenyl)-1,3-diphenylpropan-2-ol (0.63 g, 1.6 mmol) in CH2Cl2 (10 mL) at −78° C. under N2 was added BBr3 (1M in CH2Cl2, 5.0 mL, 5.0 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature over night. Water (50 mL) was added followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×10 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×50 mL). The extract was washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using ethyl acetate:hexane (1:9) gave 5-(1-benzyl-2-phenylethenyl)-2-i-propyl-1,3-benzenediol (1).(0.26 g, 47%) as a liquid, which solidified on standing at 0° C. 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.1 Hz, 6H), 3.52 (hept, J=7.1 Hz, 1H), 4.08 (s, 2H), 6.51 (s, 2H), 7.13 (s, 1H), 7.2-7.4 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1>[O:27]1[CH2:28][CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:32]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(C3=CCOCC3)cc12
Reaction time: 5 h

Procedure:
A vial was charged with (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (68.1 mg, 0.166 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.498 mmol), tetrakis(triphenylphosphine)palladium (19.18 mg, 0.017 mmol), THF (830 μL), and potassium carbonate (415 μL, 0.830 mmol) (as a 2.0 M aq. solution). The vial was sealed and placed in a 110° C. for 5 hours. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]([OH:17])(=[O:16])[CH:14]=[CH2:15]>>[C:13]([O:17][CH:2]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)O
Reactant: OCC12CC3CC(CC(C3)C1)C2
Product: C=CC(=O)OC(OCC12CC3CC(CC(C3)C1)C2)C(C)C
Yield: 78 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanemethanol instead of 2-adamantanol and acrylic acid instead of methacrylic acid, 1-[(1-adamantyl)methoxy]-2-methylpropyl acrylate was produced (four step yield 78%).
Reaction SMILES: [CH2:1]1[O:19][CH:4]([C:5]2[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=2)[O:3][CH2:2]1>C(O)C.[Pd]>[CH2:2]1[O:3][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=2)[O:19][CH2:1]1
Reactant: C(=C/c1cccnc1)\c1ccc(C2OCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1cncc(CCc2ccc(C3OCCO3)cc2)c1
Yield: 85.3 %

Procedure:
10 g (39.5 mmol) of E-4-[2-(3-pyridyl)ethenyl]benzaldehyde ethylene acetal (1a) were dissolved in 100 ml of ethanol, 1.6 g of palladium on charcoal (10%) were added, and hydrogenation was carried out at room temperature and under atmospheric pressure. Filtration and removal of the solvent in vacuo produced 8.6 g (33.7 mmol, 85%) of a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[C:23]#[N:24])[NH:19][CH:18]=[CH:17]3)=[CH:10][CH:9]=1.CN([CH:28]=[O:29])C>>[CH:28]([C:17]1[C:16]2[C:20](=[CH:21][C:22]([C:23]#[N:24])=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[CH:15]=2)[NH:19][CH:18]=1)=[O:29]
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2C#N)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Phosphorous oxychloride (84.3 mg, 0.54 mmol) was added to DMF (1 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. To this solution was added 5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile (150.0 mg, 0.60 mmol) in DMF (1 mL) and the reaction mixture was stirred at 40° C. for 1 hour. The reaction mixture was cooled to room temperature, treated with additional phosphorous oxychloride (84.3 mg, 0.54 mmol) and stirred at 45° C. for an additional hour. The reaction mixture was cooled to room temperature, and quenched with water (10 mL). The solution was concentrated in vacuo, and the residue was partitioned between water (10 mL) and EtOAc (10 mL). The layers were separated and the organic layer was concentrated in vacuo. The crude material was slurried in CH2Cl2, and the resulting solid was filtered and air dried to give the title compound (85 mg, 51% yield). MS (ES−) 275.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br. s., 1H), 10.00 (s, 1H), 8.58 (d, J=3.12 Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.51 (d, J=8.59 Hz, 2H), 7.09 (d, J=8.80 Hz, 2H), 3.83 (s, 3H).
Reaction SMILES: C([O:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 25 g. of 15-(tert-butoxy)-9-oxoprostanoic acid, ethyl ester in 100 ml. of trifluoroacetic acid is stirred in an ice bath for 1 hour and is then poured into 500 ml. of ice water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and taken to dryness. The resulting oil is dissolved in 200 ml. of 1N ammonium hydroxide in ethanol, kept at ambient temperature for 15 minutes, then taken to dryness. The residual oil is dissolved in chloroform and washed with 1N hydrochloric acid, saturated sodium chloride solution, dried and taken to dryness to give 21.7 g. (100%) of product as a yellow syrup. There is essentially no uv absorption; λmaxKBr 2.90, 5.75, 8.45 μ; nmr 2H quartet δ4.13 (OCH2 of ester), 1H broad singlet 3.63 (carbinolic proton), 3H triplet (CH3 of ester), and 3H distorted triplet 0.92 (terminal methyl); mass spectrum: m/e 368.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>ClCCl.C(N(CC)CC)C>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: OCc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a stirring solution of 2-mercaptobenzyl alcohol (1.00 g, 7.10 mmol) in dichloromethane (20 mL) at 0° C. was added methyl acrylate (0.70 mL, 7.70 mmol) followed by triethylamine (50 μL, 0.35 mmol). The mixture was allowed to warm to room temperature and stir for 4 h, at which point the solvent was removed with a rotary evaporator. The residue was subjected to column chromatography on silica gel (0-10% ethyl acetate in dichloromethane), affording 1.40 g (86%) of methyl 3-(2-hydroxymethylphenylthio)propionate. 1H NMR (CDCl3) δ2.63 (t, 2, J=7), 3.18 (t, 2, J=7), 3.68 (s, 3), 4.79 (s, 2), 7.27 (m, 2), 7.43 (m, 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:19])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:19][S:21]([CH3:20])(=[O:23])=[O:22])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (200 mg, 0.77 mmol) and methanesulfonyl chloride (90 mg) in pyridine (5 ml) was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue was treated with methylene chloride and water. The resultant precipitate was filtered to give N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide. Additional N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide was contained in the methylene chloride layer. The methylene chloride was stripped in vacuo and the residue purified by chromatography on silica gel using mixtures of ethyl acetate and methanol as eluents. The purified N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide had m.p. 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=O)[CH2:6][CH2:5]2.O>[Zn].C(O)(=O)C>[NH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=NN1CCc2cc(Cl)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: NN1CCc2cc(Cl)ccc21

Procedure:
To a stirred mixture of 50 g. (0.27 mole) of 5-chloro-1-nitrosoindoline, 80 g. (1.2 mole) of zinc and 250 ml. of water was added over a 45 minute period 100 ml. of glacial acetic acid. The mixture was filtered, the filtrate basified with 50% sodium hydroxide solution and the base-insoluble oil extracted with ether. The combined ether extracts were dried, concentrated and the residual oil distilled. 1-Amino-5-chloroindoline was distilled at 96°-98°C./0.1 mm. The oil solidified on standing at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][CH2:17][Mg+].[Br-]>C1COCC1>[CH3:1][N:2]1[C@H:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:5][CH2:4][C:3]21[CH2:17][CH2:16]2
Reactant: CC[Mg+]
Reactant: CN1C(=O)CC[C@H]1COC1CCCCO1
Agent: [Br-]
Solvent: C1CCOC1
Product: CN1[C@H](COC2CCCCO2)CCC12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a mixture of (S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-pyrrolidin-2-one (0.6 g, 2.82 mmol) in 20 mL of THF was added Ti(Oi-Pr)4 (2.56 mL, 8.45 mmol, d=0.937 g/L, Aldrich) via a syringe under nitrogen at rt. After stirring at rt for 30 min, EtMgBr (5.63 mL, 16.9 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 3 hrs. The reaction was continued to stir at rt overnight, and then quenched with a mixture of 20 mL of water and 30 mL of ethyl acetate. After stirring for 20 min, the mixture was filtered through a celite pad. The filtrate was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (50:1(v/v) CH2Cl2/CH3OH) to afford (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane as pale yellow oil (64 mg, 10%).