Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][OH:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[OH:38][CH2:37][C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:4]=1
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5CO)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-pyrrolidinylmethanol (101.15 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 0.54 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.5 mg of the title compound (69.7%).
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]([NH:16][C:17](=[O:32])[C@@H:18]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][O:20][CH:21]([F:23])[F:22])[CH2:11][O:12][CH:13]([F:15])[F:14])C1C=CC=CC=1>C1COCC1.[Pd]>[C:28]([O:27][C:25]([NH:24][C@@H:18]([CH2:19][O:20][CH:21]([F:22])[F:23])[C:17]([NH:16][C@@H:10]([CH2:11][O:12][CH:13]([F:15])[F:14])[C:9]([OH:33])=[O:8])=[O:32])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)O
Yield: 99.8 %

Procedure:
A solution of the compound of Formula II(a)(ii), (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-difluoromethoxypropionic acid benzyl ester (1.27 g, 2.63 mmol) in THF was stirred with 10% Pd/C (400 mg) under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated to give the compound of Formula II(a)(i), (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-difluoromethoxy-propionic acid (1.03 g, ˜100%) as a sticky, off-white foam. NMR (d6-DMSO, 400 MHz) δ (ppm) 8.34 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 6.66 (t, J=76 Hz, 1H), 6.62 (t, J=76 Hz, 1H), 4.57-4.51 (m, 1H), 4.37-4.29 (m, 1H), 4.15-4.09 (m, 1H), 4.04-3.97 (m, 2H), 3.92-3.83 (m, 1H), 1.37 (s, 9H). Scheme VII outlines the synthesis of compound intermediates of Formula IV(b) and Formula V(b) which are used in the preparation of the compounds of Formula (I) wherein R2 and/or R3 is a —CH2—O—CH3 moiety.
Reaction SMILES: N1CCOCC1.Cl.Cl.[N:9]1([CH2:15][C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[ClH:22].[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29]([NH:21][C:18]2[S:19][CH:20]=[C:16]([CH2:15][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:17]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(CN2CCOCC2)cs1
Agent: Cl
Solvent: C1COCCN1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CN2CCOCC2)cs1
Temperature: 25 °C
Yield: 6 %

Procedure:
A mixture of INTERMEDIATE 19 (0.50 g, 2.70 mmol) and morpholine (1.65 g, 18.92 mmol) was stirred at room temperature over night. The solvent was evaporated and the solid residue was purified by reversed phase flash chromatography on LiChroprep RP-18. The product was eluting with (1% CH3CN in H2O/0.5% conc. HCl) giving approximately a 1:1 mixture of 4-(4-morpholinylmethyl)-1,3-thiazol-2-amine dihydrochloride and morpholine (1.33 g). This material was sulphonylated with 3-chloro-2-methylbenzenesulphonyl chloride according to the preparation as described for EXAMPLE 205A giving 17 mg (6%) of a solid: 1H NMR (DMSO) δ 2.65 (s, 3H), 3.08 (br m, 4H), 3.78 (br m, 4H), 4.13 (br s, 2H), 7.07 (s, 1H), 7.40 (t, 1H), 7.68 (d, 1H), 7.91 (d, 1H); MS (Ionspray, [M+H]+) m/z 387.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:6](=[O:21])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:28]([O:34][C@@H:35]1[C@@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[O:37][C@@H:36]1Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(#N)C.O1CCCC1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=2)[C:6]([O:21][C@@H:36]2[O:37][C@H:38]([CH2:55][O:56][C:57](=[O:62])[C:58]([CH3:61])([CH3:60])[CH3:59])[C@@H:39]([O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:52])[CH3:53])[C@H:40]([O:41][C:42](=[O:47])[C:43]([CH3:44])([CH3:45])[CH3:46])[C@H:35]2[O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccc(OC(C)C)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(OC(C)C)cc2)c1C
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a suspension of 1-acetyl-1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (1.00 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassium carbonate (0.719 g) under stirring at room temperature. After stirring the mixture at 50° C. for 1 hour, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.35 g) was added to the mixture. The mixture was stirred at 50° C. for 12 hours. After the reaction completed, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. 2-Propanol was added to the residue, and the mixture was re-concentrated under reduced pressure. The residue was recrystallized in the mixed solvent of water and methanol, the obtained crystals were dried under reduced pressure to give 1-acetyl-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.19 g).
Reaction SMILES: C[N+]1([O-])CCOCC1.[Si:9]([O:26][CH2:27][C:28]1[C:29]([N:44]2[CH2:49][C@H:48]([CH3:50])[O:47][C@H:46]([CH3:51])[CH2:45]2)=[C:30]([F:43])[C:31]([F:42])=[C:32]([CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[OH:35])[CH:33]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Si:9]([O:26][CH2:27][C:28]1[C:29]([N:44]2[CH2:45][C@H:46]([CH3:51])[O:47][C@H:48]([CH3:50])[CH2:49]2)=[C:30]([F:43])[C:31]([F:42])=[C:32]([C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:35])[CH:33]=1)([C:22]([CH3:24])([CH3:23])[CH3:25])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NMO (428 mg, 0.0037 mmol) and TPAP (65 mg, 0.0002 mmol) were added to a stirred solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}(phenyl)methanol (Intermediate 17, 1.1 g, 0.002 mmol) in CH2Cl2:CH3CN (1:1, mL) 0° C. The mixture was allowed to warm to room temperature with stirring for 12 hours. The solvents were removed, and the residue was purified over a silica gel chromatography column using an ethyl acetate-pet. ether gradient, providing the title compound. Yield: 1 g, (92%)
Reaction SMILES: C=O.[OH-].[CH:4]1[CH:9]=[C:8]([CH:10]=O)[C:7]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[CH:5]=1>>[CH2:10]1[O:18][C:16](=[O:17])[C:12]2=[CH:13][CH:14]=[CH:15][C:6]3=[C:7]2[C:8]1=[CH:9][CH:4]=[CH:5]3
Reactant: O=Cc1cccc2cccc(C(=O)O)c12
Agent: C=O
Agent: [OH-]
Product: O=C1OCc2cccc3cccc1c23

Procedure:
Prepared by the action of formalin and postasium hydroxide on peri-naphthaldehydic acid by the method of Fuson et. al. (J. Amer. Chem. Soc. 71, 1870).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.[Br:11]Br.[OH-].[Na+]>O>[Br:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1cc2cn[nH]c2cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(Br)n[nH]c2cn1

Procedure:
5-Methyl-1H-pyrazolo[3,4-c]pyridine (2 g, 15.02 mmol) and bromine (0.774 mL, 15.02 mmol) in water (71.5 mL) were stirred at RT for 1 h. The reaction mixture was neutralized with NaOH (20% in water), the precipitate was filtered, washed with water and dried under high vacuum. Yellow powder, MS (UPLC/MS): 212/214 [M+H]+, 210/212 [M−H]−; tR (HPLC conditions f): 0.74 min.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>ClCCCl>[C:12]([O:11][CH:9]([CH3:10])[CH2:8][N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:26][CH3:27])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCI
Reactant: CC(CNC1CCCCC1)OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CCN(CC(C)OC(=O)c1ccccc1)C1CCCCC1
Temperature: 50 °C

Procedure:
To a stirred solution of benzoic acid 2-cyclohexylamino-1-methyl-ethyl ester (1.0 g, 3.8 mmol) in DCE (20 mL) were added successively K2CO3 (2.11 g, 15.2 mmol) and ethyl iodide (1.8 mL, 22 mmol). The resulting mixture was heated at 50° C. for 16 hours in a sealed tube. Ethyl iodide (1.8 mL) was again added and the reaction mixture heated at 60° C. for another 24 hours. The reaction mixture was filtered and washed 5% methanol-DCM. The filtrate was concentrated and the crude material was purified by Combiflash® chromatography eluting with 6-7% methanol/DCM to provide 1-(cyclohexyl(ethyl)amino)propan-2-yl benzoate. Yield: 1.04 g (94.70%). 1H NMR (DMSO-d6) δ 7.95 (d, J=7 Hz, 2 H), 7.64 (t, J=7 Hz, 1 H), 7.52 (t, J=8 Hz, 2 H), 5.08-5.04 (m, 1 H), 2.68-2.62 (m, 1 H), 2.55-2.40 (m, 4 H), 1.70-1.53 (m, 5 H), 1.26 (d, J=6 Hz, 3 H), 1.19-1.07 (m, 5 H), 0.93 (t, J=7 Hz, 3 H). LCMS: m/z=290.4 [M+H], RT=3.93 min, (Column: Y, Program: P1)
Reaction SMILES: C(Cl)(Cl)Cl.C1(C)C=CC(S(O[CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)(=O)=O)=CC=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[N:30]1([CH2:15][CH:16]2[S:28][C:20]3=[N:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:19]3[CH2:18][CH2:17]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)nc1n2CCC(CN2CCNCC2)S1
Yield: 51.9 %

Procedure:
To 30 ml of chloroform were dissolved 3 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole and 10 g of piperazine. The resultant solution was refluxed for 18 hours. The reaction mixture was cooled, added with water and then extracted with chloroform, followed by washing the chloroform layer and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure and the residue was chromatographed on silica gel and eluted with chloroform to obtain 1.2 g (Yield: 51%) of the intended product, m.p. 151°-153° C.; IR νmaxKBr cm-1 : 3600-3000, 3100-2800, 1420; Anal. Calcd. for C15H20N4S: C, 62.47; L H, 6.99; N, 19.43; S, 11.11; Found: C, 62.41; H, 7.01; N, 19.70; S, 10.88.
Reaction SMILES: [OH-].[Na+].CO.C[O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)=[CH:10][CH:9]=1.Cl>O.O1CCOCC1>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([OH:26])=[O:6])=[CH:13][CH:12]=2)=[CH:23][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=Cc1ccc(/C=C/C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A 20% aqueous solution (1.5 mL) of sodium hydroxide was added to a methanol (20 mL)-1,4-dioxane (20 mL) solution of 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid methyl ester (0.59 g) as obtained in Example 23-(1), and then the mixture was stirred for 3 hours at room temperature. A 20% aqueous solution (1.5 mL) of sodium hydroxide was added, and the mixture was stirred for 30 minutes at room temperature. Water was added, and the mixture was adjusted to pH 3 with 12 mol/L hydrochloric acid. The precipitate was filtered off to obtain 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid (orange solid) (0.55 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCCCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added valeryl chloride (0.08 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (81%) of product as an off-white solid: mp 190-192° C.; 1H NMR (DMSO-d6) 11.04 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.74-2.44 (m, 5H), 2.10-2.03 (m, 1H), 1.90 (s, 3H), 1.66-1.54 (m, 2H), 1.42-1.27 (m, 2H), 0.91 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) 172.13, 172.03, 168.75, 167.36, 136.42, 135.91, 131.20, 125.68, 117.71, 116.29, 58.81, 36.25, 29.07, 28.54, 26.83, 21.65, 20.98, 13.64; Anal. Calcd. For C19H21N3O5: C, 61.39; H, 5.70; N, 11.30. Found: C, 61.03; H, 5.51; N, 11.13+0.02H2O.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=3)([CH:49]3[CH2:54][CH2:53][CH2:52][NH:51][CH2:50]3)[C:44](=[O:48])[NH:45]2)=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:51]2[CH2:52][CH2:53][CH2:54][CH:49]([C:43]3([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[C:58]([Cl:62])[CH:57]=4)[C:42]4[C:46](=[CH:47][C:39]([Cl:38])=[CH:40][CH:41]=4)[NH:45][C:44]3=[O:48])[CH2:50]2)=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of pyridine-2,5-dicarboxylic acid-2-methyl ester (0.54 g, 3.0 mmol) (from Example 83 a supra) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 0.5 hour and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the crude (0.21 mL, 0.38 mmol) was added to a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (120 mg, 0.32 mmol) (from Example 25a supra) in dichloromethane (3 mL), followed by the addition of triethylamine (0.11 mL, 0.80 mmol) The mixture was stirred at room temperature for 0.5 hour. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-{3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 65 mg, 36.5%).
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[C@@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21].Cl.O1CCOCC1>O>[CH3:16][C@@:10]12[C:13]([CH3:14])([CH3:15])[C@@H:7]([C:6]3[C:4](=[O:5])[N:20]([CH2:19][C:18]([F:23])([F:22])[F:17])[NH:21][C:11]=31)[CH2:8][CH2:9]2
Reactant: NNCC(F)(F)F
Reactant: CCOC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Temperature: 100 °C
Yield: 17 %

Procedure:
A mixture of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (Intermediate 4; 5.00 g, 22.3 mmol) and 2,2,2-trifluoroethylhydrazine (70% in water; Aldrich; 25.00 g, 153 mmol) was heated in a sealed tube at 100° C. for 19 h. The reaction mixture was allowed to cool, and HCl in dioxane (4 M; 40 mL, 160 mmol) was added cautiously. The reaction mixture was heated again at 100° C. for 45 min, cooled to room temperature, and added to water (200 mL). The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, evaporated, purified by flash chromatography (20-50% ethyl acetate) to give (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.04 g, 17%) as a light orange solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH2:21][C:22]([NH:24][C:25]3([C:33]([O:35]C)=O)[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1.Cl>CN(C)C(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:22](=[O:23])[NH:24][C:25]4([CH2:30][CH2:29][C:28]([F:31])([F:32])[CH2:27][CH2:26]4)[C:33]=3[OH:35])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 30 °C
Reaction time: 3 h

Procedure:
Under argon and at 20 to 30° C., 3.31 g (28.0 mmol) of potassium tert-butoxide in 10 ml of N,N-dimethylacetamide were added to 11.1 g (25.5 mmol) of the compound from Example 6A in 22 ml of N,N-dimethylacetamide. The reaction mixture was stirred at 30° C. for 3 h. The reaction mixture was then added to 250 ml of ice-water, 1N aqueous hydrogen chloride solution was added dropwise until a pH of 2 had been reached and the precipitate was filtered off with suction and washed with water. For further purification, the product was taken up in methylene chloride and extracted with 50 ml of 1N aqueous sodium hydroxide solution, the aqueous phase was acidified with aqueous 1 N hydrochloric acid, filtered off with suction, washed with water and, for purification, suspended in 25 ml of hot acetonitrile on an ultrasonic bath, filtered off with suction, washed and dried. This gave 5.70 g (55% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][CH2:13][CH2:14]CCC.C([Li])CCC.C(Br)C#C>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[C:12]#[C:13][CH3:14]
Reactant: CCCCCC
Reactant: CNc1nc2ccccc2s1
Agent: C#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC#CN(C)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
2-Methylaminobenzothiazole (c) (14.0 g) was dissolved in anhydrous tetrahydrofuran (250 ml) and a hexane solution (73 ml) of butyl lithium (6.53 g) was added thereto at -78° C. with stirring. The mixture was stirred for 1.5 hours under cooling and 2-propynyl bromide (8.4 ml) was dropwise added thereto. The resultant mixture was allowed to stand at room temperature overnight and then evaporated to remove the solvent. After addition of water, the residue was extracted with ether. The extract was washed with water, dried and evaporated to remove the solvent. The resultant residue was applied to column chromatography on silica gel (280 g) to give 2-(N-methyl-N-propynylamino)benzothiazole (d) (14.5 g, yield 84%) from chloroform eluate.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([CH:24]=[CH2:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C.[I].[I].[CH2:29]([Zn]CC)C.N>C(#N)C.O.FC(F)(F)C(O)=O.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:23]=[C:22]([CH:24]2[CH2:29][CH2:25]2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CC[Zn]CC
Reactant: C=Cc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Agent: C
Agent: N
Agent: [I]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(C2CC2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To a mixture of 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-vinyl-nicotinamide described in Example A-168 (6.0 mg, 0.017 mmol) and toluene (0.5 mL) were added diiodine methane (0.0055 mL, 0.068 mmol) and diethyl zinc (1.1M toluene solution, 0.046 mL, 0.051 mmol) on an ice bath, and the solution was stirred at room temperature for 30 minutes. Water, ethyl acetate and an aqueous solution of 29% ammonia were added to the reaction solution for extraction, the organic layer was then washed with brine. The organic layer was evaporated in vacuo, then, residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (0.40 mg, 0.00083 mmol, 4.9%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=CC(C)=O)c1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCC(C)=O)c1
Yield: 99.2 %

Procedure:
A solution of 30.1 g of 4-(3-methoxyphenyl)-3-buten-2-one in 200 ml of MeOH was hydrogenated over 200 mg of 10% palladium on carbon for two hours. The catalyst was filtered and the solvent evaporated in vacuo to give 30.2 g of yellow oily 4-(3-methoxyphenyl)-2-butanone.