Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1.[CH3:27][C:28]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:29]2[C:28]([CH3:27])=[CH:33][N:32]=[C:31]([NH:34][C:35](=[O:37])[CH3:36])[CH:30]=2)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cn1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)c(C)cn1
Yield: 80.6 %

Procedure:
A mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (0.39 g, 0.78 mmol), N-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide (0.36 g, 1.32 mmol), tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol) and cesium carbonate (1.64 g, 5.04 mmol) in dioxane (13 mL) and water (1.8 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (0.33 g, 81%). LCMS (AA): m/z=525.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]>C(O)(C(F)(F)F)=O.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]
Reactant: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: COc1nc(CC(=O)O)c([N+](=O)[O-])cc1C
Yield: 94.4 %

Procedure:
A solution of tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.0 g, 294 mmol) in TFA (200 mL) was heated in a hot water bath for 1 h. The solution was concentrated in vacuo to give a brown oil. The oil was diluted with hexane and stirred. The resulting solid was collected by filtration and air dried to give 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetic acid (62.8 g, 94% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.70 (s br, 1H), 8.20 (s, 1H), 4.25 (s, 2H), 4.03 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.59, 163.80, 146.52, 139.16, 135.30, 121.53, 54.86, 42.88, 15.32. An analytical sample was recrystallized from hexane: mp 135-137° C. Anal. calcd. for C9H10N2O5: C, 47.79, H, 4.46, N, 12.39. Found: C, 47.65, H, 4.14, N, 12.30.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C(#N)C.CCOC(C)=O.[Cu]I>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CN1CCN(C(=O)c2cccc(I)c2)CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(C(=O)c2cccc(C#C[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
(3-Iodophenyl)(4-methylpiperazin-1-yl)methanone (1.15 g, 3.5 mmol) and ethynyl-trimethyl-silane (0.58 mL, 4.2 mmol) in dry acetonitrile (30 mL) were purged with nitrogen and treated with TEA (0.97 mL, 7.0 mmol, 2 eq.), CuI (0.033 g, 0.17 mmol) and Pd (Ph3P)2Cl2 (0.120 g, 0.17 mmol). The reaction was stirred at room temperature for 2 h, then was diluted with EtOAc (30 mL), washed with water (2×20 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 95/5) to afford the title compound (0.95 g, 91%).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[CH2:11][C:12]#[N:13].C(N(C(C)C)CC)(C)C>O1CCCC1>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([CH2:11][C:12]#[N:13])[CH2:4][CH2:5]1
Reactant: N#CCCl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CCN1CCC(=O)CC1

Procedure:
A suspension of 25.0 g of 4-piperidinone monohydrochloride monohydrate, 11.5 ml of chloroacetonitrile and 57.0 ml of diisopropylethylamine in 250 ml of tetrahydrofuran was refluxed for 10 hours. After the reaction, an insoluble matter was filtered off. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with a mixture of ethyl acetate and methanol (10:1). The extract was dried, and the solvent was evaporated to give brown crystals. The crystals were washed with a mixture of ethyl acetate and n-heptane to give 15.7 g of pale brown crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].CCCCCC.BrB(Br)Br.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[OH:8]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1F
Agent: BrB(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc([N+](=O)[O-])c(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
To a solution of 2-fluoro-1,3-dimethoxy-4-nitrobenzene (1.5 g) in toluene (100 mL) was added 1 M tribromoborane hexane solution (16 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 10 min. The reaction solution was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (860 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O.O[N:17]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:38][C:39]1([C:45]2[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=2)[CH:44]2[CH:40]1[CH2:41][NH:42][CH2:43]2.C(N(CC)CC)C>CN(C)C=O>[NH3:17].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([N:42]3[CH2:43][CH:44]4[CH:40]([C:39]4([C:45]4[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=4)[CH3:38])[CH2:41]3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc4c(c3)OCO4)CC21
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 3-(1,3-benzodioxol-5-yl)propanoic acid (120 mg, 0.62 mmol) in N,N-dimethylformamide (13 ml) was added 1-hydroxybenzotriazole monohydrate (100 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) and triethylamine (133 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 nml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol: 0.88 ammonia (300:8:1) to afford the title compound as a white foam (107 mg, 38%).
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].O.[CH3:22][CH2:23]OCC>CN(C)C=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>[C:1]([C:3]1[C:7]([CH:22]=[CH2:23])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: CCOCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (58 g) in dimethylformamide (350 ml) containing yinyltri-n-butyltin (116 ml) and tetrakis(triphenylphosphine)palladium(0) (3.5 g) was stirred at 75° C. for 3 hours. The reaction nixture was poured into water (600 ml) and ether (600 ml). The organic layer was washed with water (5 times), brine (700 ml) and dried over sodium sulphate. Removal of the solvent in vacuo was followed by recrystallisation of the residue from propan-2-ol, to give the title compound as a pale brown solid, m.p. 75-6° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43]OS(C)(=O)=O)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH2:6]>O.CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:4]([O:7][N:8]([CH:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37])[CH:23]=[C:22]1[CH2:43][C:1]#[N:2])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH2:6]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COS(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC#N)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of sodium cyanide (4.94 g, 100.85 mmol) in water (20.0 mL) was added (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((methylsulfonyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 20.17 mmol) in DMF (100 mL). The mixture was then stirred at room temperature for 15 h. It became a dark orange solution. It was then diluted with sat. NaHCO3 and water and extracted with ethyl acetate, dried over MgSO4. The crude was subjected to silica gel column eluting with 0-100% ethyl acetate/hexanes to give a pale yellow oil, 5.92 g, 47.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31]N)[C:6]=2[CH:33]=1.C=O.[C:36]([BH3-])#[N:37].[Na+].[C:40](=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:37]([CH3:36])[CH3:40])[C:6]=2[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: NCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-chloro-5-(2-aminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g)in methanol (2,0 ml) is added 37% formalin (1.4 ml), and thereto is added sodium cyanoborohydride (0.2 g), and further thereto is added with stirring acetic acid (0.9 ml) at 10° C., and the mixture is stirred at room temperature for 3 hours. The mixture is poured into ice-water, and the mixture is made basic with potassium carbonate, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-dimethylaminoethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.37 g) as colorless amorphous.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([N:12](CCC)[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].[OH-].[Na+].[C:31]1(C)[CH:36]=CC=C[CH:32]=1>>[CH:6]1([N:12]=[C:13]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:32][CH2:31][CH3:36])[N:25]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cc1ccccc1
Reactant: CCCNCCC
Reactant: CCCNC(=O)N(CCC)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C(=NC1CCCCC1)N(CCC)CCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus oxychloride (86 ml, 142 g, 0.92 mol) is added dropwise over a 1 hour period to a toluene (800 ml) solution of cyclohexyl-dipropylurea (191 g, 0.845 mol). The reaction is stirred overnight at room temperature. Dipropylamine (221 g, 300 ml, 2.19) is added dropwise for over a 2 hour period, then stirred 2 hours at room temperature. Sodium hydroxide solution (6×0.92 mol NaOH and 500 ml water) is slowly added to the reaction mixture in an ice-water bath. The water layer is extracted with diethylether (3×100 ml). The organic layers are combined and dried over Na2CO3, filtered and concentrated. The residue is further distilled under vacuum (ca. 0.3-0.5 torr) collecting product, cyclohexyl-tetrapropylguanidine, at 150° C. (235 g, 90%) of 99% purity as judged by gas chromatography. 1H NMR (CDCl3) δ 3.10 (m, 1H), 3.02 (b , 4H), 2.88 (t, 4H, 1.77-1.12 (m, 10H), 1.42 (q, 8H), 0.82 (t, 6H), 0.80 (t, 6H) ppm.
Reaction SMILES: CO[C:3](=O)[C@H:4]([O:15]S(C)(=O)=O)[C@@H:5](C1C=CC(Cl)=C(Cl)C=1)C.[O-2:21].[Cr+6:22].[O-2:23].[O-2:24].[S:25](=[O:29])(=[O:28])([OH:27])[OH:26].ClC1C=C([C@@H](C)[C@@H](OS(C)(=O)=O)CO)C=CC=1Cl>CC(C)=O.C(O)(C)C.O>[CH3:3][C:4]([CH3:5])=[O:15].[OH:28][S:25]([OH:29])(=[O:27])=[O:26].[O:21]=[Cr:22](=[O:24])=[O:23]
Reactant: [Cr+6]
Reactant: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Reactant: [O-2]
Agent: C[C@H](c1ccc(Cl)c(Cl)c1)[C@H](CO)OS(C)(=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=[Cr](=O)=O
Reaction time: 4 h

Procedure:
(2R,3R)-3-(3,4-Dichloro-phenyl)-2-methanesulfonyloxy-butyric acid methyl ester. Jones reagent was prepared by mixing chromium (VI) oxide (2.87 g, 28.7 mmol), sulfuric acid (2.44 mL), and water (9.5 mL) for 10 min. The solution was used directly, and was added dropwise to a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butan-1-ol (1.50 g, 4.79 mmol) in acetone (100 mL). After 4 h, isopropanol (9 mL) was added and the mixture was concentrated. Water was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give the crude acid. To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid (1.57 g, 4.80 mmol) in DMF (20 mL) were added KHCO3 (1.44 g, 14.4 mmol) and Mel (0.90 mL, 14.4 mmol). After 12 h, the mixture was diluted with water and extracted with EtOAc (2×), and the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography to give 1.13 g (69% over 2 steps) of the desired product. 1H NMR (400 MHz, CDCb3): 7.38 (d, J=8.3, 1H), 7.31 (d, J=2.1, 1H), 7.08 (dd, J=8.3, 2.1, 1H), 5.14 (d, J=4.7, 1H), 3.73 (s, 3H), 3.47-3.43 (m, 1H), 3.07 (s, 3H), 1.43 (d, J=7.2, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]1[CH2:23][CH2:22]N2C(=NCCC2)C[CH2:14]1.F[C:25](F)(F)C([O-])=O>CC#N>[CH3:25][C:13]([CH3:14])([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:23]#[CH:22]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])C(F)(F)F
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Solvent: CC#N
Product: C#CC(C)(C)Oc1cc([N+](=O)[O-])ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile (413.6 mg, 2.52 mmol, prepared as described in Yasubiro Imakura et al, Chem. Pharm. Bull, 40 (7), 1691-1696, (1992)) in CH3CN (1.5 mL) cooled to −5° C. was added DBU (0.48 mL, 3.2 mmol) and CuCl2.2H2O (2 mg), followed by addition of a solution of trifluoroacetate prepared above over 30 min while maintaining the reaction temperature below 0° C. After addition, the reaction mixture was stirred at 0° C. for 2 h, then concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (30 mL), and the separated organic layer washed with 1 N aqueous HCl (2×20 mL), 1 N aqueous NaOH (20 mL), 1 N aqueous NaHCO3, brine, then dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 0% to 50% EtOAc/hexane to furnish the title compound (280 mg, 48%).
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@H:8]([NH:7][C:26]([C:25]1[CH:24]=[N:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:30][CH:29]=1)=[O:28])[CH2:9]2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)nc1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 6-(trifluoromethyl)nicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) S (ppm): 8.84 (s, 1H), 8.34 (dd, J=8 Hz, 1H), 8.23 (s, 1H), 8.12 (dd, J=8 Hz, 1H), 4.18 (m, 1H), 3.39 (ddd, J=10, 14 Hz, 1H), 2.96-2.87 (m, 4H), 2.68 (ddd, J=16 Hz, 1H), 2.06 (m, 1H), 1.82 (m, 1H), 1.74 (m, 1H), 1.55 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: [H][H].[Br-].II.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: c1ccc2[nH]ncc2c1
Agent: II
Agent: [Br-]
Product: CC(=O)n1ncc2ccccc21

Procedure:
To prepare 1-substituted 1H-indazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl ##STR45## R2'OCO or R5CO wherein R2', R5, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodine, a compound of the formula ##STR46## R2'OCOHal or R5COHal wherein R2', R5, X", p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[O:34][N:33]=2)=[CH:28][CH:27]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:40]3[CH2:39][CH2:38][CH:37]([C:35]4[O:34][N:33]=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=5)[N:36]=4)[CH2:42][CH2:41]3)[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC2CO2)C1
Reactant: Clc1ccc(-c2noc(C3CCNCC3)n2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCC(c3nc(-c4ccc(Cl)cc4)no3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
1-[3-(4-Chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.069 g. 0.20 mmol) was dissolved in CH2Cl2 (1 mL), and 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine (0.105 g, 0.4 mmol) was added, followed by Yb(OTf)3 (0.031 g, 0.22 mmol). The mixture was stirred at room temperature for 16 h. Preparative TLC (silica, 7.5% MeOH/CH2Cl2) afforded 84 mg (69%) of the title compound. MS (electrospray): exact mass calculated for C31H34Cl2N6O3, 608.21. m/z found, 609.2 [M++H]. 1H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers): 8.00 (d, J=8.4 Hz, 2H), 7.56-7.53 (m, 1H), 7.48-7.42 (d, J=8.6 Hz, 2H), 7.41-7.30 (m, 2H), 4.84 and 4.73 (A and B of AB quartet J=15.6 Hz, 1H), 4.62 (br s, 1H), 4.25-4.13 (m, 2H), 4.10-3.98 (m, 2H), 3.90-3.70 (m, 2H), 3.04-2.71 (m, 5H), 2.51-2.40 (m, 6H), 2.30-2.15 (m, 6H), 2.10-1.90 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[S:7][C:8]([Cl:17])=[C:9]([Cl:16])[C:10]=1[CH2:11][C:12]([O:14]C)=[O:13])C.[OH-].[Na+]>CO>[C:12]([CH2:11][C:10]1[C:9]([Cl:16])=[C:8]([Cl:17])[S:7][C:6]=1[CH2:5][C:4]([OH:18])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1sc(Cl)c(Cl)c1CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1sc(Cl)c(Cl)c1CC(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 279.2 %

Procedure:
A solution of the product from step (c) (1.14 g, 3.66 mmol) in MeOH (7 ml) at 0° C. was treated dropwise with 2M NaOH (3.8 ml). The reaction was warmed to 22° C. and stirred overnight. The solvent was evaporated and the residue was dissolved in 2 M NaOH (50 ml) and extracted with ether (2×50 ml). The basic layer was cooled to 0° C. and acidified to pH 1 with 6 M HCl. The acidic layer was back extracted EtOAc (4×100 ml) and the organic layer was dried (MgSO4) and concentrated. The crude solid was triturated with hexanes and filtered providing 2.75 g (73%) of the subtitle compound. MS: ESI (negative): 267, 269 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C(OCC)(=O)C>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9]
Reactant: N#CC1=C(N)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC1CCCCC1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a cold solution of 2-aminocyclohex-1-enecarbonitrile (I-7a: 50 mg, 0.41 mmol) in methanol (3 mL) was added NaCNBH3 (103 mg, 1.64 mmol) and acetic acid (5 drops) at 0° C. The resulting mixture was stirred at room temperature for 16h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated to afford 40 mg (78%) of diastereomeric mixture of 2-aminocyclohexanecarbonitrile (I-7b) as a gum.