Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].[Cl:14][Sn]Cl>Cl.O>[ClH:14].[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][NH2:10]
Reactant: Cl[Sn]Cl
Reactant: Cc1cccc(C)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1NN
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.) solution of 2,6-dimethylaniline (5.0 g, 41.3 mmol) in 50% aqueous HCl (45 mL), was added slowly under stirring a cold (0° C.) solution of NaNO2 (2.85 g, 41.3 mmol) in water (22.5 mL). The temperature was closely monitored during the addition and was not allowed to exceed 5° C. Upon completion of the addition, the bright orange solution containing the diazonium salt intermediate was stirred at the same temperature for 20 min. A mixture of SnCl2 (11.0 g, 57.8 mmol) in conc HCl (30 mL) was added to the reaction mixture at 0° C. over a period of ˜5 min. The reaction mixture was then warmed to rt and stirred for 6 h. The precipitate was collected by filtration and washed with a small volume of cold water. Drying in vacuo afforded the title compound as a white amorphous solid (7.00 g, 98%). The product was used in the next step without further purification. ES-MS m/z 137.0 (MH+); HPLC RT (min) 1.09.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH2:8])[CH2:4][CH3:5])[CH3:2].[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[CH3:21][N:22]([CH3:41])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][NH:8][C:9]([N:37]1[CH2:38][CH2:39][CH2:40][CH:35]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:22]([CH3:41])[CH3:21])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[CH2:36]1)=[O:10])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CN(C)CCOc1ccc(S(=O)(=O)C2CCCNC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CCN(CC)CCNC(=O)N1CCCC(S(=O)(=O)c2ccc(OCCN(C)C)cc2)C1
Yield: 33.1 %

Procedure:
Following the procedure of Example 16, N,N-diethyl aminoethylamine and 1,1'-carbonyldiimidazole and N,N-dimethyl-2-[4-[(3-piperidinyl)sulfonyl]phenoxy]ethanamine were reacted to give the title compound which was crystallized from diethyl ether-hexane as white crystals in 33.1% yield, m.p. 79°-80° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[C:19](P(=O)(OCC)OCC)([F:21])[F:20]>C(#N)C.O.C(OCC)(=O)C>[F:20][CH:19]([F:21])[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: O=C(Nc1cc2ccc(O)cc2cn1)C1CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(Nc1cc2ccc(OC(F)F)cc2cn1)C1CC1
Temperature: -78 °C
Yield: 38.5 %

Procedure:
A solution of N-(7-hydroxyisoquinolin-3-yl)cyclopropanecarboxamide (91.2 mg, 0.40 mmol), diethyl bromodifluoromethylphosphonate (212 mg, 0.80 mmol) in acetonitrile/water (1:1, 5 mL) was mixed and stirred at −78° C. After the reaction mixture was warmed to room temperature and stirred for 20 minutes, the reaction mixture was diluted with ethyl acetate, and the organic phase was separated. The water phase was extracted with ethyl acetate, and the combined organic layer was dried, concentrated and purified by prep-HPLC to give product (42.8 mg, 26%). LCMS (ESI): RT (min)=0.994, M+H+=279.0, method=A. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.54 (s, 1H), 7.43 (dd, J=2.4, 8.8 Hz, 1H), 6.61 (t, J=73.2 Hz, 1H), 1.71-1.57 (m, 1H), 1.15-1.11 (m, 2H), 0.95-0.89 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][CH:43](O[Si](C(C)C)(C(C)C)C(C)C)[C@H:42]5C)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:77][OH:78]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][C@@H:43]([CH2:77][OH:78])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@H]5C)n4c3)c3ccccc32)cc1
Reactant: CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H](CO)C5)n4c3)c3ccccc32)cc1

Procedure:
A brown solution of Intermediate 77d (135 mg, 0.168 mmol) and TBAF (1M in THF, 0.184 mL, 0.184 mmol) in THF (3 mL) was stirred at RT for 1 h. The solution was concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc-MeOH (19:1, 2×10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a brown solid. FCC, using 5-9% MeOH in DCM, gave a pale brown solid. Further purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white powder after freeze-drying (63.9 mg, 59%). LCMS (Method 5): Rt 4.33 min, m/z 649 [MH+]. NMR (400 MHz, d6-DMSO): 1.27 (9 H, s), 1.29-1.35 (1H, m), 1.71-1.77 (3H, m), 1.82-1.96 (3H, m), 2.01-2.17 (2H, m), 2.36 (3H, s), 3.02-3.07 (2H, m), 3.20 (1H, dd, J 11.9, 3.3), 3.25-3.28 (1H, m), 3.42 (1H, dt, J 10.5, 5.0), 3.52-3.58 (1H, m), 4.69 (1H, t, J 5.1), 4.81 (1H, td, J 8.6, 5.4), 5.48 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.3), 7.12 (1H, dd, J 9.9, 2.1), 7.27-7.39 (8H, m), 7.60 (1H, d, J 9.9), 7.80 (1H, d, J 2.1), 8.04 (1H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=1.CC(C)([O-])C.[K+].C1COCC1>O>[CH3:17][C:15]1[NH:14][N:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)n[nH]1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.413 g of 3-amino-5-methylpyrazole, and 0.286 g of potassium tert-butoxide were added to a solution of 2.5 ml of THF. The reaction medium was heated at 60° C. for 7 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.361 g of 5-methyl-N-(4-nitrophenyl)-1H-pyrazol-3-amine (1) was obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: CCCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.41 g), sodium hydrogen carbonate (2.13 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-4-propyl-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.74 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 46%).
Reaction SMILES: [C:1]12([CH3:12])[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:4](=O)[C:2]2=[O:3].[CH2:13]([NH2:16])[CH2:14][NH2:15].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1.O>C1C=CC=CC=1>[C:1]12([CH3:12])[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:4][C:2]2=[O:3].[N:15]1[CH2:17][CH2:18][N:16]=[CH:13][CH:14]=1
Reactant: CC12CCC(C(=O)C1=O)C2(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NCCN
Solvent: O
Solvent: c1ccccc1
Product: C1=NCCN=C1
Product: CC12CCC(CC1=O)C2(C)C
Yield: 72 %

Procedure:
A solution of 15.6 g of camphorquinone, 7.2 g of ethylenediamine and 1 g of p-toluenesulphonic acid in 1 liter of anhydrous benzene is heated at reflux for 3 hours, 1.7 ml of water being produced. The mixture is cooled and washed with 100 ml of a 5 wt.% sodium hydroxide solution. The organic phase is decanted off and the benzene distilled off. The residue is fractionated in vacuo and there is obtained camphor-2,3-dihydropyrazine (formula I: R1 and R2 = H) with a boiling point of 90°-81°C/2.5 mm Hg. [α]D = +9.4° (ethanol). Yield 72%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([CH2:29][C:30]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH2:33]O)#[N:28]>C(Cl)Cl>[C:35]1([C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:31][CH2:32][CH2:33][I:25])[CH2:29][C:27]#[N:28])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N#CCC(CCCO)(c1ccccc1)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CCC(CCCI)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of triphenylphosphine (1.68 g) in methylene chloride (30 ml) and imidazole (0.44 g) was added iodine (1.62 g). To this mixture was added a solution of 5-cyano-4,4-diphenylpentanol (1.3 g) in methylene chloride (5 ml) dropwise. After completion of dropwise addition, the mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated to dryness. To the group was added isopropyl ether, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to provide the title compound (1.5 g) as colorless syrup.
Reaction SMILES: ClCCO[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](C)[CH:6]=1.[Br-].[OH:16][CH2:17]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:44]1[CH2:48][O:47][CH2:46][CH2:45]1>CCCCCC>[CH3:17][O:16][C:7]1[CH:6]=[C:5]([CH:46]=[CH:45][CH2:44][CH2:48][OH:47])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Reactant: Cc1cc(OCCCl)ccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1cc(C=CCCO)ccc1[N+](=O)[O-]

Procedure:
The Wittig reaction in THF (100 ml) between 3-methoxy-4-nitrobenzaldehyde (1) (2 g) and 3-hydroxypropyltriphenylphosphonium bromide (2) (5.3 g) in presence of a solution of n-butyllithium (1.6M) in hexane (16.5 ml) gave the title compound (2.6 g) as an oil.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][I:14].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+].CCCCCC.C(OCC)(=O)C>C(#N)C>[I:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCS
Reactant: ICCCCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)CCSCCCCCCCCCCCCI
Yield: 32.2 %

Procedure:
1,12-diiodododecane (2.66 g, 6.3 mmol) was dissolved in 20 mL acetonitrile. Methyl 3-mercaptopropionate (0.76 g, 6.3 mmol) and K2CO3 (1.1 g, 8 mmol) were added and the mixture was allowed to react at room temperature for 20 h. The mixture was acidified with ice-diluted HCl and the solution was extracted twice with ether (20 mL). The combined ether fractions were washed successively with dilute NaHCO3, water and brine, dried (MgSO4 and evaporated under reduced pressure. The product 1 (0.84 g, 32% yield) was isolated by column chromatography (hexane/ethyl acetate 9:1) and recrystallized in MeOH. TLC (hexane/ethyl acetate 9:1) Rf=0.4. Melting point=33° C. 1H-NMR δ1.4 (m, 20H, CH2), 2.52 (t, 2H, C(2)H2), 2.61 (t, 2H, C(5)H2), 2,79 (t, 2H, C(3)H2), 3.20 (t, 2H, C(16)H2), 3.71 (s, 3H, —COO—CH3).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH:12]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH3:28][C:24]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:31])[C:20]2[CH:19]=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[CH:27]=[CH:26][C:25]1=2
Reactant: CCCCCC(C#Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(C#Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 45 °C
Yield: 49.2 %

Procedure:
The ester (609 mg) was dissolved in 9 ml of ethanol and treated with 1.59 g of potassium hydroxide in 6 ml of water. The heterogeneous mixture was further treated with 4 ml of THF and the resulting clear solution was heated to 45° C. for 1.5 hour. The mixture was diluted with 20 ml of water and the pH was adjusted to 2 with HCl 25%. The mixture was extracted with 3 portions of 25 ml of ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The resulting orange oil was purified by flash chromatography (SiO2, 25% ethyl/hexanes) followed by trituration in pentane, giving 290 mg of (RS)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-ynyl]-benzoic acid as a white solid, m.p. 115-116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Cc4ccccc4)cc3c2C1
Yield: 85.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.1 μL (0.051 mMol) phenylacetyl chloride, 13.6 mg (85%) of the title compound were recovered as a grey-brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:16])([F:15])[F:17])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:35])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 156 mg (0.88 mmol) of 5-amino-8-fluoroquinolin-2(1H)-one and 0.55 ml of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-8-fluoroquinolin-2(1H)-one. 480 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) yields 119 mg of desired product.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][N:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)=[O:10])[C@H:6]([CH3:22])[CH2:5][CH2:4]1)#[CH:2].C([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.[CH3:30]N(C=O)C>[Cu]I.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>[CH3:22][C@@H:6]1[CH2:5][CH2:4][C@H:3]([C:1]#[C:2][C:28]2[CH:29]=[CH:30][CH:27]=[CH:26][N:25]=2)[CH2:8][N:7]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1)=[O:10]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: C#C[C@H]1CC[C@@H](C)N(C(=O)c2ccccc2-n2nccn2)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H]1CC[C@H](C#Cc2ccccn2)CN1C(=O)c1ccccc1-n1nccn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of [(2R,5R)-5-ethynyl-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (0.015 g, 0.051 mmol) in DMF (0.5 mL) under an atmosphere of nitrogen was added triethylamine (0.071 mL, 0.51 mmol), copper(I) iodide (2.9 mg, 0.015 mmol), and palladium tetrakis (5.9 mg, 0.0051 mmol). The reaction was heated to 100° C. for 17 h, then cooled to RT. Excess QuadraPure TU was added, and after 1 h, the solids were removed via filtration. The solution was subjected to purification via reverse phase HPLC to provide the [(2R,5R)-2-methyl-5-(pyridin-2-ylethynyl)piperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which gave a high resolution mass spectrum (ES+) m/z of 372.1812, calculated for M+H+ [C22H21N5O: 372.1819].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc(COC(=O)CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CNCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a cold (0-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3 )δ1.41 (s, 9 H), 1.61 (quint, J=7 Hz, 2 H), 2.63 (t, J=7 Hz, 2 H), 3.17 (q, J=6 Hz, 2 H), 3.38 (s, 2 H), 3.78 (s, 3 H), 5.07 (s, 2 H), 6.86 (m, 2 H), and 7.26 (m, 2 H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].C([O-])(=O)C.[Na+].[H][H]>[Co]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CC#N
Agent: [Co]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1CCN
Yield: 103.3 %

Procedure:
This example was run in an analogous manner as example 5 but using 6.00 g (30 mmol) of (5-Methyl-2-phenyl-oxazol-4-yl)-acetonitrile in the presence of 0.60 g of wet Raney Cobalt catalyst (Johnson Matthey 8B0022, wet, ca. 50 weight %) in the presence of 50 mg of sodium acetate as modifier in a 185 mL autoclave at 70° C. under 9 bar of hydrogen pressure for 1.5 h. Removal of the catalyst by filtration, evaporation of the solvents and drying (50° C./10 mbar/2 h) afforded 6.27 g of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamine with a purity of 89.3% (HPLC area %).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
7-Benzyl-3,7-dihydro-1H-purine-2,6-dione (5.0 g, 21 mmol) was mixed with sodium carbonate (3.3 g, 31 mmol) and 1-iodopentane (4.0 mL, 31 mmol) in DMF (60 mL). After being stirred at 40° C. for 18 h, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated. The resulting white solid was collected and dried in vacuum oven at 50° C. for 18 h to provide the desired product (2.84 g, 44% yield). LCMS calculated for C17H21N4O2 (M+H): 313.2; found: 313.2.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:20][NH2:21].O>C(O)C>[N+:16]([C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:21][N:20]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of 2-chloro-5-nitrobenzophenone (15 g, 57 mmol) in ethanol (300 mL) was added hydrazine monohydrate (50 mL, 1 mol). The resultant solution was stirred overnight (16 hrs.) at ambient temperature, then poured into water (2L) and stirred for an additional 2 hours. The precipitate that formed was collected by filtration, washed with water (2×100 mL) and air dried to give 5-Nitro-3-phenyl-1H-indazole 11a (13.1 g, 80%) as a yellow solid: 1H NMR (DMSO-d6) 67 7.48 (tt, 1H, J=1.3, 7.4 Hz), 7.58 (dd, 2H, J=7.1, 7.4 Hz), 7.78 (d, 1H, J=9.2 Hz), 8.01 (dd, 2H, J=1.3, 7.1 Hz), 8.25 (dd, 1H, J=2.1, 9.2 Hz), 8.91 (d, 1H, J=2.1 Hz), 13.88 (s, 1H). Anal. (C13H9N3O2) C, H, N.