Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:25][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (200 mg, 0.719 mmol) in DMF (30 mL) was added cyclopropylamine (98 mg, 0.719 mmol), HATU (0.719 mmol, 273 mg), and triethylamine (0.726 mmol, 0.1 mL). This solution was allowed to stir at room temperature overnight. The reaction was worked up via aqueous wash and extraction with ethyl acetate (3×50 mL). The organic layer was then dried with MgSO4, filtered and concentrated to yield a dark oil. Flash column chromatography (30–70% Ethyl Acetate/Petroleum Ether) afforded the 3-(1H-benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide as a yellow solid. (0.130 g, 57%) 1H NMR (DMSO-d6) δ 13.88 (1H, s), 8.63 (1H, m), 8.51 (1H, d, J=8.5 Hz), 8.09 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.63 (2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS (APCI positive) 318.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: COc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(OC)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo 4-methoxy-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.94 (d, 1H), 7.49 (d, 1H), 7.26-7.38 (m, 8H), 7.06 (m, 1H), 6.94 (m, 2H), 6.63-6.70 (m, 3H), 4.97 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:7]=2[CH:25]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30].[I-].[Na+]>>[CH2:28]([N:31]([CH2:16][C:13]1[N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:25][C:7]=3[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])=[N:9][CH2:10][C:11]2=[N:15][N:14]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: CCCNCCC
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Br)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [Na+]
Product: CCCN(CCC)Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-1-(chloromethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine was reacted with dipropylamine in the presence of sodium iodide to give 1-[(dipropylamino)methyl]-8-trifluoromethyl-6-(o-bromophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:13][CH2:14]1)[O:11][CH2:10]2>N1C=CC=CC=1.CCOC(C)=O.[Zn]>[CH3:22][C:20]1[S:21][C:17]([C:12]23[CH2:13][CH2:14][C:9]([CH2:8][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([CH2:16][CH2:15]2)[CH2:10][O:11]3)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1
Reactant: C=CC(=O)OC
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CCCC12CCC(c3sc(C)nc3-c3ccccc3)(CC1)OC2
Temperature: 75 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of zinc powder (154 mg, 2.351 mmol), anhydrous pyridine (5 mL) and methyl acrylate (0.212 ml, 2.351 mmol) at 50° C. was added NiCl2.6H2O (56 mg, 0.235 mmol). The resulting mixture was warmed to 75° C. and stirred for 2 h until its green color turned to reddish brown. After cooling to 0° C., a solution of 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole (100 mg, 0.235 mmol) in anhydrous pyridine (3 mL) was added and the reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with EtOAc (10 mL) and the resulting precipitate was filtered off through a pad of CELITE®. The filtrate was washed with 1 N aqueous HCl and brine, dried (Na2SO4), and concentrated in vacuo to afford the title compound (77 mg, 85% yield) as a clear oil. LCMS, [M+H]+=386.0. 1H NMR (500 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.40-7.32 (m, 3H), 3.72 (s, 2H), 3.65 (s, 3H), 2.64 (s, 3H), 2.24 (t, J=7.4 Hz, 2H), 2.07-1.97 (m, 2H), 1.87-1.77 (m, 2H), 1.57-1.45 (m, 6H), 1.12-1.02 (m, 2H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.CN([CH:28]=[O:29])C>C1COCC1>[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[C:21]([CH2:28][OH:29])[S:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccsc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (7.79 g) in THF (150 ml) was added n-butyllithium (1.6 M in hexane, 34.5 ml) at −78° C., and the mixture was stirred at 0° C. for 10 min. The solution was cooled to −78° C., and stirred for 30 min. To the solution was added 3-(trifluoromethyl)thiophene (6.99 g) in THF over 30 min, and the mixture was stirred for 1 h at same temperature. Then DMF (10.1 g) was added to the mixture, and the mixture was stirred overnight at room temperature. The mixture was quenched with 1 M HCl and extracted with EtOAc. The organic layer was separated, washed with 1 M HCl and brine successively, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc). The resulting residue was dissolved in MeOH (100 ml), and NaBH4 (0.865 g) was added to the mixture at 0° C. After stirred at room temperature for 30 min, the mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was separated, washed with saturated NH4Cl solution and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (1.79 g) as a colorless oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[C:24]([CH:37]([OH:41])[CH:38]([CH3:40])[CH3:39])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[N:25]([S:33]([CH3:36])(=[O:34])=[O:35])[C:24]([C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])=[CH:23]2)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol (2.3 g, 3.8 mmol) in dry CH2Cl2 (25 mL) was added Dess-Martin periodiane (1.94 g, 4.56 mmol) in one portion. The mixture was allowed to stir at rt for 2 h. The reaction was quenched with a solution of Na2S2O3 (5 g in 30 mL H2O) and sat. aq. NaHCO3 (40 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with EtOAc/hexanes (2/8) to provide 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one (2.0 g, 86% yield). LC-MS m/z 612 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.03 (s, 1H), 7.70-7.68 (m, 4H), 7.46-7.36 (m, 6H), 7.22 (s, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 3.36 (m, 1H), 2.89 (s, 3H), 1.29 (d, J=6.8 Hz, 6H), 1.13 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 197.83, 141.53, 136.69, 136.05, 135.50, 135.04, 132.81, 131.14, 129.99, 127.88, 123.17, 117.12, 114.21, 62.87, 44.19, 44.03, 39.09, 26.88, 19.30, 18.41.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[NH:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.C[Al](C)C.[CH3:24][C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[CH:27][C:26]=1[C:37]1[CH:42]=[CH:41][C:40]([C:43](OC)=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[N:18]([C:43]([C:40]4[CH:39]=[CH:38][C:37]([C:26]5[CH:27]=[CH:28][C:29]([N:31]6[CH2:35][CH2:34][CH2:33][C:32]6=[O:36])=[CH:30][C:25]=5[CH3:24])=[CH:42][CH:41]=4)=[O:44])[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Reactant: CN(C)CCN1CCOc2cc3c(cc21)NCCC3
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)N(CCN(C)C)CCO4)cc1
Temperature: 82.5 °C
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
A stirred solution of 4-(2-dimethylaminoethyl)-2,3,6,7,8,9-hexahydro-4H-pyrido[2,3-g][1,4]benzoxazine (D5, 130 mg, 0.49 mmole) in toluene (4 ml) under argon was treated with trimethylaluminium (0.27 ml of 2M in toluene, 0.54 mmole) and stirred for 20 mins. Methyl 2'-methyl4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylate (D29, 154 mg, 0.50 mmole) was added and the mixture heated at 80-85° C. for 6 h, then further trimethylaluminium (0.45 ml) was added and the mixture heated under reflux for 6 h. The reaction mixture was allowed to cool, poured into a slurry of silica gel (4 g) in dichioromethane (10 ml), then loaded onto a chromatography column and eluted with 0-16% methanol/dichloromethane. The product obtained was further purified by prep. plate TLC on silica gel eluting with 10% methanol/dichloromethane to afford the title compound as a light green semi-solid (16 mg). This was converted to it hydrochloride salt as a pale yellow solid.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([CH2:14][CH2:15][CH:16]2[CH2:25][CH2:24][CH2:23][C:22]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:12][N:13]=1.Cl>C(#N)C.C(O)(=O)C.[Zn]>[S:10]1[C:11]([CH2:14][CH2:15][CH:16]2[CH2:25][CH2:24][CH2:23][C:22]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:12][N:13]=[CH:9]1
Reactant: CCOC(=O)c1cccc2c1CCCC2CCc1cnc(N)s1
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2c1CCCC2CCc1cncs1
Yield: 75.7 %

Procedure:
0.87 g of cupric chloride was suspended in 20 ml of acetonitrile and 0.82 g of tertiary butyl nitrite was added thereto. A solution of 1.8 g of ethyl 5-(2-(2-aminothiazole-5-yl)ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate in 5 ml of acetonitrile was added dropwise to the mixture. After evolution of gas ceased, 15% hydrochloric acid was added to the mixture. The resulting mixture was extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography with chloroform eluent to give an oily product. The product was dissolved in 30 ml of acetic acid, and a small amount of zinc powder was added thereto under refluxing. The above procedure was repeated four times at hourly intervals and the total amount of zinc was 0.4 g. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform. The solution was washed with water and dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 1.3 g of ethyl 5-(2-(5-thiazolyl)ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:41])[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.ClC(Cl)C>C(O)(C)(C)C>[CH3:27][C:28]1[CH:29]=[C:30]([NH:41][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:15]#[C:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2ncnc3ccc(C#CC4CCNCC4)cc23)ccc1Oc1cccnc1
Yield: 105 %

Procedure:
4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.21 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (43 mg, 0.21 mmol) were mixed together in tert-butanol (1 mL) and dichloroethane (1 mL) and heated in a sealed vial at 90° C. for 20 minutes. The reaction was cooled down and HCl (gas) was bubbled through for 5 minutes. EtOAC was then added whereupon yellow precipitation occurred. The precipitate was collected and dried to afford the desired product [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine as a yellow solid (96 mg, 95%). 1H NMR (CDCl3) δ 2.01 ((m, 2H), 2.22 (m, 2H), 2.35(s, 3H), 3.20 (m, 2H), 3.45(m, 2H), 7.28 (d, 1H, J=8.7 Hz), 7.75(dd, 3H, J1=8.7, J2=8.7 Hz), 8.06 (dd, J=8.7), 8.10 (dd, J1=J2=8.7 Hz), 8.17 (m, 1H), 8.60 (d, 1H, J=5.4 Hz), 8.80 (s, 1H), 8.89 (s, 1H). MS: M+1, 436.6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)C>>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15](=[O:25])[N:14]([CH3:26])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:32][N:33]([CH3:35])[CH3:34])=[CH:12][CH:11]=4)=[CH:23][CH:22]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Product: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9C above with compound B 6-acetyl-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=2[N+:10]([O-:12])=[O:11])=[CH:15][CH:16]=1)#[N:19]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C#N)cc2)c([N+](=O)[O-])c(C)n1

Procedure:
A solution of 4-chloro-2,6-dimethyl-3-nitropyridine (9.80 g, 52.5 mmol) and 4-aminobenzonitrile (6.20 g, 52.5 mmol) in ethanol (160 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (200 ml), and washed with saturated aqueous sodium bicarbonate (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give a gum which was crystallised by adding ether (100 ml) and sonicating for 5 minutes. The yellow solid (9.80 g, 70%) was filtered off and dried in vacuo, mp 171°-172° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.ClC(Cl)(Cl)C[O:23][C:24](=O)[NH:25][C:26]1[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([C:29]1[CH:30]=[C:26]([NH:25][C:24]([NH:19][CH2:18][C:17]2[C:12]([O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:23])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:28]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cn1ncc2cc(Oc3ncccc3CN)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cccnc2Oc2ccc3c(cnn3C)c2)cc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
C-[2-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-methylamine (4n) (0.017 g, 0.067 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (5n) (0.035 g, 0.087 mmol) were placed in a 10 mL reactor vial and dissolved in DMF (5 mL). DIEA (0.058 mL, 0.334 mmol) was added to the reaction mixture and the system heated to 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography using Sep-pak 10 g (35 cc) silica cartridge (50% EtOAc/Hexanes) to furnish the desired product (6n) (0.034 g, 100% yield). 1H NMR (400 mHz, DMSO) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=4.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 2H), 6.26 (s, 1H), 4.37 (d, J=6.3 Hz, 2H), 4.06 (s, 3H), 2.36 (s, 3H), 1.25 (s, 9H); MS (ESI+) m/z 510 (M+H) detected.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (464 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (767 mg, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl-acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:18][CH2:17][C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:10]=2[CH:11]=1)([O-])=O>O.C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]2[S:18][CH2:17][C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:10]=2[CH:11]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)-c1[nH]ncc1CS2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)-c1[nH]ncc1CS2
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred mixture of iron powder (8.53 g) and ammonium chloride (0.85 g) in water (22 ml) and ethanol (66 ml) was added portionwise 8-nitro-1,4dihydro[1]benzothiopyrano[4,3-c]pyrazole (6.6 g) under reflux over a period of 15 minutes. After being stirred for 30 minutes under reflux, the mixture was filtered and the filtrate was evaporated in vacuo. To the residue were added aqueous sodium bicarbonate and ethyl acetate and the mixture was stirred at room temperature. The resulting precipitate was collected by filtration, washed with water, and recrystallized from a mixture of tetrahydrofuran and methanol to give 8-amino-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (3.79 g).
Reaction SMILES: C1(S(O[CH2:11][CH2:12][C:13]2([OH:29])[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])[CH2:15][CH2:14]2)(=O)=O)C=CC=CC=1.[Br-:30].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:30][CH2:11][CH2:12][C:13]1([OH:29])[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=2[Cl:28])[CH2:15][CH2:14]1
Reactant: [Br-]
Reactant: COc1cc(N2CCC(O)(CCOS(=O)(=O)c3ccccc3)CC2)c(Cl)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(N2CCC(O)(CCBr)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.8 %

Procedure:
A solution of 2-(1-(2,4-dichloro-5-methoxyphenyl)-4-hydroxypiperidin-4-yl)ethyl benzenesulfonate (300 mg, 0.652 mmol) in acetone (5 mL) was treated with potassium bromide (194 mg, 1.629 mmol) and 18-crown-6 (189 mg, 0.717 mmol). The mixture was stirred at RT for 60 h before being concentrated in vacuo. The resultant residue was dissolved in EtOAc, and the resultant solution was washed with brine, dried (Na2SO4), and concentrated to give a residue. This residue was purified by a flash column using 0-30% EtOAc in heptanes as eluent to give 4-(2-bromoethyl)-1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-ol (102 mg, 0.266 mmol, 41% yield) as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].B.C1COCC1>O1CCCC1.C1(C)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc([C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
Solutions of 4.006 g (15 mmol) of 2-bromo-1-(3-trifluoromethylphenyl)-ethanone, 15 mL of anhydrous tetrahydrofuran and 15 mL of 1M borane-THF in tetrahydrofuran were added simultaneously to a stirring solution of 1.5 mL of 1M (R)-(3aR)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene and 15 mL of anhydrous tetrahydrofuran, cooled in an ice water bath at ca. 15 degrees, over 12.5 minutes. The cooling bath was removed and the mixture stirred at room temperature. After 1.5 h, ca. 0.48 g of methanol was added dropwise (gas evolution) and the mixture stirred for 5 minutes, then 15 mL of 2 M sodium hydroxide was added over 3 minutes. The mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated under reduced pressure to remove the tetrahydrofuran, and the remaining aqueous phase was extracted twice with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2.553 g (90%) of (R)-2-(3-trifluoromethyl-phenyl)oxirane as a light amber liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.87 (dd, J=5.27, 2.51 Hz, 1H) 3.12 (dd, J=5.27, 4.02 Hz, 1H) 4.04 (dd, J=4.27, 2.51 Hz, 1H) 7.54-7.58 (m, 2H) 7.60 (s, 1H) 7.62-7.67 (m, 1H).