Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:9](=[O:23])[CH2:8][CH2:7]2)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:9](=[O:23])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1
Temperature: 25 °C

Procedure:
6-nitro-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (98 mg, 0.309 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g slurry in water) followed by hydrazine hydrate (96 uL, 3.08 mmol) at room temperature and the resulting mixture was refluxed for 30 minutes. The reaction was cooled to room temperature, filtered through a celite bed, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5:97.5). Yield: 71 mg of yellow oil (80%). 1H NMR (CDCl3) δ: 6.90 (d, J=8.4 Hz, 1H), 6.55 (dd, J=2.7, 8.4 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 3.91 (m, 2H), 2.80-2.76 (m, 2H), 2.61-2.56 (m, 2H), 2.38-2.33 (m, 6H), 1.84-1.79 (m, 2H), 1.60-1.55 (m, 4H), 1.46-1.42 (m, 2H). MS (ESI): 288.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:26])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19](S(C)(=O)=O)[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[N:3]([CH3:26])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:28])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylsulfonyl)[1,3]thiazolo-[5,4-d]pyrimidine (Intermediate 38) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 17). Yellow solid (52 mg, 61%);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:32][C:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])([CH3:35])([CH3:34])[CH3:32]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
The mixture of 2-chlorobenzoic acid (20 g, 128 mmol), HOBT (34.6 g, 256 mmol), EDCI (48.8 g, 256 mmol), 2-methylpropan-2-amine (9.3 g, 128 mmol) and TEA (25.9 g, 256 mmol) in THF (600 mL) was stirred at room temperature overnight. After solvent evaporation, the mixture was diluted with ethyl acetate (600 mL) and washed with water (3×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/PE (1:5) to give the title product as a white solid (23.9 g, yield: 88.5%). LC-MS: m/e=212 (M+H)+; Rt=0.85 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Brc1cccc(-n2ccnc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-n4ccnc4)n3)cnc2n1
Yield: 15.9 %

Procedure:
2-Bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g, 0.8 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.9 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-10%) and trituration with ethyl acetate gave 3-[6-(1H-imidazol-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (42 mg) as an off-white solid: δH (400 MHz, CDCl3) 7.30 (1H, s), 7.35 (1H, d, J 8), 7.43 (1H, d, J 7), 7.65 (1H, s), 7.79 (1H, d, J 8), 8.00 (1H, dd, J 8 and 8), 8.38 (1H, s), 8.59 (1H, s), 10.24 (1H, d, J 7); m/z (ES+) 331 (M++H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)c1ncccn1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ncccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 3-methyl-1-(pyrimidin-2-yl)butan-1-amine (CAN 1178500-15-6) as starting materials, MS (EI): m/e=432.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([I:15])=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(Cl)ccc1I
Temperature: 105 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of N-(6-chloro-3-iodopyridin-2-yl)pivalamide (17.0 g, 50.2 mmol) in dioxane (80 mL) is added 2 N aqueous HCl (50 mL) and the resulting mixture is stirred at 105° C. for 2 h. After cooling to RT, the reaction mixture is slowly poured into a saturated aqueous NaHCO3 solution (200 mL) and the resulting mixture is extracted with ethyl acetate (400 mL×3). The combined organic extracts are washed with brine (300 mL×3), dried over MgSO4, and solvent is evaporated on a rotary evaporator to provide 6-chloro-3-iodopyridine-2-amine as light brown solid (12.8 g, yield 100%). 1H NMR (300 MHz, DMSO-d6), δ 7.85 (d, J=8.1 Hz, 1H), 6.36 (d, J=8.1 Hz, 1H), 6.50 (br s, 2H). LCMS-ESI (m/z): calcd for C5H4ClIN2 253.9; [M+H]+ found 255.3.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].O1CCOCC1.[OH-].[CH2:24]([N+:31](C)(C)C)[C:25]1C=CC=C[CH:26]=1.C(#N)C=C>CO>[C:1]([C:4]1([CH2:26][CH2:25][C:24]#[N:31])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Solvent: C1COCCO1
Product: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A 4.2 g. portion of 9-carbamoylfluorene was dissolved in 300 ml. of dioxane at 45° C. To the solution was added 0.4 ml. of Triton B (40% benzyltrimethylammonium hydroxide in methanol) and 1.1 g. of acrylonitrile. The reaction mixture was stirred at 70° C. for one hour and was then allowed to cool to ambient temperature and stand overnight. The dioxane was removed under vacuum, and the remaining oil was taken up in ethyl acetate/water. The layers were separated, and the organic layer was washed three times with water and once with saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate, filtered and evaporated under vacuum to a foam, which was taken up in dichloromethane. The solution was boiled, and hexane was added until crystallization occurred. The mixture was chilled overnight, and the crystals were collected by filtration. The crystals were washed with hexane and dried under vacuum at 40° to obtain 3.2 g. of the desired product, m.p. 148°-152°, with sintering at 143°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Br[Mg][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[CH2:34]>C1COCC1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH2:34])[CH:3]=[C:4]([NH:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Br)nn23)ccc1C(=O)NC1CC1
Reactant: C=C([Mg]Br)c1ccccc1
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cc(NCCC(F)(F)F)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 24 mg (50 μmol) 4-{6-bromo-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 247a in 1 mL THF is dropwise added 1.0 mL (0.5 mmol) of a 0.5 M solution of bromo(1-phenylethenyl)magnesium in THF at rt. After stirring overnight at rt, the mixture is heated at 50° C. and stirred for 3 more days to give after working up and purification 1.7 mg (5%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:16])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-])=O.Cl.[OH-].[Na+]>[Fe].CO>[C:10]1([C:7]2[N:6]=[C:5]([NH2:16])[C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(-c2ccccc2)nc1N
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 101.7 %

Procedure:
A suspension of 3-nitro-6-phenyl-2-pyridine amine (Compound of Reference Example 112) (0.8 g), iron filings (1.3 g) and methanol (7 ml) was cooled with ice and to the suspension was added dropwise concentrated hydrochloric acid (3 ml). After the dropwise addition, the mixture was stirred at room temperature for 10 minutes and at 80° C. for 50 minutes. The reaction mixture was poured onto ice, neutralized with an aqueous solution of 8 N sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v) (At that time, insolubles were filtered off by means of celite). The organic layer was dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain 6-phenyl-2,3-pyridine diamine (0.7 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[C:31]([C:35]2[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:33]4[CH:34]=[CH:29][CH:30]=[C:31]([C:35]5[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ncccc1-c1cccc(Br)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(3-bromo-phenyl)-2-methoxy-pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1
Yield: 69.3 %

Procedure:
4-Chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto, followed by reaction at 80° to 90° C. for 2 hours. Then, the solvent was removed by distillation under reduced pressure, and 10 ml of hexane was added to the residue to wash it. The solvent was removed by decantation. The residue was further similarly treated with 10 ml of ether. The residue was purified by silica gel column chromatography [eluent: hexane:ethyl acetate=2:1 (v/v)] to obtain 1.41 g of a yellow solid (yield: 68.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (50 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL), piperidine (50 mg, 0.59 mmol, 6.73 equiv), and cyclopropanecarbaldehyde (50 mg, 0.71 mmol, 5.54 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1, 50:1) to give 0.0179 g (32%) of the title compounds as an off-white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[C:12]1([C:18]2([CH:24]([CH3:29])[C:25](OC)=[O:26])[CH:23]=[CH:22][CH2:21][CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>O>[CH3:29][CH:24]([C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:22][CH2:21][CH:20]=[CH:19]1)[CH2:25][OH:26]
Reactant: COC(=O)C(C)C1(c2ccccc2)C=CCC=C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(CO)C1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.76 g. of lithium aluminum hydride is placed in 20 ml. of absolute ether. 2.42 g. of methyl 2-(1-phenyl-2,5-cyclohexadien-1-yl)-propionate in 20 ml. of absolute ether are added dropwise thereto. After stirring at room temperature for 5 hours, the mixture is worked-up as follows: The mixture is treated with ethyl acetate and water, filtered under suction and the organic phase is separated from the aqueous phase. The organic phase is dried with sodium sulfate, filtered and evaporated. The crude product obtained is chromatographed on 80 g. of silica gel with ether/petroleum ether (1:2), oily β-methyl-1-phenyl-2,5-cyclohexadien-1ethanol being obtained.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>O>[F:10][C:8]1[CH:9]=[C:4]2[C:5]([CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[O:2][C:3]2=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(F)ccc1C#Cc1ccc(C)cc1
Solvent: O
Product: Cc1ccc(-c2cc3ccc(F)cc3c(=O)o2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 5-fluoro-2-p-tolylethynyl-benzoic acid methyl ester (359 mg, 1.34 mmol) and polyphosphoric acid (4 g) is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is allowed to cool to room temperature and water is added. The mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/dichloromethane as eluent to afford 7-fluoro-3-p-tolyl-isochromen-1-one as off-white solid; HPLC/MS 2.16 min (A), [M+H] 255.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[O:4]([CH2:3][CH2:2][O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: BrCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(OCCOc2ccccc2)cc1
Yield: 52.8 %

Procedure:
160 g of 2-bromoethylphenyl ether are added to a mixture of 94 g of phenol, 30 ml of water and 60 g of sodium hydroxide, at a temperature of 100° C. After a reaction time of 16 hours, the mixture is poured into water, filtered by suction, and the product is recrystallized from ethyl acetate. 90 g (53%) of 1,2-diphenoxy ethane having a melting point of 95° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([N:26]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:4]=1.C(O)C.O>[Zn].C(O)(=O)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:13][C:12]([C:18]3[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)[CH:4]=1)[NH2:26]
Reactant: CN(N=O)c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N)c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113.8 %

Procedure:
To a mixture of N-methyl-N-nitroso-3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]aniline (1.00 g) obtained by Reference Production Example 9, ethanol (2 ml), water (2 ml) and acetic acid (2 ml) was added zinc (695 mg) at room temperature. After stirring at room temperature for 5 hours, this mixture was filtrated. To the filtrate was added anhydrous sodium hydrogen carbonate, and then the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain crude N-methyl-N-{3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}hydrazine (1.1 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[CH:9][CH:8]=1.[C:18](=O)([O-])[O-:19].[K+].[K+]>CN(C)C=O>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2cccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phosphoryl chloride (136.3 g) was slowly added dropwise to a solution of 1-(4-fluorophenyl)pyrrole (136.3 g) in N,N-dimethylformamide (250 ml) under ice cooling so as to keep the temperature of the reaction solution under 50° C., and then the mixture was stirred at room temperature for 24 hours. The reaction solution was made alkaline by pouring into an aqueous solution of potassium carbonate under ice cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and concentrated in vacuo. n-Hexane was added to the residue and the resulting precipitated solid was collected by filtration to give 1-(4-fluorophenyl)-2-formylpyrrole (152 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccccn6)c5)c4c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)nc1
Yield: 11.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (110 mg, 0.205 mmol) was deprotected in TFA/DCM (5/5 ml). This afforded 10 mg (11.1% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.73 (s, 1H), 8.68-8.67 (d, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.16-8.11 (t, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.75-7.72 (d, 2H), 7.66-7.61 (t, 1H), 7.49-7.42 (m, 3H), 5.68 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (m, 2H), 3.03-2.95 (m, 1H), 2.14-1.90 (m, 4H). MS: m/z=434.9 (M+1), HPLC: 92.12% in method A.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CN1C(=O)CCC1>[C:17]([C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1)#[N:18]
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(CCNC(=O)C(F)(F)F)cc1
Temperature: 200 °C

Procedure:
A mixture of N-(4-bromophenethyl)-2,2,2-trifluoroacetamide (2.96 g, 10 mmol), NiBr2 (2.19 g, 10 mmol) and NaCN (0.98 g, 20 mmol) in 2.0 mL of NMP was heated at 200° C. in microwave twice. After cooling down to RT, the mixture was filtered with the help excess of DCM. The filtrate was evaporated to dryness and was submitted to flash chomatography (SiO2, DCM to DCM/EtOAc=3:1) to give (N-(4-cyanophenethyl)-2,2,2-trifluoroacetamide was a white solid, together with 1.1 g for recovered starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24]>CC(C)=O>[CH2:24]([N:10]1[C:11](=[O:15])[N:12]([CH2:13][CH3:14])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:23]#[CH:22]
Reactant: CCN1C(=O)N=NC1c1ccc(Cl)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(CC)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
To the solution of 3-(4-chlorophenyl)-4-ethyl-1,2,4-triazolin-5-one (2.23 g, 0.01 mole) in dry acetone (40 ml) was added, at room temperature, potassium carbonate (1.67 g, 0.0012 mole) followed by propargyl bromide (1.8 g of 80% in toluene, 0.012 mole). The reaction mixture was then refluxed with stirring for 6 hr. The mixture was cooled down to room temperature and solvent was evaporated to give a residue. The product was purified by crystallization from hexane/ether, affording 1.8 g (69.2% yield) of 1-propargyl-3-(4-chlorophenyl)-4-ethyl-1,2,4-triazolin-5-one as a white solid, m.p. 115°-119° C. A proton NMR spectrum was consistent with the desired structure.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(OC(C)C)(=O)C>[F:29][C:30]1[CH:31]=[C:32]([NH:33][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (NaBH(OAc)3 74 g, 0.35 mol) was added to a stirred solution of 1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (50 g, 0.25 mol) and 3-Fluoroaniline (24 ml, 0.25 mol) in isopropyl acetate (1-PrOAc, 500 ml) and the slurry stirred overnight.