Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([C:22]#[C:23][C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1>C(#N)C.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]([C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:22]2
Reactant: CC(C)(C#Cc1cc(N)c(F)cc1NC[C@@H](O)COCc1ccccc1)COCc1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(COCc1ccccc1)c1cc2cc(N)c(F)cc2n1C[C@@H](O)COCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
Bis-acetonitriledichloropalladium (0.1 eq) and CuI (0.1 eq) are charged to the reactor and then suspended in a solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol obtained above (1 eq) in acetonitrile (9.5 vol total). The mixture is sparged with nitrogen gas for 1 h and then is heated to 80° C. The reaction progress is monitored by HPLC and the reaction is typically complete within 1-3 h. The mixture is filtered through Celite and the cake is washed with acetonitrile. A solvent swap into ethyl acetate (7.5 vol) is performed. The ethyl acetate solution is washed with aqueous NH3—NH4Cl solution (2×2.5 vol) followed by 10% brine (2.5 vol). The ethyl acetate solution is then stirred with silica gel (1.8 wt eq) and Si-TMT (0.1 wt eq) for 6 h. After filtration, the resulting solution is concentrated down. The residual oil is dissolved in DCM/heptane (4 vol) and then purified by column chromatography. The oil thus obtained is then crystallized from 25% EtOAc/heptane (4 vol). Crystalline (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol is typically obtained in 27-38% yield. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J=12.8 Hz), 6.77 (d, 1H, J=9.0 Hz), 6.06 (s, 1 H), 5.13 (d, 1H, J=4.9 Hz), 4.54 (s, 2H), 4.46 (br. s, 2 H), 4.45 (s, 2 H), 4.33 (d, 1 H, J=12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J=9.2 Hz), 3.56 (d, 1H, J=9.2 Hz), 3.49 (dd, 1H, J=9.8, 4.4 Hz), 3.43 (dd, 1H, J=9.8, 5.7 Hz), 1.40 (s, 6 H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[OH-].[Na+].[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>CC(O)C.O>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:19][CH:18]=1
Reactant: OC(CCl)CCCl
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CCCl)cc1
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a solution of 500 g (3.5 mole) of 1,4-dichloro-2-butanol was added, dropwise, 500 ml (6.25 mole) of a 50% sodium hydroxide solution. The mixture was stirred for 16 hr and then 500 ml of water was added, dropwise, with the temperature maintained below 35° C. The mixture was extracted with 500 ml of isopropyl ether, dried over sodium sulfate and concentrated to give an oil which was purified by distillation. To 14.3 g (0.1 mole) of the purified epoxide was added a solution of 15.1 g (0.1 mole) of 4-acetamidophenol in 150 ml of 2-propanol and 4 g of (0.1 mole) of sodium hydroxide in 10.0 ml of water. The mixture was stirred for 15 hr and then poured into 400 ml of water at 0° C. The crude, collected solid was washed with water and allowed to air dry. The solid was suspended in 350 ml of acetone, collected by filtration, and washed with additional portions of acetone. The filtrate was concentrated under reduced pressure to give 13.8 g (53% yield) of solid. A portion of this solid was recrystallized from tetrahydrofuran to give cream-colored solid, m.p. 124°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[F:19])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:21]1[CH:22]=[C:23]2[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]2[C:25](=[O:27])[N:26]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:21]3[CH:22]=[C:23]4[N:30]([CH3:31])[C@@H:29]([CH3:32])[CH2:28][N:24]4[C:25](=[O:27])[N:26]=3)=[CH:13][C:12]=2[F:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Oc2ccc(CO)cc2F)ccc1Cl
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(Cl)c(C#N)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-chloro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)CCCOc1ccc(CCCO)cc1

Procedure:
After the method of Preparation 3, 4.13 g (15.51 mmol) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid, ethyl ester is saponified with potassium carbonate to produce a solid. This is recrystallized from an ethyl acetate-hexane mixture giving 2.45 (66%) of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid as white crystals: m.p. 92°-94° C.; IR (KBr) 3420 (br.), 1710 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (CI) m/e 239 (M+ +H). Analysis calculated for C13H18O4 : C, 65.53; H, 7.61; O, 26.86. Found: C, 65.75; H, 7.87; O, 26.38.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](O)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29].O>ClCCl>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=C(O)CCC(=O)O
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2-Phenylchroman-6-yloxy)pyridin-3-ylamine (example 35) (270 mg) and succinic acid (151 mg) were dissolved in dichloromethane (16 ml). 1-(3-Dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (245 mg) was added into a reaction mixture and it was stirred at room temperature for 3 hours. Water was added and the mixture was filtered. The precipitate was collected and treated with methanol and filtered again. The methanol-filtrate was evaborated to dryness to yield N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid. 1H NMR (400 MHz, d6-DMSO) δ: 12.0 (bs, 1H), 10.08 (s, 1H), 8.29 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 8.8, 2.4 Hz), 7.46-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (d, 1H, J 8.6 Hz), 2.96 (m, 1H), 2.70 (m, 1H), 2.56-2.52 (m, 4H), 2.16 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)[C:3]=2[N:10]=1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3oc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 7-chloro-2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidine (42 mg, 0.13 mmol), 4-trifluoromethyl-phenylamine (22 mg, 0.13 mmol), and p-TsOH.H2O (51 mg, 0.27 mmol) in toluene (2 mL) was heated to 120° C. in a sealed tube. After 2 h, the solution was cooled purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (20 mg, 34%). MS (ESI): mass calcd. C19H11Cl2F3N4O, 438.0; m/z found, 439.1 [M+H]+. 1H NMR (CDCl3): 8.57 (s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.31-7.27 (m, 1H), 4.66 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CCN(CC)CC.[Cl:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].[Na+].[Cl-]>C(Cl)Cl>[Si:6]([O:5][CH2:4][C@@H:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][Cl:28])([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)CCCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCCl)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
(S)-tert-butyl 1-amino-3-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (1 g, 3.29 mmol) was taken up in 10 mL of CH2Cl2 and cooled to 0° C. To this was added Et3N (0.731 g, 7.24 mmol), followed by 5-chloro-pentanoyl chloride (0.557 g, 3.62 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. Upon completion of the reaction, satd NaCl solution was added. The organic layer was extracted with EA, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-(5-chloropentanamido)propan-2-ylcarbamate (1.2 g, 86%). 1H NMR (CDCl3, 300 MHz) δ 6.31 (s, 1H), 5.04 (d, 1H), 3.65 (m, 3H), 3.53 (m, 2H), 3.40 (m, 2H), 2.18 (t, 2H), 1.78 (m, 4H), 1.43 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:9]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Yield: 93.9 %

Procedure:
In a similar manner to Step 1 of Example 16, 2,5-dichloropyridine-3-carbonylchloride (669 mg, 3.19 mmol) was dissolved in dichloromethane (13 mL), and the solution was treated with cumylamine (0.505 mL, 3.51 mmol), triethylamine (0.667 mL, 4.79 mmol) and DMAP (39.0 mg, 0.319 mmol), followed by purification by slurry using diisopropylether/hexane to obtain 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (926 mg, yield 94%).
Reaction SMILES: [C:1]([C:3]1([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:24][C:25]([O:27]CC)=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:10]=2[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=2[F:41])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:24][C:25]([OH:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:11][C:10]=2[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=2[F:41])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCC3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
To a solution of ethyl 3-(3-(((2-((1-cyanocyclopentyl)methyl)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (143 mg) in ethanol (3.0 mL) was added 2N aqueous sodium hydroxide solution (0.26 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (88 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].O=[C:11]1[CH2:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:12]1>C(O)C>[OH:3][N:2]=[C:11]1[CH2:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:12]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=NO)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g (8.36 mmol) of potassium carbonate are added to a solution of 1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (U.S. Pat. No. 6,498,159) in 60 mL of ethanol, and the mixture is then left stirring at room temperature for 12 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and water, the aqueous phase is separated out and extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia. 0.831 g of pure product is thus obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25](O)=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1.Cl.[CH3:33][NH:34][CH3:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[C:15]=2[NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([N:34]([CH3:35])[CH3:33])=[O:26])[CH2:21][CH2:20]2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CN(C)C(=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
trans-4-{[(2-{[(5-Chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]carbonyl}cyclohexane-carboxylic acid (176 mg) obtained in Example 8(2) is suspended in pyridine (8 ml), and thereto are added successively dimethylamine hydrochloride (65 mg), 1-hydroxybenzotriazole (108 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg) under ice-cooling, followed by stirring at room temperature for 19 hours. To the reaction solution is poured ice-water and the precipitates are collected by filtration. The resulting precipitates are dissolved in chloroform and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate) The resulting residue is suspended in n-hexane and the precipitates are collected by filtration to give the title compound (137 mg). APCI-MS M/Z:469/471[M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([N+:25]([O-])=O)[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Yield: 96.1 %

Procedure:
6-(1H-Indol-4-yl)-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (714 mg, 1.97 mmol) was dissolved in ethyl acetate (100 ml) and the compound was hydrogenated using the H-cube® (available from THALESNano) using 10% Pd/C catalyst at 30° C. and under 30 bar pressure of hydrogen. Solvent was removed in vacuo to give the title compound (629 mg) as an orange/brown solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.C>CO.O.[Pd]>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(C(=CCN2CCN(Cc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Fc1ccc(C(CCN2CCNCC2)c2ccc(F)cc2)cc1
Yield: 99.8 %

Procedure:
A mixture of 32,5 g of 1-[3,3-bis(4-fluorophenyl)-2-propenyl]-4-(phenylmethyl)piperazine dihydrochloride and 3,3 g of 5% Pd at activated charcoal in 150 ml of methanol and 100 ml of water was hydrogenated under 60 psi. The catalyst was filtered off and after evaporation of the solvent basification with sodium hydroxide was achieved. The base was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to yield 21,5 g (90,7%) of crude 1-[3,3-bis(4-fluorophenyl)propyl]piperazine.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1

Procedure:
A solution of 0.083 g (0.255 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.083 mL (1 mmol) of pyridine and 0.12 mL (1 mmol) of benzoyl chloride in 2 mL of methylene chloride was mixed for 18 hr. The reaction was diluted with methylene chloride and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[C:13]([CH2:12][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[N:14]
Reactant: N#CCBr
Reactant: Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(C=O)c1OCC#N
Temperature: 55 °C

Procedure:
A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75.0 mmoles, Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmoles), and potassium carbonate (11.4 g, 82.5 mmoles) in DMF (150 mL) is heated to 55° C. for 3 hours, cooled, then diluted with ether. The mixture is washed with distilled water, saturated NaCl solution, then the organic layer dried over MgSO4 and concentrated to give the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ10.20 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.29 (m, 1H), 4.81 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1>O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
3.5 g (0.111 mol) of methylamine were passed over the course of 20 minutes into a stirred solution of 11 g (0. 055 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1, 3,5-triazine in 150 ml of tetrahydrofuran at 0° C. The mixture it was stirred at 0° C. for one hour and at 22° C. overnight. was then concentrated under reduced pressure, stirred with water and dried. 10.8 g (93.1% of theory) of the title compound of melting point 155°-157° C. (decomposition) were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-Hydroxybenzoic acid (1.1 g, 7.96 mmoL) and aniline (742 mg, 7.23 mmol) were dissolved in 20 mL of dry DMF. To the above solution EDCl (1.53 g, 7.23 mmol) was added in one portion and the resulting mixture was stirred at rt overnight under nitrogen. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed consecutively with 1 N HCl, water, saturated sodium bicarbonate solution, water, and brine, and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified by column chromatography using 10% EtOAc in hexane to give 450 mg (29% yield) of 4-Hydroxy-N-phenyl-benzamide. MS (ES) m/z: 214.08 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:10]=3[N:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]OC(OC)N(C)C>>[CH:1]1([N:7]2[CH:29]=[CH:17][S:14](=[O:15])(=[O:16])[C:13]3[CH:12]=[N:11][C:10]4[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:9]=4[C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(S(C)(=O)=O)cnc21
Reactant: COC(OC)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)S(=O)(=O)C=CN3C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Cyclohexyl-5-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (6.1 mg, 0.014 mmol) in N,N-dimethylformamide dimethyl acetal (2.5 mL) was stirred at 170° C. for 3 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (1 mL) and stirred with 1 M hydrochloric acid (1 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting pale yellow oil (8.5 mg) containing the title compound was used for the next step without further purification.