Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].CS(C)=O.[F:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH2:17].Cl[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>O>[NH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([F:7])[C:9]=2[O:18][CH3:19])[N:13]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[N:12]=1
Reactant: N#Cc1cccc(CCl)c1
Reactant: COc1c(F)ccc2[nH]nc(N)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(F)ccc2c1c(N)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 48 %

Procedure:
Finely ground potassium hydroxide (6.59 g, 118 mmol, 2.5 equiv.) was treated with DMSO (100 mL). To this was added 5-fluoro-4-(methyloxy)-1H-indazol-3-amine (for a preparations see Intermediate 56) (8.5 g, 47 mmol) and the mixture stirred at room temperature for 50 minutes. To the red coloured mixture was added 3-chloromethyl benzonitrile (8.9 g, 59 mmol, 1.25 equiv.) in one portion. A small exotherm of ˜5° C. was observed. The mixture was allowed to stir at room temperature for 25 minutes before pouring into water (600 mL) and extracting with chloroform (400 mL). The aqueous was re-extracted with chloroform (2×400 mL). The organic extracts were combined, washed with water (3×500 mL), dried over MgSO4, filtered and evaporated to give the crude product. This was dry loaded onto silica and chromatographed eluting with 20% petrol up to 70% EtOAc-petrol. The material came off impure so was re-chromatographed on a suction column. The impure material was loaded in DCM and eluted with DCM up to 30% EtOAc-DCM to give the title compound (8.25 g, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:25])([C:20]1[O:21][CH:22]=[N:23][N:24]=1)[CH3:19]>>[CH3:17][C:18]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:21][CH:22]=[N:23][N:24]=1)[CH3:19]
Reactant: CC(C)(N)c1nnco1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1nnco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,3,4]oxadiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 343.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([NH2:14])=[N:8][C:9]=2[NH2:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:13][C:9]1[N:8]=[C:7]([NH:14][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[N:6]=[C:5]2[C:10]=1[N:11]=[CH:12][N:4]2[CH2:3][CH2:2][Cl:1]
Reactant: Nc1nc(N)c2ncn(CCCl)c2n1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(NCc2cccnc2)nc2c1ncn2CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
100 mg (0.47 mmol) of 9-(2-chloroethyl)-2,6-diamino-purine (example 12, step A) were dissolved in 10 ml MeOH and 3 g molecular sieves (4 Å), 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde and 0.135 ml (2.35 mmol) acetic acid were added. The mixture was stirred for 2 hours at room temperature. 23.6 mg (0.38 mmol) sodium cyano-borohydride were added and stiffing was continued for 4 hours. Additional 0.044 ml (0.47 mmol) 3-pyridinecarboxaldehyde were added and 72 mg sodium cyano-borohydride were added in three portions over three days at room temperature. The solvent was evaporated and the residue was taken up in 50 ml ethyl acetate. The organic layer was washed with sat. aqueous sodium carbonate and brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give 0.254 g of the crude product as yellow oil. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 99.5/0.5→80:20) to give 88 mg of the desired product as white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:23][CH2:24][CH3:25]>>[C:1]1([CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH3:25])[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(NCCc2ccccc2)cc1C(F)(F)F
Reactant: CCCI
Product: CCCN(CCc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in a manner similar to step B of Example 1 using 4-[(2-phenylethyl)amino]-2-(trifluoromethyl)benzonitrile, Example 122A and iodopropane: MS (ES) m/z 333 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1.CCCCCC>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (7.15 g) [CAS No.59942-88-0] in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and then a solution of n-butyllithium in hexane (1.6 M; 46 mL) was added dropwise and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise at −78° C., and stirring was continued for 1 hour. After increasing the temperature of the reaction mixture to room temperature and adding water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (7.1 g) was obtained from the n-hexane:ethyl acetate (50:1) fraction as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccncc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)c(O)c1)C(F)(F)F
Yield: 17.7 %

Procedure:
To a stirred suspension of N-[3-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.05 g, 2.6 mmol) in dry methylene chloride (30 mL) was added boron tribromide (10.4 mL of a 1.0M solution of boron tribromide in methylene chloride, 10.4 mmol). The resulting solution was stirred at reflux for 2 hours. An additional 5 mL of 1.0M boron tribromide solution in methylene chloride was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an oil. Purification by flash column chromatography (20% v/v methanol in ethyl acetate) yielded the title propanamide as a white solid (0.18 g, 18%); mp 188-189° C. 1 H-NMR (250 MHz, d6-DMSO): 1.54 (s, 3H, CH3) 7.35 (d, 1H, J=9.0 Hz, aromatic) 7.51 (s, 1H, OH) 7.61 (s, 1H, aromatic) 7.77 (d, 2H, J=5.5 Hz, aromatic) 7.84 (d, 1H, J=8.9 Hz, aromatic) 8.83 (d, 2H, J=5.5 Hz, aromatic) 10.26 (s, 1H, NH) 11.04 (s, 1H, ArOH). MS (CI, CH4): 391 (M+1).
Reaction SMILES: [NH2:1]/[C:2](=[N:30]\[S:31]([C:34]1[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]2[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=2[C:44]=1[CH3:45])(=[O:33])=[O:32])/[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:8](=[O:15])[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.Cl[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(Cl)(Cl)Cl>[CH2:61]([O:60][C:58]([N:12]1[CH2:11][CH2:10][N:9]([C:8](=[O:15])[C@@H:7]([NH:16][S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][NH:3]/[C:2](/[NH2:1])=[N:30]/[S:31]([C:34]2[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]3[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=3[C:44]=2[CH3:45])(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:59])[CH3:62]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCNCC2)c(C)c2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of compound D (8.0 g, 11.1 mmol) in CHCl3 (50 ml) was added DIEA (4.1 mL, 23.3 mmol) at room temperature and stirred for 15 min. The mixture was cooled to ˜5° C., ethyl chloroformate (1.06 mL, 11.1 mmol) was added drop wise. After stirring at room temperature overnight (˜18 h), solvent removed in vacuo. The residue was dissolved in MeOH (˜25 ml) and Et2O (˜500 mL) was added. The precipitated crude product was filtered off, washed with Et2O and dried under vacuo to afford compound E (8.5 g, 11.1 mmol). LC-MS [M+H] 757.6 (C36H48N6O8S2+H, calc: 757.9). Compound E was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.B(Br)(Br)[Br:21].C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[Br:21][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][C:9]=1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: N#Cc1ccc2[nH]c(-c3cnccc3O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 190 mg, 0.80 mmol) and DCE (8 mL), and 1.0 M BBr3 in DCM (4.8 mL, 4.8 mmol) is added. The mixture is stirred at room temperature overnight. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with DCM. The aqueous phase is concentrated, acidified with 1M HCl in water and concentrated in vacuo. The residue is purified with an Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give 3-bromo-2-(4-hydroxy-pyridin-3-yl)-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (d, J=7.1 Hz, 1H), 7.48 (dd, J=8.5, 1.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.81 (dd, J=7.1, 1.3 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 313.9932 [(M+H)+ calcd for C14H9BrN3O: 313.9929].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][N:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]=3[CH2:33][CH3:34])[N:25]=[CH:24]2)[CH:17]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:12][C:15](=[O:14])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]3[CH:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:32]=4[CH2:33][CH3:34])[N:25]=[CH:24]3)[CH:17]=2)[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: Cc1ncc(C(C)(C)C)cc1N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cnc4C)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 152 was prepared from 5-tert-butyl-2-methyl-pyridin-3-ylamine (see U.S. provisional application 60/567,693) and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 519 [C32H34N6O+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[N:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][N:37]([C:10]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=4)[CH:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:17]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:11]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COC(=O)/C=C/c1ccncc1N=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)CC1c2ccncc2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting from 250 mg (0.34 mmol) of the carbodiimide from Example 17A and 69 mg (0.36 mmol) of 3-methoxyphenylpiperazine, general procedure [C] and purification by preparative HPLC result in 90 mg (46% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:27])[C:21]([O:23]C)=[O:22])[CH:15]=2)[N:10]=1.[OH-].[Na+].O.Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:27])[C:21]([OH:23])=[O:22])[CH:15]=2)[N:10]=1
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCCC[C@H]2C(=O)NC(Cc2ccc3nc(-c4c(Cl)cccc4Cl)ccc3c2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 455 mg of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[({(2S)-1-[(4-methylphenyl)sulfonyl]piperidinyl}carbonyl)amino]propanoate 46 in CH3OH (5 ml) are added 0.8 ml of 1 N NaOH and 1 ml of water. The solution is stirred at RT overnight, and 1 N HCl (0.8 ml) is added to obtain a weakly acidic pH. Methanol is then evaporated, and the solid obtained is filtered, washed with water and dried to give 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-[({(2S)-1-[(4-methylphenyl)sulfonyl]piperidinyl}carbonyl)amino]propanoic acid 90.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]1[N:18]([CH3:35])[C:19](=[O:34])[C:20]([CH3:33])=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25])C(=O)OC(C)(C)C.Cl.O1CCOCC1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:17]1[N:18]([CH3:35])[C:19](=[O:34])[C:20]([CH3:33])=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: Cc1cc(NS(=O)(=O)C2(CCO)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)C2(CCO)CC2)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl (2-fluoro-4-iodophenyl)[3-({[1-(2-hydroxyethyl)cyclopropyl]sulfonyl}amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl]carbamate (324 mg, 0.521 mmol) in dry THF under a nitrogen atmosphere was added a solution of HCl in dioxane (30 eq, 3.80 ml, 15.640 mmol). The mixture was stirred at room temperature for 18 hours, after which again a solution of HCl in dioxane (8 eq, 1.01 ml, 4.055 mmol) was added and stirred for another 18 hours. The mixture was partitioned between ethyl acetate and aq. NaOH (2 N) and the aqueouse layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated in vacuo. The crude material was purified by flash chromatography to afford the title compound (172 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C(Cl)Cl>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: Clc1ncccn1
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3ncccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (300 mg, 0.62 mmol) and 2-chloropyrimidine (71 mg, 0.68) were stirred at 100° C. overnight. The reaction mixture was taken up in 1 mL methylene chloride and chromatographed on silica gel with methylen chloride/methanol/triethyl amine 90:10:1. The desired product (181 mg, 47%) was a light yellow solid, MS: m/e=564.3 (M+H+).
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH3:18][CH:19]([OH:22])[CH2:20][CH3:21]>CCC(C)=O>[Cl:9][C:6]1[C:7]([C:1]([O:22][CH:19]([CH2:20][CH3:21])[CH3:18])=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10])=[O:8]
Reactant: CCC(C)O
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC(C)OC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
Chloranil (12.3 parts) was dissolved in MEK (300 parts) before adding sodium hydrogen carbonate (8 parts). Aqueous butan-2-ol (50 parts, 1:1) was then added and the mixture was stirred at room temperature until no starting material remained. At the end of the reaction the filtered solution was shown by HPLC to contain 86% title product. The product was used in subsequent reactions without isolation.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:9])=[CH:10][CH:11]=1)#[N:2]
Reactant: CCOC(=O)CCCN
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a solution of 4-cyanobenzoic acid (2.0 g, 13.59 mmol), ethyl 4-aminobutyrate hydrochloride (2.507 g, 14.95 mmol), HOBt (0.918 g, 6.80 mmol) and TEA (6.63 mL, 47.58 mmol) in DMF (20 mL) was added WSC (3.26 g, 16.99 mmol), and the mixture was stirred at room temperature for 14 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give ethyl 4-(4-cyanobenzamido)butanoate (1.558 g, 5.99 mmol, 44.0%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[N:7][CH:8]=1)[CH3:2].[Br:11]P(Br)Br>C(Cl)(Cl)Cl>[Br:11][CH2:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: CCc1cncc(CO)c1
Solvent: ClC(Cl)Cl
Product: CCc1cncc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of (5-ethylpyridin-3-yl)methanol (3.31 g, 24.12 mmol) in anhydrous chloroform (50 mL) at 0° C. was added tribromophosphane (7.18 g, 2.49 mL, 26.54 mmol) dropwise. The reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated to provide crude 3-(bromomethyl)-5-ethylpyridine (4.82 g, 100% yield), which was used in the next step without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C@H:22]1[CH2:24][C@H:23]1[CH:25]=O)#[N:2].[CH3:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C@H:22]1[CH2:24][C@H:23]1[CH2:25][N:28]([CH3:29])[CH3:27])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc([C@H]3C[C@H]3CN(C)C)c3cc(C#N)ccc32)cc1

Procedure:
A mixture of the crude cis-2-[5-Cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropanecarboxaldehyde, dimethylamine (0.35 ml, 0.7 mmol, 2.0 M/THF), and anhydrous ethanol (10 ml) was heated with stirring until all solids were dissolved. The reaction vessel was removed from the heating source and sodium triacetoxyborohydride (300 mg, 1.41 mmol) was added. After stirring for 1 h, the solvent was evaporated. The residue was taken up in brine (10 ml) and aqueous 1N sodium hydroxide was added until solids disappeared. The aqueous layer was extracted with ethyl acetate ((4×10 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the crude cis-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]-1-(N,N-dimethylaminomethyl)cyclopropane.
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:27]([O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[C:30]([Si:27]([O:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][I:1])=[CH:40][CH:39]=1)([CH3:29])[CH3:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(CO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At 0° C., iodine (1.2 eq.) and imidazole (1.2 eq.) were added to a CH2Cl2 solution (0.05 M) of triphenylphosphine (1.2 eq.). The resulting yellow-orange suspension was stirred at 0° C. for 10 min and then at RT for 15 min. Finally, [4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]methanol from the previous step (1 eq.) was added over 30 min as a 0.2 M CH2Cl2 solution. After another 10 h of stirring at RT, the volatiles were removed in vacuo. The resulting brown residue was suspended in ether and rapidly passed through a plug of SiO2. Removal of the volatiles in vacuo afforded the title compound as a pink oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].N1CCCCC1>C1C=CC=CC=1>[C:11](/[C:12](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)/[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:17]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)/C(=C\c1ccc(F)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 4-fluorobenzaldehyde (25.5 g, 0.220 mol), methyl 3-oxobutanoate (21.80 g, 0.220 mol), and piperidine (1.0 mL) in anhydrous benzene (250 mL) was stirred for 10 minutes at room temperature and subsequently refluxed overnight in a Dean-Stark apparatus. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo to afford methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate as a black solid (48.6 g, 99%), which was used for next step without purification.