Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(F)cc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)c(CBr)cc1Cl

Procedure:
A solution of 75 mmol of 1-bromo-4-chloro-5-fluoro-2-methyl-benzene, 75 mmol of 1-bromo-pyrrolidine-2,5-dione and 0.74 mmol of benzoyl peroxide in 100 ml of carbon tetrachloride is heated to reflux for 15 hours. After evaporation of the solvent, the residue is partitioned between water and ethyl acetate. The organic layer is washed with water, and then with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])(O)=[O:8].[NH4+:18].[OH-].Cl>C(Cl)Cl.CN(C=O)C>[C:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])(=[O:8])[NH2:18]
Reactant: [NH4+]
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C=O)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
Oxalyl chloride (13.3 mL, 152 mmol) and DMF (50 μL) were added to suspension of 3-carboxybenzaldehyde (11.4 g, 76.2 mmol) in 200 mL CH2Cl2 and stirred at 23° C. for 18 h. The resulting clear solution was concentrated, dissolved in 100 mL CH2Cl2, and concentrated again. The crude acid chloride was dissolved in 20 mL THF, poured into a mixture of concentrated NH4OH (26 mL, 381 mmol) with 100 mL crushed ice, and allowed to warm to 23° C. with stirring. The mixture was acidified with conc. HCl to pH ˜3, then concentrated to remove THF. The resulting aqueous suspension was filtered and the white solid product dried under vacuum to give 7.4 g (65%) of 3-carbamoyl-benzaldehyde compound 1a: 1H NMR (DMSO-d6)δ 10.06 (1 H, s), 8.40 (1 H, s), 8.19 (1 H, s), 8.17 (1 H, d, J=6.6 Hz), 8.04 (1 H, d, J=7.7 Hz), 7.69 (1 H, t, J=7.7 Hz), 7.56 (1 H, s); IR (KBr pellet) 3391, 3205, 1711, 1694, 1664, 1385, 1217. Anal. (C8H7NO2•0.1H2O) C, H, N.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[Cl:37])C=CC=CC=1.[CH3:39][N:40](C)C=O.CN.O1CCCC1>O>[CH2:30]([O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH3:39])=[O:7])=[C:11]([Cl:37])[CH:12]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[C:27]#[N:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C=O
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccnc2cc1OCc1ccccc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Reaction time: 0.17 h

Procedure:
[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro phenyl]carbamic acid phenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then a methylamine-containing 2N tetrahydrofuran solution (0.4 ml) was added and the mixture was stirred for 10 minutes. Water (15 ml) was added, and the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (968 mg)
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1.[CH3:43]C(C)=O>C(Cl)Cl>[CH3:9][CH:8]([CH3:43])[C@H:7]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([C:36](=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:35]1)=[O:12])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@H](NC(=O)c1c(CN2CCNCC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1c(CN2CCN(C(=O)CCC(=O)O)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 54 %

Procedure:
200 mg (0.42 mmol) of 2-phenyl-3-piperazin-1-ylmethylquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (compound of Description 13) were dissolved in 5 ml acetone and 42 mg of succinic anhydride were added. The mixture was then refluxed for 10 hours. After cooling the mixture was diluted with 50 ml of CH2Cl2, washed three times with 30 ml water, dried over MgSO4, concentrated to dryness. The residue was purified by flash chromatography on silicagel (CH2Cl2/MeOH: 90/10) to afford 130 mg of the title compound as white crystals (yield 54%).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH3:5])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1cccc(I)c1)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 79.4 %

Procedure:
Following General Procedure D and using cyclopropyl-(3-iodo-benzyl)-methyl-amine (Intermediate 89, 0.97 g, 3.4 mmol), triethyl amine (10 mL), copper(I)iodide (0.051 g, 0.27 mmol), trimethylsilyl acetylene (2 mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.27 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-5% ethyl acetate in hexane as the eluent, the title compound (0.695 g, 80%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:27]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[N:24][CH:23]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[CH:27]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1cncc(-c2cccc(Cl)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cncc(-c3cccc(Cl)c3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 3-Chloromethyl-5-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 131 mg (71%) of the title compound as white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:25])=[C:7]([C:9]2[N:14]=[C:13]3[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]3=[CH:11][CH:10]=2)[CH:8]=1.[C-:26]#[N:27].[K+]>CN1C(=O)CCC1>[CH3:22][C:19]([CH3:21])([CH3:20])[CH2:18][N:17]1[C:12]2[C:13](=[N:14][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][C:26]#[N:27])[CH:4]=[CH:5][C:6]=3[CH3:25])=[CH:10][CH:11]=2)[N:15]([CH3:24])[C:16]1=[O:23]
Reactant: [C-]#N
Reactant: Cc1ccc(CBr)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CC#N)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 15 h

Procedure:
To a solution of 82-1 (180 mg, 0.45 mmol) in NMP was added potassium cyanide (32 mg, 0.49 mmol), the vessel was sealed and heated to 120 C. After 15 hours, the reaction was purified by reverse phase chromatography (Sunfire C18, 40-95% CH3CN/0.1% TFA/water). Fractions containing product were partially concentrated, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give 82-2 as an oil. HRMS (M+H)+: observed=349.1, calculated=349.4.
Reaction SMILES: Cl(O)(=O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])=[CH:16][CH:15]=2)[CH:10]=[C:11]([F:13])[CH:12]=1>C(#N)C.C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH2:32][CH2:33][N:34]4[C:35](=[O:44])[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:42]4=[O:43])[C@H:24]([OH:28])[C@H:25]([OH:26])[O:31]3)=[CH:16][CH:15]=2)[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cc(F)cc(F)c4)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.3 mL) was added to a solution of the compound obtained from step b above (0.2 g) in acetonitrile (6 mL) and water (2 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated and washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.15 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([S:11][CH3:10])[N:3]=1)#[N:9]
Reactant: C[S-]
Reactant: N#Cc1cncc(Cl)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1cncc(C#N)n1
Yield: 82.7 %

Procedure:
A mixture of 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol), sodium thiomethoxide (0.78 g, 11.0 mmol) and THF (100 ml) was refluxed for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the titled compound (1.25 g, 83%) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: CCCCC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.011 g, 0.27 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (6 mL). After stirring for 10 minutes, (1-bromopentyl)benzene (0.061 g, 0.27 mmol, from Step 1) was added. After stirring for 45 minutes, the reaction was quenched by the addition of water and the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.01 g, 10%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[N:7][CH:8]=1.[O:17]=[C:18]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.[Cl-].[Li+]>O.O1CCCC1>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:6]1[N:7]=[CH:8][C:3]([CH2:2][CH:19]([C:18](=[O:17])[CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:5]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cn1
Reactant: CCCCC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Yield: 51 %

Procedure:
Process 1: Under argon atmosphere, tetrahydrofuran (900 mL) solution of 2-[5-(bromomethyl)pyridin-2-yl]benzonitrile (31.9 g, 117 mmol), methyl 3-oxoheptanoate (27.8 g, 176 mmol), diisopropylethylamine (31.0 g, 240 mmol), and lithium chloride (8.2 g, 193 mmol) was refluxed under heating for 23 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (hexane/ethyl acetate=2:1) to give methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (20.9 g, 51%) as brown oil.
Reaction SMILES: C([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](C#N)[CH:17]=1)(=O)C.[OH-:25].[K+].[CH2:27]([OH:29])C>O>[NH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:27]([OH:29])=[O:25])[CH:17]=1
Reactant: [OH-]
Reactant: CCO
Reactant: CC(=O)Nc1c(C(=O)c2cccc(C#N)c2)[nH]c2cc(Cl)ccc12
Agent: [K+]
Solvent: O
Product: Nc1c(C(=O)c2cccc(C(=O)O)c2)[nH]c2cc(Cl)ccc12
Yield: 72 %

Procedure:
A mixture of 3-acetylamino-6-chloro-2-(3-cyanobenzoyl)indole (Example 130, 2.7 g, 7.99 mmol) and potassium hydroxide (2.2 g, 40 mmol) in ethanol (100 ml) and water (100 ml) was heated at reflux for 5 h. The mixture was cooled and concentrated, and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was separated and acidified with 2N aqueous hydrochloric acid, extracted with ethyl acetate (100 ml×2) and the combined extracts dried (MgSO4). After removal of solvent the residual solids were recrystallization from ethyl acetate to afford 1.8 g (72%) of the title compound as brown solids.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:14]=3)[CH:10]=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=2)[CH:6]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[F:28][C:25]([F:26])([F:27])[CH2:24][O:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:29]([F:31])([F:30])[F:32])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:37]4[CH:38]=[CH:39][C:34]([NH2:33])=[N:35][CH:36]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.54) (0.268 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.056 g, 20%). MS (ISP) 549.2 [(M+H)+]; mp 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36].C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)c[nH]c12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c(C#N)c[nH]c12
Reaction time: 1 h
Yield: 94.2 %

Procedure:
(±)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (70 mg, 0.137 mmol) was stirred in TFA (2 mL, 26.0 mmol) at 0° C. for 20 minutes. The solvent was evaporated at a bath temperature of 23° C. The residue was taken up in Ethanol (5 mL), then triethylamine (1 mL), formaldehyde (0.102 mL, 1.367 mmol) and sodium triacetoxyborohydride (87 mg, 0.410 mmol) were added. The reaction was stirred 1 hour, then solvent was evaporated. The residue was taken up in aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (4×10 mL). The organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane to give (±)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile (55 mg, 0.129 mmol, 94% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=2.8 Hz, 1H), 7.08 (t, J=8.5 Hz, 2H), 6.93 (d, J=1.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 4.55 (m, 1H), 3.19 (d, J=8.6 Hz, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.35 (m, 1H), 1.95-2.20 (m, 2H), 1.86 (m, 1H), 1.48 (m, 1H), 1.41 (d, J=6.5 Hz, 3H). LC/MS (HPLC method 4): tR=2.84 min, 426.14(MH)+.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[CH:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N+](C1C=CC([O:48][C:49](=O)[NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=CC=1)([O-])=O.O>CN(C)C=O>[N:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:49]([N:27]1[CH2:28][CH2:29][CH:24]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:25][CH2:26]1)=[O:48]
Reactant: c1ccc(COc2ccc(C3CC[NH2+]CC3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccn1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 3.3 %

Procedure:
0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium chloride is suspended in 5 ml of dimethylformamide and then 0.43 ml of N,N-diisopropylethylamine is added, as is 0.38 g of pyridin-2-ylcarbamic acid 4-nitrophenyl ester in solution in 2 ml of dimethylformamide. The reaction mixture is stirred for 24 hours at 80° C. It is heated at 80° C. for 24 hours. 50 ml of water are added, and the reaction mixture is then extracted with 50 ml of ethyl acetate. The solvents are evaporated off and then the residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 20 mg of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid pyridin-2-ylamide are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:31]2[O:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)[CH:13]=[CH:14][C:15]=1[NH:16][C:17]([C:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:20]=1)=[O:18])#[N:9].[OH-].[Na+]>O.C(#N)C>[C:8]([C:10]1[CH:11]=[C:12]([CH:31]2[O:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH:13]=[CH:14][C:15]=1[NH:16][C:17]([C:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[N:20]=1)=[O:18])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)c3ccn(-c4ccc(F)cc4)n3)c(C#N)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(C2CNCCO2)ccc1NC(=O)c1ccn(-c2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a stirred solution of trifluoroacetic acid (84 μl) in water (4.5 ml) was added a solution of tert-butyl (RS)-2-(3-cyano-4-(1-(4-fluorophenyl)-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (41 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2; gradient: 0% to 10% methanol in dichloromethane) to afford (RS)—N-(2-cyano-4-(morpholin-2-yl)phenyl)-1-(4-fluorophenyl)-1H-pyrazole-3-carboxamide (20 mg, 61%) as a white solid. MS (ISP): 392.2 ([M+H]+).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH3:25])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:25][C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1
Reactant: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 76.5 %

Procedure:
Trichloromethyl chloroformate (6.37 g, 32.19 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-1-propanol (10) (6.65 g, 29.26 mmol) and triethylamine (6.31 g, 62.3 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 5 h at the same temperature, poured into a brine solution (150 ml), and diluted with more dichloromethane. After collecting insoluble impurities through the Buchner funnel, the organic layer was separated and the aqueous layer was washed once with a mixture of dichloromethane and AcOEt. The combined organic extracts were dried over MgSO4/K2CO3 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether, water, AcOEt and diethyl ether again, to obtain the title compound (11) (5.67 g, 76%) as a white solid. m.p. 264–266° C. [α]D25=−279.71° (c, 0.0414 in DMSO). δH 0.82 (3H, d, 3J=6.30 Hz, CH3), 4.65 (1H, q, 3J=6.0 Hz, CH—NH2), 7.10–7.70 (10H, m, Ar—H), 7.93 (1H, broad s, NH). δC 19.6 (CH3), 55.9 (CH—NH2), 85.6 (C—O), 126.3, 126.4, 128.1, 128.6, 128.8 and 129.1 (o-, m- and p-Ar), 140.6 and 144.2 (α-Ar), 157.6 (C═O). ir 3254 (NH), 1745 and 1725 (C═O). m/e (CI—NH3) 254 (MH+, 9%), 271 (MNH4+, 55%), 52 (100%).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].O.Cl>CCO.ClCCl>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: OCc1cccc(O)c1
Reaction time: 0.12 h

Procedure:
NaBH4 (775 mg, 20.5 mmol) is gradually added to a solution of 3-hydroxybenzaldehyde (5 g, 40.9 mmol) in EtOH (25 mL) while cooling the reaction mixture with cold water. This mixture is stirred for 5-10 min at the same temperature. And then dichloromethane (DCM) (100 mL) is added followed by a 2M HCl aqueous solution (until pH ˜3). The organic phase is separated and the final product is extracted 4 times from the aqueous phase with a EtOH/DCM mixture in the proportion of 1:3. The collected organic phases are dried on Na2SO4. After evaporation of the solvents under reduced pressure, a viscous colorless oil is obtained (4.9 g, 97%), which gradually crystallizes.