Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][OH:19]>>[CH2:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:16][CH2:17][CH2:18][OH:19])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: OCCCBr
Product: OCCCOc1ccccc1Cc1ccccc1

Procedure:
By using 2-hydroxydiphenylmethane and 3-bromopropanol, the title compound was obtained as colorless oil by similar procedures to those of Example 60b (yield: 28%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([NH2:15])=[O:13]
Reactant: CN(C)C=O
Reactant: O=C(O)c1sc2cnccc2c1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1sc2cnccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) mixture of 3-bromothieno[2,3-c]pyridine-2-carboxylic acid (50 mg, 0.19 mmol), DCM (1 mL) and DMF (10 μL, 0.1 mmol) was added oxalyl chloride (29 μL, 0.34 mmol). The ice bath was removed and the mixture was stirred at room temperature for 1 h. Oxalyl chloride (29 μL, 0.34 mmol) was added again and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and THF (1 mL) was added. Ammonium hydroxide (0.7 mL, 20 mmol) was added to the mixture and stirred at room temperature for 1 h. The precipitate was filtered and washed with DCM and used without further purification. 1H NMR (400 MHz, CD3OD): δ 9.20-9.27 (m, 1 H), 8.61 (d, J=5.8 Hz, 1 H), 7.89 (dd, J=5.7, 0.9 Hz, 1 H); MS (ESI): 257.33, 259.35 [M+H]+; HPLC tR=0.52 min (HPLC: Analytical—2 min).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:18]1[CH:19]=[C:20]([CH3:28])[C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1>>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:18]1[CH:19]=[C:20]([CH3:28])[C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1)[CH3:16]
Reactant: Cc1nc2c(C)cc(Cl)nn2n1
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Product: CCC(CC)(COc1cc(C)c2nc(C)nn2n1)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19].[OH-].[Na+].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19]
Reactant: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)OC)nc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)O)nc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of methyl 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (475 mg) in 1,4-dioxane was added 1N aqueous sodium hydroxide solution, and the mixture was heated to 60° C. and stirred for 30 min. It was air cooled and adjusted to pH 4 by dropwise addition of 1N hydrochloric acid. Water (25 ml) was added and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure at 60° C. Thereto was added acetonitrile (3 ml) and the mixture was heated and stirred at room temperature. The crystals were collected by filtration and dried under reduced pressure at 60° C. to give 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as thin yellow crystals (426 mg).
Reaction SMILES: [NH:1]([C:8]([CH2:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:14][CH2:13]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[NH:1]([C:8]([CH2:10][NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[CH2:16][CH2:17]1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(CNC1CCN(CCCC(O)c2ccccc2)CC1)Nc1ccccc1

Procedure:
4-Anilinocarbonylmethylamino-1-(4-phenyl-4-oxobutyl) piperidine may be reduced using sodium borohydride to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
4-(trifluoromethyl)phenylboronic acid (319 mg, 1.68 mmol), 2,4-dichloropyrimidine (250 mg, 1.68 mmol), Na2CO3 (445 mg, 4.20 mmol) and Pd(PPh3)4 (97.0 mg, 0.0839 mmol) were combined in a 5 mL reaction vial and diluted with toluene (3 mL) and water (300 μL). The reaction was purged with argon, heated to 60° C. and stirred overnight. The reaction was loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to yield the desired compound (120 mg, 0.464 mmol, 27.6% yield).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:59][O:60][C:61]([C:63]1[C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]=2[CH:66]=[CH:65][CH:64]=1)=[O:62]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:59][O:60][C:61]([C:63]1[C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[N:68]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=3)[C:67]=2[CH:66]=[CH:65][CH:64]=1)=[O:62]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)c1cccc2[nH]c3ccccc3c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)c(F)c1
Yield: 81.1 %

Procedure:
0.43 g of 4-bromo-2-fluorobenzonitrile, 2.2 g of caesium carbonate, 0.12 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 0.04 g of palladium acetate are added successively to a solution of 0.40 g of 9H-carbazole-4-carboxylic acid methyl ester, obtained according to stage 2 of Example 1, in 30 ml of dioxane under an inert argon atmosphere. The reaction mixture is refluxed for 3 hours, and then cooled, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of heptane and ethyl acetate (96/4 by volume), so to give 496 mg of 9-(4-cyano-3-fluorophenyl)-9H-carbazole-4-carboxylic acid methyl ester, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.Cl[CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH3:28][C:14]1[N:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[S:17][C:13]=1[CH2:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 44 %

Procedure:
A mixture of 4-hydroxyindole (100 mg, 0.75 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (219 mg, 0.75 mmol; PCT Int. Appl. (2002), WO 0262774 A1), cesium carbonate (489 mg, 1.5 mmol) and a trace of potassium iodide were suspended in acetone (10 ml). The suspension was stirred at ambient temperature for 14 h, the solvent evaporated under reduced pressure and the residue dissolved in 1 N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 130 mg (0.33 mmol, 45%) of the title compound as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(=O)Cl
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-2-methoxybenzoic acid (1.0 g, 5.36 mmol) in toluene (10 ml) was added thionyl chloride (2.76 ml, 37.52 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 80° C. for 1 h. After the completion of the reaction (TLC monitoring), the solvent was evaporated under vacuum and was carried forward as such for the next step.
Reaction SMILES: C(OC([N:8]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:17]1=[O:37])C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:8][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:17]1=[O:37]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Yield: 0.1 %

Procedure:
A solution of di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate (0.481 g, 0.895 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (3 mL). After 1 h the reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2×). The organic washes were combined, dried over magnesium sulfate, and concentrated to afford the title compound (0.30 mg). MS 338.2 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:45]I>CC#N.O>[I:45][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCCO)c2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1cc(CCCI)c2ccccc21
Reaction time: 3 h

Procedure:
To a stirring solution of tert-butyl 3-(3-hydroxypropyl)-1H-indole-1-carboxylate in MeCN were added imidazole (44 mg), PPh3 (129 mg) and iodine (124 mg) at ambient temperature. After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=15:1) to give tert-butyl 3-(3-iodopropyl)-1H-indole-1-carboxylate (63 mg).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]([F:24])([F:37])[F:36])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4OC(F)(F)F)c3c2CC1
Yield: 29.4 %

Procedure:
3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (4.00 g, 10.8 mmol) was suspended in benzene (170 mL). 2-(Trifluoromethoxy)phenylboronic acid (4.48 g, 21.7 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.433 g, 0.617 mmol) and 2M Na2CO3 (17.6 mL) were added to the reaction mixture. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated at reflux for 11 h. After cooling, the reaction mixture was concentrated. The residue was combined with EtOAc (250 mL) and H2O (400 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (7.95 g) was recrystallized from CH3OH to yield 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.43 g). The crude product from the mother liquors was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to give 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.21 g). The yield of the reaction was 87%. IR (diffuse reflectance) 3266, 3227, 3187, 1615, 1574, 1498, 1483, 1464, 1428, 1382, 1354, 1334, 1323, 1288, 1253, 1221, 1202, 1167, 926, 790, 767, 750, 732, 704, 626 cm−1; MS (ESI+) for C26H21F3N2O2 m/z 450.9 (M+H)+; Anal. Calcd for C26H21F3N2O2: C, 69.32; H,4.70; N, 6.22; found: C, 69.25; H, 4.78; N, 6.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]([C:20](=[O:21])[CH2:19][Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Nc2c(C)cc(F)cc2Cl)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)CCl)c2c(C)cc(F)cc2Cl)cc1

Procedure:
1.32 g of N-(2′-Chloro-4′-fluoro-6′-methylphenyl)-4-methylaniline is reacted with chloracetylchloride (1.76 g) at 90° C. for 30 minutes. The cooled mixture is stirred with toluene (20 ml) and aqu. sodium carbonate for 30 minutes and the organic phase is evaporated. The residue is purified flash-chromatography on silica using toluene affording 1.04 g of N-(2′-chloro-4′-fluoro-6′-methylphenyl)-N-chloroacetyl-4-methylaniline as a solid which is recrystallised from heptane/2-propanol (9:1), mp.: 96-97° C.
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[SH:10][C:11]1[N:15]=[CH:14]N[N:12]=1.N>ClCCl>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[CH:14]=[N:15][C:11]([S:10][Si:4]([CH3:7])([CH3:6])[CH3:5])=[N:12]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Sc1nc[nH]n1
Agent: N
Solvent: ClCCl
Product: C[Si](C)(C)Sc1ncn([Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 134.4 %

Procedure:
1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole was prepared by adding 29.2 ml (140 mmoles) of hexamethyldisilazane to a refluxing suspension of 9.70 g (96 mmoles) of 3-mercapto-1H-1,2,4-triazole and 100 mg (0.25 mmole) of di-4-nitrophenyl-N-(4-toluenesulfonyl)-phosphoramidate in 200 ml of dichloromethane and the calculated amount of ammonia was evolved after refluxing for 75 minutes. Refluxing was continued for 30 minutes and then the clear solution obtained was evaporated to dryness to obtain 23.1 g (98% yield) of 1-trimethylsilyl-3-trimethylsilylthio-1H-1,2,4-triazole melting at 90°-94° C.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.Cl.Cl.[NH2:29][CH:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.C(N(CC)CC)C>>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[CH:30]([NH:29][CH2:2][C:3]1[NH:4][C:5]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=4)[N:8]=[C:7]([C:24]#[N:25])[C:6]=3[N:26]=1)[CH2:31]2
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2cc3[nH]c(CNC4CN5CCC4CC5)nc3c(C#N)n2)cc1C(F)(F)F
Yield: 52.4 %

Procedure:
A solution of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.06 mmol), 3-aminoquinuclidine dihydrochloride (22.9 mg, 0.12 mmol) and triethylamine (18.2 mg, 0.18 mmol) in dimethylsulfoxide(500 μL) was heated in the Creator microwave at 120° C. for 5 minutes. The mixture was filtered and purified by preparative HPLC to afford 2-[(1-aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (14.8 mg) 1H NMR (MeOD) δ 8.34-8.27 (m, 3H) 7.29 (d, 2H) 4.95 (s, 2H) 4.29-4.21 (m, 3H) 4.00 (m, 1H) 3.86-3.69 (m 5H) 2.46 (m, 1H) 2.27-2.10 (m, 4H) 1.45 (t, 3H). MS m/z 471.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][C:29](=[O:36])[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][C:29]([N:30]2[CH2:35][CH2:34][N:33]([C:4](=[O:6])[C:3]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=3[Br:1])[CH2:32][CH2:31]2)=[O:36])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(OCc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
2-Bromo-5-methoxy benzoic acid (121 mg, 0.53 mmol) was added to 4-benzyloxy-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamide (155 mg, 0.44 mmol) in DMF (5 mL). EDCI.HCl (126 mg, 0.66 mmol), HOBT (71 mg, 0.53 mmol) and DIPEA (227 μL, 1.32 mmol) were added and the resulting mixture was stirred at room temperature for 4 hours. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified twice by column chromatography using (i) silica gel of mesh size of 60-120 and 70:30 EtOAc:Hexane as the eluent (1st purification) and (ii) neutral alumina and 65:35 EtOAc:Hexane as the eluent (2nd purification) to afford 4-benzyloxy-N-{2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide in 43% yield. LC-MS purity: 99.6%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.5 (m, 6H), 7.2 (s, 1H), 7 (d, 2H), 6.8 (d, 2H), 5.2 (s, 2H), 4.4 (d, 2H), 4 (m, 2H), 3.8 (s, 3H), 3.7 (t, 3H), 3.6 (t, 2H), 3.5 (m, 2H), 3.3 (m, 1H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37]([NH:39][C@@H:40]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C:41]([OH:43])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C@:51]12([CH3:61])[C:57]([CH3:59])([CH3:58])[CH:54]([CH2:55][CH2:56]1)[CH2:53][CH:52]2[NH2:60]>CN(C=O)C>[C:32]([O:36][C:37](=[O:38])[NH:39][C@H:40]([C:41](=[O:43])[NH:60][C@H:52]1[CH2:53][C@@H:54]2[C:57]([CH3:59])([CH3:58])[C@@:51]1([CH3:61])[CH2:56][CH2:55]2)[CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
3.53 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 mmol, 1.0 equiv.), 1.25 g of 1-hydroxybenzotriazole (9.2 mmol, 0.5 equiv.) and 7.3 ml of Hünig's base were added to a solution of 5.0 g of (S)-2-tert-butoxycarbonylamino-3-cyclohexylpropionic acid (Boc-Cha-OH, 18.4 mmol, 1.0 equiv.) in DMF (60 ml) at 0° C. under argon, and the mixture was stirred for 30 min. Then 2.83 g of (R)-(+)-bornylamine (18.4 mmol, 1.0 equiv.) and 3.7 ml of Hünig's base were added, and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO3 (saturated, aq.) and extracted three times with ethyl acetate. The combined organic phases were washed twice with water and dried over Na2SO4 and concentrated. Purification by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent afforded 6.58 g (88% yield) of the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:11][CH2:12][CH2:13][CH2:14]Br.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH2:6][CH2:5][N:4]([CH2:14][CH2:13][CH2:12][Br:11])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: BrCCCBr
Reactant: c1ccc2c(c1)NCCS2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCCN1CCSc2ccccc21
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1.0 eq, 13.24 mmol), 1,3-dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrous Na2CO3 (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as yellow oil (2.13 g, 59% yield).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:2]
Reactant: CCNCC
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Diethylamine(1.2 mmol) and 2-[(5-chloro-1H-indol-2-carbonyl)-amino]3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. for 5 days) substituting the following workup: the crude product was suspended in 1:1 chloroform/dichloromethane, sonicated, filtered to remove solids, concentrated, and the residue purified by column chromatography on silica gel eluted with 10, 20 and 30% ethyl acetate in hexanes: Yield 14 mg, 6%; HPLC (60/40) 8.88 minutes (98%); PBMS 398/400 (MH+, 100%);