Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)[CH:3]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(-c3cccs3)c2)C1c1ccc(C#N)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidin-5-carboxylate (Example 35) (40 mg, 0.07 mmol), 2-thiophen-boronic acid (10.69 mg, 0.08 mmol), 2 M aqueous sodium carbonate (100 μl, 0.2 mmol) and bis-(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) in dimethylformamide (2.0 ml) is stirred at 90° C. overnight (16 h). Additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added, and the reaction is stirred at 90° C. for another 24 h, after which time additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added and the reaction stirred 3 h longer at 90° C. The reaction mixture is diluted with dimethylformamide (5 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The product fractions are concentrated and pulled through a thin layer of silica gel 60 with dichloromethane as eluent. Concentration in vacuo gives the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC([OH:28])(C)C.[OH-].[K+]>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([CH2:21][C:22]([NH2:23])=[O:28])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(CC#N)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(CC(N)=O)cccc21
Yield: 77 %

Procedure:
Add {1-[3-(tert-Butyldimethylsilyloxy)propyl]-1H-indol-4-yl}acetonitrile (1.9 g, 11.0 mmol) to 2-methyl-2-propanol (20 mL). Heat to reflux under nitrogen and add potassium hydroxide pellets (7.4 g, 132 mmol). Stir and reflux under nitrogen for 30 minutes. Pour solution off of the excess potassium hydroxide and dilute with ethyl acetate. Wash with a 1:1 mixture of aqueous saturated sodium chloride, aqueous saturated sodium hydrogen carbonate. Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Rinse the solid with cold diethyl ether and dry under vacuum to obtain 1.62 g (77%) of the title compound as an off-white solid. ESMS (M++1): 347.2.
Reaction SMILES: [CH:1]([CH:4]([CH:14]1[CH2:17][C:16](=[O:18])[C:15]1(Cl)Cl)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[CH:1]([CH:4]([CH:14]1[CH2:15][C:16](=[O:18])[CH2:17]1)[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(C(C)C)C(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C(C1CC(=O)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 60 °C

Procedure:
Zinc dust (25.5 g, 0.39 mol) was added to a solution of 3-(triisopropyl -siloxyethyl)-2,2-dichlorocyclobutanone (22.21 g, 65.4 mmol) in glacial acetic acid (110 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.03-1.08 (m, 21H), 1.80-1.85 (m, 2H), 2.49-2.60 (m, 1H), 2.71-2.80 (m, 2H), 3.12-3.21 (m, 2H), 3.74-3.77 (t, J=6.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 12.12, 18.22, 21.38, 39.36, 52.92, 62.37, 209.00. MS (FAB): expected for C15H30O2Si (M+H)+ 271.48. Found 271.20887. IR (neat) νmax 3053, 2925, 2866, 1778, 1462, 1265, 1103, 1013, 883, 740, 705.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(Br)c3O2)cc1
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(-c4ccccc4)c3O2)cc1
Yield: 99 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:36]4[CH:42]=[CH:43][CH:44]=[CH:45][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:36]4[CH:42]=[CH:43][CH:44]=[CH:45][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:12]1.CN1CCOCC1.Cl.[CH3:34][N:35]([CH3:52])[C:36]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:40][C:39](=[CH:42][C:43](O)=[O:44])[CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:52][N:35]([CH3:34])[C:36]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:41][CH2:40][C:39](=[CH:42][C:43]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:44])[CH2:38][CH2:37]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: NCCCCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 25 %

Procedure:
1-Hydroxybenzotriazole (819 mg, 6.0 mmol), 5-(1H-indol-3-yl)pentylamine (606 mg, 3.0 mmol) and N-methylmorpholine (0.666 ml, 6.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (887 mg, 3.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (1.25 g, 6.0 mmol) was added. The reaction mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 3 d. The crude product thereby precipitated out as a beige-coloured solid in a yield of 69% (915 mg). After chromatography on silica gel (50 mg) with EA/methanol (1:1) and methanol, the product was isolated as a colourless solid (333 mg) with an m.p. of 68-72° C. in a yield of 25%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([F:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:22].[ClH:22].[Cl:22][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:20]([F:21])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)ncc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cnc(Cl)nc1NC1CCNCC1

Procedure:
A solution of 4-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.05 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 231.1 [M+H]+.
Reaction SMILES: C(OCC)(=O)C(OCC)=O.COC1C=CC(N2CCOCC2)=CC=1N.C([O:28][C:29](=[O:47])[C:30]([NH:32][C:33]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:34]=1[O:45][CH3:46])=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:49]>C1(C)C(C)=CC=CC=1>[CH3:46][O:45][C:34]1[CH:35]=[CH:36][C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:38][C:33]=1[NH:32][C:30](=[S:49])[C:29]([OH:28])=[O:47]
Reactant: CCOC(=O)C(=O)Nc1cc(N2CCOCC2)ccc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: COc1ccc(N2CCOCC2)cc1N
Solvent: CCOC(=O)C(=O)OCC
Solvent: Cc1ccccc1C
Product: COc1ccc(N2CCOCC2)cc1NC(=S)C(=O)O
Temperature: 180 °C

Procedure:
In accordance with scheme 1, the compounds of formula I are prepared as follows: Diethyl oxalate (2) is heated to about 120° C. 2-Methoxy-5-morpholin-4-yl-phenylamine (1) is added very cautiously in small quantities and the mixture is heated for 90 minutes at about 180° C. After cooling to room temperature and filtration n-hexane is added. The resulting precipitate is collected by filtration. After washing with hexane and drying N-(2-methoxy-5-morpholin-4-yl-phenyl)-oxalamic acid ethyl ester (3) is obtained. Then, to the obtained compound of formula (3) in boiling xylene is added phosphorus pentasulfide in small portions over a period of about 30 minutes. The mixture is refluxed for about 5 hours, cooled to room temperature and filtered. The solution is extracted with 1N NaOH. The aqueous phase is washed with toluene, filtered, and treated at 0-5° C. with concentrated hydrochloric acid until pH 1 was reached. Filtration of the precipitate yielded (2-methoxy-5-morpholin-4-yl-phenylamino)-thioxo-acetic acid (4).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][P:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Agent: [Li]CCCC
Product: CC(C)(C)c1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2ccccc2C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.54 g of 4-tert-butyl-N1-(2-tert-butylphenyl)benzamidine (Amidine VII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow solid was collected and dried (2.31 g, 94%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([C:26]2[N:30]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=4[N:3]=3)[CH:29]=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: Brc1cccc(-c2ncc[nH]2)c1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3cccc(Br)c3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 26, with Intermediate C instead of Intermediate B and with 2-(3-bromophenyl)-1H-imidazole instead of 2-phenyl-1H-imidazole. LCMS: 455.0 m/z (M+H)+; ret. Time: 4.34 min (Analytical Method D).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>C(O)C>[CH3:12][NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: CNc1ccccc1CCl
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Solvent: CCO
Product: CNc1ccccc1CSc1nc2ncccc2[nH]1
Yield: 68.1 %

Procedure:
To a dispersion of 1.51 g of 2-mercaptoimidazo[4,5-b]pyridine in 25 ml of ethanol was added at once 1.92 g of 2-(methylamino)benzyl chloride hydrochloride at room temperature under stirring. The resulting mixture was further stirred for 3.5 hours. The precipitated crystals were collected by filtration and washed with ethanol. The obtained crystals were added portionwise to a mixture of 100 ml of chloroform and 100 ml of 1N NaOH solution for neutralization. The aqueous NaOH phase was separated, and to this phase were successively added 200 ml of chloroform and a saturated ammonium chloride solution until the aqueous phase showed no turbidity upon addition of the solution. The chloroform phase was separated, washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was crystallized by addition of diethyl ether. The crystalline product was collected by filtration and dried to give 1.84 g (yield: 68.1%) of 2-[2-(methylamino)benzylthio]imidazo[4,5-b]pyridine as a white crystalline powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Si]([N:18]=[C:19]=[O:20])(C)(C)C.CCN(C(C)C)C(C)C>ClCCl>[NH:1]([C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)[C:19]([NH2:18])=[O:20]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (180 mg, 1 mmol) in dichloromethane was added TMS-NCO (1 g, 8.7 mmol) and DIPEA (1.2 g, 10 mmol). The mixture was stirred at room temperature overnight, then was concentrated in vacuo. The residue was treated with EtOAc/H2O, the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title compound.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[CH3:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:32][O:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:3]
Reactant: COc1cnccc1B(O)O
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: [K+]
Solvent: CN(C)C=O
Product: CNc1cnccc1-c1ccncc1OC
Temperature: 100 °C

Procedure:
To a solution of (4-bromo-pyridin-3-yl)-methyl-amine (50 mg, 0.267 mmol, example 25, intermediate b) and 3-methoxypyridine-4-boronic acid (CAS RN 1008506-24-8) (61.35 mg, 0.4 mmol) in dry DMF (3 mL) in a sealed tube was added potassium carbonate (2.14 mmol) and the reaction mixture was purged with argon for 10 min. Then, Pd(PPh3)4 (30.89 mg, 0.03 mmol) was added and again purged with nitrogen for 15 min. The reaction mixture was heated at 100° C. for 16 hours. After cooling to room temperature the reaction mixture was filtered through a bed of celite and the filter cake washed with EtOAc. The solvent was evaporated, the residue was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulphate and evaporated to get compound that was used in next step without further purification. Brown solid (55 mg, 95%). MS (ESI): m/z=216.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[NH:7][CH:8]=1)[CH3:2].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]=[C:6]([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[N:7]([CH3:31])[CH:8]=1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(SCc2ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c2)nc1=O
Yield: 38.8 %

Procedure:
The same procedure as E64 from 5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (250 mg, 0.579 mmol), DIPEA (0.202 mL, 1.159 mmol) and MeI (0.054 mL, 0.869 mmol) in DCM (2 mL). to afford the title compound (100 mg, 38.7% yield). LCMS: rt=3.25 min, [M+H+]=446
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([CH:28]2[NH:27][C@H:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]4[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:25])[CH2:30][C@H:29]2[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: Cc1ccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: Cc1ccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)NC2C(=O)Cn2cncn2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 4, (2S,4R)-5-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): σ 9.02 (br s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.40 (m, 2H), 7.12 (d, 2H), 7.08 (d, 2H), 7.03-6.98 (m, 2H), 6.94-6.87 (m, 4H), 4.98 (dd, 2H), 4.78 (d, 1H), 3.62 (m, 1H), 3.23 (t, 1H), 3.02-2.87 (m, 2H), 2.65-2.60 (m, 2H), 2.34 (s, 3H), 1.74-1.66 (m, 1H); MS (EI) for C29H28FN5O3. found 514.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd].O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of [2-(4-nitro-phenyl)-ethyl]-carbamicacid tert-butyl ester (18.7 g, 70.30 mmol) in ethanol (200 ml) a slurry of 10% palladium on charcoal (2 g) in water (10 ml) was added. At 80° C. ammonium formate (44.3 g, 703 mmol) in water (90 ml) was added slowly. After complete addition the mixture was stirred at 80° C. for 1 h. The mixture was allowed to come to room temperature, filtered and concentrated in vacuo. The residue was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow oil (13.5 g, 81%).