Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>C(Cl)Cl.O1CCCC1.O.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:6][CH:5]=[CH2:4])=[CH:12][CH:11]=2)([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:7][CH:2]=[CH2:3])=[CH:21][CH:22]=2)[CH3:9])=[CH:4][CH:3]=1)[CH:27]=[CH2:28]
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(C(C)(c2ccc(OCC=C)cc2)c2ccc(OCC=C)cc2)cc1
Reaction time: 36 h

Procedure:
In a 500 mL three neck-round bottom flask equipped with condenser, magnetic stirring bar, dropping funnel, and Argon inlet, 15.00 g (49 mmol) of 1,1,1 tris(4-hydroxy-phenyl) ethane was dissolved in a 1:1 mixture of methylene chloride and tetrahydrofuran. To this mixture, a solution of sodium hydroxide 10.70 g (267 mmol) dissolved in 60 mL of distilled water was added while vigorously stirring. Allyl bromide, 33.36 g (276 mmol) was added followed by 2.5 g (5.96 mmol) tetraphenylphosphoniumbromide catalyst. The reaction mixture was left under positive pressure of Argon while stirring at room temperature. The reaction was monitored by TLC and stopped after 36 hours. The reaction mixture was transferred into separatory funnel and the product was extracted twice with 200 mL of methylene chloride. The organic layers were combined and extensively washed several times with distilled water. The organic extract was dried over anhydrous magnesium sulfate and filtered using Whattman filter paper. To this filtrate, activated charcoal was added and the mixture was stirred for 12 h. The charcoal was filtered and the solvent was evaporated using rotary evaporator. The resulting viscous compound was purified through column chromatography using silica as stationary phase and methylene chloride as an eluent. The solvent was removed using rotary evaporator to yield 14.50 g (70%) of clear, colorless, viscous liquid of 1,1,1 tris (4-allyloxy-phenyl) ethane. 1H NMR and IR spectra were consistent with 1,1,1 tris (4-allyloxy-phenyl) ethane. 1H NMR (CDCl3): 4.58 (m, CH2O, 6H), 2.17 (s, —CH3), 5.2 (m, ═CH2, 6H), 6.1 (m, ═CH, 3H), 6.81 (dd, 6 aromatic H ortho to OR), 7.03 (dd, 6 aromatic H meta to OR). IR (NaCl): Major bands at 1293 cm−1 (aromatic ether), 2912 cm−1 (aliphatic hydrocarbon), and 1648 cm−1 (unsaturated hydrocarbon).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[OH:45][C:46]([CH3:51])([CH3:50])[C:47](O)=[O:48].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:51])([OH:45])[CH3:50])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a dichloromethane to methanol-dichloromethane 1:19 gradient to give 1-(4-(1,3-benzodioxol-5-yl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2-methyl-1-oxopropan-2-ol as a solid (0.10 g, 44%). HRMS C33H42N4O4 m/z 559.3284 (M+H)Cal. 559.3276 (M+H)Obs..
Reaction SMILES: [Na].[OH:2][C:3]1(C2C=CC=CC=2)[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:23](Br)([CH3:25])[CH3:24]>C(O)C>[C:23]1([C:4]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3](=[O:2])[NH:7][C:6]([S:8][CH:11]([CH3:16])[CH3:12])=[C:5]2[C:9]#[N:10])[CH:25]=[CH:5][CH:4]=[CH:3][CH:24]=1
Reactant: CC(C)Br
Reactant: N#CC1=C(c2ccccc2)C(O)(c2ccccc2)NC1=S
Agent: [Na]
Solvent: CCO
Product: CC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Reaction time: 0.33 h

Procedure:
1.2 g. Sodium is dissolved in 150 ml. ethanol, 15.2 g. 5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are added thereto and the reaction mixture is then boiled for 20 minutes. A solution of 7.0 g. isopropyl bromide in 25 ml. absolute ethanol is then added dropwise thereto within the course of 10 minutes and refluxing continued for a further 3 hours. After cooling, the solvent is stripped off on a rotary evaporator and the residue is triturated with 100 ml. water. The precipitate is filtered off with suction and crystallised from ethanol. There are obtained 11.1 g. (64.0% of theory) of the desired product in the form of colourless crystals; m.p. 160° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9](I)[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cu][C:20]#[N:21]>CN1C(=O)CCC1>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([C:20]#[N:21])[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc2c(I)cc(C(=O)OC)cc21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCCn1ccc2c(C#N)cc(C(=O)OC)cc21
Temperature: 150 °C
Yield: 47.4 %

Procedure:
To a mixture of methyl 1-butyl-4-iodo-1H-indole-6-carboxylate (EXAMPLE SP-218, Step 4) (1.47 g) in N-methyl pyrrolidinone (15 mL) was added copper (I) cyanide (1.1 g). The mixture was heated to 150° C. for 6 h, removed from heat and cooled to room temperature. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was washed three times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 20% ethyl acetate as eluent to give 0.5 g of the title compound: 1H NMR (CDCl3) δ 0.955, 1.32, 1.85, 3.98, 4.23, 6.76, 7.43, 8.16, 8.30.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:39]=[CH:38][C:20]4[C:21](=[O:37])[C:22]5[N:26]=[N:25][N:24](CC6C=CC(OC)=CC=6)[C:23]=5[O:36][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:39]=[CH:38][C:20]4[C:21](=[O:37])[C:22]5[NH:26][N:25]=[N:24][C:23]=5[O:36][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nnc3c(=O)c4ccc(OCCCN5CCN(Cc6ccc(Cl)cc6)CC5)cc4oc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2oc2nn[nH]c12
Yield: 25.3 %

Procedure:
6-{3-[4-(4-Chlorobenzyl)-1-piperazinyl]propoxy}-3-(4-methoxybenzyl)-9-oxo-9H-benzopyrano[2,3-d]-1,2,3-triazole (100 mg) was stirred at 40° C. in trifluoroacetic acid (2 ml) for 1.5 hours and the resulting solution was evaporated to dryness in vacuo. Water was added to the residue followed by dilute aqueous sodium bicarbonate to pH 7. The supernatant was decanted and the residual yellow gum washed by decantation with water. After drying the product was boiled with ethyl acetate to give 20 mg (25%) of title compound of mp 215°-216° C., identical spectroscopically with that prepared in EP No. 34,004.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:19])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)[O-].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]#[N:37])([O-:29])=[O:28]>>[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[N:37][C:11]1[CH:12]=[C:13]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:14]=[C:9]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)([CH3:8])[CH3:7])[C:10]=1[OH:19])([O-:29])=[O:28]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Reactant: N#[N+]c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Product: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
The title compound is prepared according to the method given in Example 12 using 45 g of 2-(4-chloro-α-cumyl)-4-tert-butylphenol prepared in Example 5 and 161 g of the diazonium salt solution (ca. 23%) prepared in Example 10. The desired compound is prepared in a yield of 70 g as a crimson viscous oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:18][CH:19]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(OCCCCN2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1ccc(OCCCCN2CCOCC2)cc1
Yield: 88 %

Procedure:
According to a similar manner as that in Reference Example 78, 4-(4-morpholinobutoxy)benzonitrile obtained above was reduced by lithium aluminium hydride to give the title compound (88%). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH2:10][CH3:11]>>[CH2:9]([O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:10][CH3:11]
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1
Product: CCCOc1cccc(-c2ccc(N)cc2)c1
Yield: 72.5 %

Procedure:
The title compound (280 mg) was prepared from 4-bromoaniline (300 mg, 1.7 mmol) and 3-propoxyphenylboronic acid (408 mg, 2.3 mmol) as a colourless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Cl)[CH2:26][CH:27]=[CH2:28]>>[CH2:28]([N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[CH2:27][CH:26]=[CH2:25]
Reactant: C=CCCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: C=CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 46.4 %

Procedure:
The title compound (0.028 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-but-3-enyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C17H22ClN3O, 301.13; found, m/z 302.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.40-7.37 (m, 2H), 7.31-7.28 (m, 2H), 6.75-6.67 (m, 1H), 5.02-5.00 (br m, 2H), 4.07 (t, J=7.3 Hz, 2H), 2.99-2.97 (br m, 2H), 2.91-2.89 (br m, 2H), 2.80-2.78 (br m, 2H), 2.71-2.69 (br m, 2H), 2.48 (q, J=7.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]=[CH:23][C:22]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCO4)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4occc4c3O2)cc1

Procedure:
A solution of 0.54 g (0.67 mmole) of (2R)-2,3,8,9-tetrahydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 0.46 g (2.0 mmole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 20 ml of benzene was refluxed under nitrogen for 15 hours. The solvent was removed in vacuum and the residue column chromatographed on silica gel with methylene chloride as eluant. The product fractions were combined and concentrated in vacuum to give 0.40g of the (R)-enantiomer of the of the title compound as a tan solid. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.52 δ (1H); doublet 7.3 δ (2H); doublet 6.95 δ (1H); doublet 6.8 δ (1H); doublet 6.65 δ (1H); multiplet 4.5 δ (1H); multiplet 4.25 δ (3H); doublet of doublets 4.1 δ (1H); singlet 2.4 δ (3H).
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[N:9]=[C:8]([CH:10]=[CH:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([N:4]([C:5]2[N:9]=[C:8]([CH2:10][CH2:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH3:24])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)n2nc(CCc3nc(N(C)C4CC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
N-cyclopropyl-5-(2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)vinyl)-N,1-dimethyl-1H-1,2,4-triazol-3-amine (10 mg, 30.8 μmol, Eq: 1.00) was stirred in Ethyl acetate (6 ml) using 5% Pd on Ba2SO4 (3 mg, 30.8 μmol, Eq: 1.00) as catalyst in a hydrogen atmosphere. The mixture was stirred at room temperature for 4 h. No reaction. Palladium on activated charcoal 10% (5 mg, 30.8 μmol, Eq: 1.00) was added an stirring was continued for 4 h. TLC showed new product but still starting material left. Palladium on activated charcoal 10% (4 mg, 30.8 μmol, Eq: 1.00) was added and stirring was continued for 4 h again. TLC showed nearly complete conversion. The crude material was applied on silica gel an purified by column chromatography using ethyl acetate/methanol (0-5% methanol) as eluent to give Cyclopropyl-{5-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (8.4 mg, 83.5%) as off-white semisolid.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4]>CC(C)=O>[OH:15][C:9]1[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[NH2:1])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 60 °C

Procedure:
Ammonia gas was bubbled through a solution of 107 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 250 ml acetone at 0° C. for 2 h. Argon gas was then bubbled through the reaction mixture for 1 h to purge excess ammonia. The mixture was then diluted with water, the pH adjusted to pH 14 by addition of 5 M aq NaOH solution, and the mixture was then extracted with ether/ethyl acetate (1:1). The aqueous phase was acidified with concentrated HCl, saturated with NaCl, and extracted twice with THF. The combined THF extracts were dried with Na2SO4. Evaporation of the solvent in vacuo followed by drying of the residue by heating at 60° C. overnight in vacuo yielded the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:30])OCC(Cl)(Cl)Cl)[C:4]=1[CH3:31])[CH3:2].[NH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[CH2:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23]([NH:32][CH2:33][CH2:34][OH:35])=[O:30])[C:4]=1[CH3:31])[CH3:2]
Reactant: CCc1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: NCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
Using 2,2,2-trichloroethyl (7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 139 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 57%. Melting point: 147-148° C. (hexane-ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].CN([CH:14]=[O:15])C>C1COCC1>[CH:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10])=[O:15]
Reactant: CN(C)C=O
Reactant: Cc1cc(C#N)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C=O
Temperature: -50 °C

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (20 g, 102 mmol) in THF (500 mL) at −100° C. was slowly added a solution of n-Buli 1.6M in hexanes (70 mL, 112 mmol). DMF (11 mL, 143 mmol) was then added and the mixture was allowed to warm to −50° C. over 30 min. The reaction mixture was quenched with brine. The reaction mixture was diluted with EtOAc and extracted with brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 80:20) the residue was triturated in Et2O/hexane 90:10 to afford the title compound. tR: 0.86 min (LC-MS 2); Rf=0.40 (hexane/EtOAc, 8:2).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:21]I>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:21])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Nc2nc(C)nc3ccccc23)cc1
Reactant: CI
Product: CCc1ccc(N(C)c2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine (122 mg, 0.46 mmol) and methyl iodide (0.2 ml, 3.25 mmol) by a procedure similar to example 36. 1H NMR (CDCl3): 7.74 (d, J=8.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61 (s, 3H), 2.73-2.63 (m, 5H), 1.26 (d, J=7.5 Hz, 3H).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CCCN1C(=O)CCS

Procedure:
1-(3-Acetylthiopropanoyl)-L-proline (0.8 g.) is dissolved in 5.5 N methanolic ammonia (5 ml.) and the solution kept under argon at room temperature. After 2 hours the solvent is removed in vacuo, the residue is dissolved in water and applied to an ion exchange column on the H+ cycle [Dowex 50(Analytical grade)] and eluted with water. The fractions that give thiol positive reaction are pooled and concentrated to dryness, yield 0.6 g. This product is crystallized from ethyl acetate-hexane as in Procedure A to obtain 1-(3-mercaptopropanoyl)-L-proline.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 43 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (78.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (50.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 493; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br. s), 8.20-8.17 (1H, m), 8.11 (1H, br. s), 7.81 (1H, m), 7.70 (1H, m), 7.57 (1H, m), 4.25 (2H, m), 3.37-3.35 (2H, d), 3.32 (2H, s), 3.18 (3H, s), 1.35-1.32 (3H, t), 1.14 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N12CN3CN(CN(C3)C1)C2.FC(F)(F)[C:24](O)=[O:25]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:25])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(Br)cc(C(=O)O)c1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
36 g (0.17 mol) of 5-bromo-2-hydroxy-benzoic acid was dissolved in 500 mL of trifluoroacetic acid. 112 g (0.80 mol) of 1,3,5,7-tetraaza-tricyclo[3.3.1.13,7]decane (urotropine) was added and the resulting mixture heated to 100° C. for 23 h. The reaction mixture was concentrated to half its volume and the residual liquid poured into 1.8 L of dilute aqueous hydrochloric acid and stirred for 8 h at ambient temperature. The resulting precipitate was filtered off and crystallized from aqueous ethanol to afford 20.3 g (82.9 mmol, 50%) of 5-bromo-3-formyl-2-hydroxy-benzoic acid a pale yellow crystalline solid. 1H-NMR (500 MHz, d6-DMSO): δ 10.29 (s, 1H), 8.13 (d, 1H), 7.95 (d, 1H); MS: m/z 242.9+244.9 (M−H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[S:54][CH:55]=[C:56]([CH2:58][S:59][C:60]3[C:65]([C:66]#[N:67])=[C:64]([C:68]4[CH:73]=[CH:72][C:71]([O:74][CH2:75][CH2:76]O)=[CH:70][CH:69]=4)[C:63]([C:78]#[N:79])=[C:62]([N:80]4[CH2:84][CH2:83][CH2:82][CH2:81]4)[N:61]=3)[N:57]=2)=[CH:49][CH:48]=1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([O:13][CH2:76][CH2:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([C:64]2[C:63]([C:78]#[N:79])=[C:62]([N:80]3[CH2:81][CH2:82][CH2:83][CH2:84]3)[N:61]=[C:60]([S:59][CH2:58][C:56]3[N:57]=[C:53]([C:50]4[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][CH:51]=4)[S:54][CH:55]=3)[C:65]=2[C:66]#[N:67])=[CH:73][CH:72]=1)=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
218 mg (1.15 mmol) of N-(tert-butoxycarbonyl)-L-alanine were initially charged in 5 ml of DMF. 240 mg (1.254 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 240 mg (1.568 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 0.455 ml (2.613 mmol) of N,N-diisopropylethylamine were added, 300 mg (0.523 mmol) of 2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitrile (Example 1) were then added and the mixture was stirred at RT overnight. The reaction mixture was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 382 mg (98% of theory) of the target compound.