Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@H:38]([C:49](O)=[O:50])[CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:49]([C@@H:38]([NH:37][S:34]([C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)(=[O:35])=[O:36])[CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)=[O:50])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-nitrobenzenesulfonyl)-L-tryptophan (120 mg, 0.3 mmol) which was prepared in step A of example 5. The final product was purified by HPLC to give 66 mg (36%) of pure adduct.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3.0 g, 0.01 mol) in phosphorous oxychloride (7.7 g, 0.05 mol) was heated and stirred at 100° C. for 1 hour. After the solution was allowed to cool to room temperature, the reaction solvent was evaporated under reduced pressure, and the residue water was added to iced water. After neutralization by the addition of an aqueous sodium hydroxide solution, organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel chromatography (ethyl acetate) gave the title compound (1.72 g, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[NH:5][C:4]=1[CH:17]=O.[CH3:19][C:20]1[NH:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.Cl>CO.CCOCC>[CH3:25][C:23]1[CH:24]=[C:20]([CH3:19])[NH:21][C:22]=1/[CH:17]=[C:4]1\[N:5]=[C:6]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:7]=[C:3]\1[O:2][CH3:1]
Reactant: COc1cc(-c2cc3cccnc3[nH]2)[nH]c1C=O
Reactant: Cc1c[nH]c(C)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC1=CC(c2cc3cccnc3[nH]2)=N/C1=C\c1[nH]c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 3-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrrole-2-carbaldehyde (8 mg) and 2,4-dimethyl-1H-pyrrole (3.2 mg) in 1 mL of MeOH was added 2 small drops of a solution of 2 N HCl in ether. The dark-red reaction solution was stirred at r.t. for 1 h and then quenched with 3 mL of pH 7 sodium phosphate buffer solution. The product was extracted with 2×5 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash on a silica gel column eluted with a gradient up to 80% EtOAc/hexanes to give 8 mg of the title compound as a dark solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:15])=[O:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ncccc1O
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1O

Procedure:
By the procedure of Example 4(i), 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine (from the dihydrobromide (4.2 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio- 2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino]ethylene which, on reaction with methylamine by the process of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino] ethylene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[N:12]=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:19]
Reactant: O=C(Cc1ncccn1)c1ccc(F)cc1F
Reactant: CI
Product: CC(C(=O)c1ccc(F)cc1F)c1ncccn1
Yield: 89 %

Procedure:
Methylation of the product of part (i) (3.50 g) with iodomethane (5.32 g) according to the method of Example 11(ii) gave the title compound (3.30 g), m.p. 118°-119°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:11]=[C:10]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:37]1[C:45]2[C:40](=[C:41](B3OC(C)(C)C(C)(C)O3)[C:42]([F:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)(C(C)(C)C)(C)C>>[F:46][C:42]1[C:41]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[N:11]=[C:10]([C:12]([N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]4)=[O:13])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:40]2[C:45](=[CH:44][CH:43]=1)[NH:37][CH:38]=[CH:39]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(O)C1CCN(C(=O)c2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(C(=O)c2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methanone (88 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to yield 41.5 mg 118 following reverse phase HPLC purification. MS (Q1) 519.2 (M)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To 1.37 g of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 460 mg of 2-aminopyrazine, 277 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2.04 g of tripotassium phosphate and 248 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 30 ml of 1,4-dioxane, and the mixture was subjected to degassing and was substituted with argon gas, and then was stirred at 100° C. for 2 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 960 mg of the objective compound as pale yellow powder.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]3[CH:2]=2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1ccnc(N)c1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CBr
Solvent: CC#N
Product: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])cc3)nc2c1
Yield: 55.8 %

Procedure:
A mixture of 4-bromo-1-(4-nitrophenyl)but-1-en-3-one (5.7 g) and 2-amino-4-methylpyridine (6.8 g) in acetonitrile (50 ml) was stirred under reflux for 1.5 hours. The precipitate was collected by filtration and washed with acetonitrile to give 2-[2-(4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (3.29 g).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cn1nnc2ccc3nc(O)c(O)nc3c21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c21
Yield: 65.4 %

Procedure:
Finely powdered potassium nitrate (0.71 g, 7 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-1-methyl-1H-1,2,3-triazolo[4,5-f]quinoxaline (1.52 g, 7 mmol) in 28 ml of conc. sulfuric acid at 0° C. After about 1 h the ice bath was removed and stirring was continued over night at room temperature. Then an additional amount of potassium nitrate (0.7 g) was added and the mixture was stirred for 4 h at room temperature. Now the solution was poured into 150 ml of ice/water and the precipitated yellow solid was isolated by filtration and washed with water. Recrystallization from water/ethanol (1:1) afforded 1.2 g (65%) of the pure nitro compound; m.p.>300° C.; IR (KBr): 3600-2500, 1720 cm-1 ; 1H-NMR (DMSO-d6): 4.62 (s,3H, CH3), 8.07 (s, 1H, ArH), 12.4 (broad s, 1H, OH, only one exchangeable proton could be seen).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([OH:15])=[N:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CS(C)=O>[Cl:9][C:7]1[CH:6]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([O:15][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:11]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
A 1.8 g portion of sodium was dissolved in 75 ml of absolute ethanol, and the solution was added slowly with stirring to a solution of 18.5 g of 1-(3,5-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole in 200 ml of dimethylsulfoxide. The solution was stirred at 60° for 1 hour, 14.5 g of ethyl 2-bromopropionate was added, and the mixture was heated for 2 hours at 100°-110°. It was then poured over ice water, and the solid was collected, dried and recrystallized from ether to obtain 10 g of the desired product. The mother liquor was chromatographed to obtain 1.3 g of additional product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[CH:52][CH:51]=1>>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:59]6[CH2:60][CH2:61][N:56]([C:53]7[CH:54]=[CH:55][N:50]=[CH:51][CH:52]=7)[CH2:57][CH2:58]6)=[O:35])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:45][CH:44]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccncc5)CC4)cc3)cn2)cc1
Yield: 119.1 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (80.0 mg, 0.121 mmol) obtained in Step A in Example 1-D-19 and 1-(4-pyridyl)piperazine (29.7 mg, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone as a brown solid (116 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-265) as a yellow powder (47.4 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:32])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
To a solution of intermediate 49 (Example 99) (4.0 g, 19 mmol) in THF (30 mL) at 0° C. under the argon atmosphere was added PPh3 (6.3 g, 24 mmol) followed by CBr4 (8.0 g, 24 mmol). The mixture was stirred at the same temperature for 15 min and then stirred at room temperature for additional 15 h. Most of the solvent was removed and the residue purified by flash chromatography on silica gel (hexane) to afford the title compound (3.5 g, 66%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Yield: 58.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid (170 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 4 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-N-thiazol-2-yl-propionamide (123 mg, 58.3%) as a white solid: mp 172-173° C.; EI-HRMS m/e calcd for C25H30N2O2S (M+) 422.2028, found 422.2023.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4](Cl)[C:3]=1[Cl:13].[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:4]1[C:5]([Cl:11])=[C:6]([Cl:10])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[Cl:13]
Reactant: NCCN
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Product: N#Cc1c(Cl)c(Cl)c(NCCN)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
55 g of pentachlorobenzonitrile are introduced into 300 g of ethylenediamine at room temperature in such a way that the temperature does not exceed 30° C. The mixture is then stirred for a further half an hour at room temperature, after which 0.75 l of ice water is slowly added and stirring is continued for 15 minutes. The precipitate is filtered off under suction, washed with water and dried to give 55 g of product which, when recrystallized from toluene with the addition of active carbon, has a melting point of 140°-144° C.
Reaction SMILES: [CH2:1]([CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:2][CH:3]=C.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[O:15]=[C:12]1[N:11]2[CH:5]([CH2:1][CH2:2][CH:3]=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2=[N:14][O:13]1
Reactant: C=CCCC1CCCCc2noc(=O)n21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCCC1CCCCc2noc(=O)n21
Temperature: 25 °C

Procedure:
To a solution of the product of Example 18 in dioxane and water is added sodium periodate and osmium tetraoxide. The reaction is stirred at room temperature and monitored by thin layer chromatography. Water is added to the reaction mixture and the solution is extracted with CH2Cl2. The organic layer is dried over magnesium sulfate, filtered, and stripped of all solvent under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH2:11]=[CH:12][CH2:13]CC>C1COCC1>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:11][CH2:12][CH3:13]
Reactant: C=CCCCCCCCO
Reactant: C=CCCC
Solvent: C1CCOC1
Product: CCC/C=C\CCCCCCCO
Reaction time: 4 h
Yield: 73 %

Procedure:
In a glovebox, a 20 mL vial was charged with 8-nonenol (0.58 g, 4.1 mmol), 1-pentene (4 mL), and THF (4 mL). A solution of 1 (0.026 g, 1 mol %) in THF (0.5 mL) was added, and the mixture was stirred in an open vial for 4 hours. The vial was removed from the glovebox, the reaction was quenched with excess ethyl vinyl ether, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of hexanes to 20% EtOAc in hexanes) provided 12 (0.56 g, 73% yield, 86% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.36 (2H, m), 3.64 (2H, br t, J=5.3 Hz), 2.01 (4H, m), 1.36 (2H, m), 1.28-1.40 (11H, m), 0.90 (3H, t, J=7.4 Hz); 13C NMR (CDCl3): δ 130.0, 129.7, 63.1, 32.8, 29.3 (4C), 27.2, 25.7, 22.9, 13.8; HRMS (EI): 184.1805, [C12H24O]+ requires 184.1827.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:34]([O:36][CH3:37])=[O:35])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Reactant: COC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: [2′-(benzylamino-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][OH:16]>>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:16][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CO
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
Into a round bottom flask, 2,5-difluoro-4-nitro-benzoic acid (5.00 g, 0.0246 mol) and methanol (20.0 mL, 0.494 mol;) was added. The reaction was heated at 45° C. for one hour. The solvent was removed under vacuum. 1N HCl was added to pH 4. The solid was filtered and washed with water to give 2-fluoro-5-methoxy-4-nitro-benzoic acid as an off white solid (2.84 g, 54%). 1H-NMR (DMSO-D6, 400 MHz): δ 13.90 (bs, 1H), 8.08 (d, 1H), 7.72 (d, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(SCc3ccc(C)cc3)nc2c1
Reaction time: 24 h

Procedure:
To a mixture of 5-methoxy-2-mercaptobenzimidazole (1.673 g, 9.285 mmol) and p-xylyl bromide (1.718 g, 9.285 mmol) in DMF (33.5 mL) at 0° C., Cs2CO3 (4.53 g, 13.93 mmol) was added and the suspension was stirred for 24 h while being allow to warm from 0° C. to rt. Distilled water (150 mL) was added with vigorous stirring. The murky white suspension turned into a clearer solution with white granules. After being stirred for 20 min at rt, the mixture was filtered and the residue was rinsed with water (3×20 mL) and hexanes (3×20 mL). The crude product was >95% pure by 1H NMR analysis and was not further purified. The yield was 2.437 g, 92%. 1H NMR (500 MHz, CDCl3): δ 2.25 (s, 3H), 3.76/3.78 (app d*, 3H), 4.38/4.42 (app d*, 2H), 6.74-7.17 (m, 6H), 7.52 (d, 1H, J=7.5 Hz), 8.87 (brs, 1H); 13C NMR (125 MHz, CDCl3): δ 21.30, 37.39, 37.63, 55.89, 55.96, 94.15, 101.18, 110.39, 111.10, 112.45, 119.07, 128.98, 129.58, 133.94, 156.61. *The apparent doublets may arise from the 1,3-proton shift between the nitrogen atoms in the heterocycle.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O.N.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Agent: N
Solvent: O
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
5,6-Dichloro-1,3-dihydro-2H-benzimidazol-2-one (11.5 g) was suspended in phosphorus oxychloride (40 mL), and the mixture was stirred at 120° C. for 24 hours. After cooling the reaction mixture, water was added to the reaction mixture, and to the mixture was added 28% aqueous ammonia solution to alkalize. The solid was collected by filtration and dried to give the title compound (5.0 g).