Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:15][CH2:14][CH2:13][C:12]#[C:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])(=[O:26])=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC#CCCOS(C)(=O)=O
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.9 g of 3-hexyn-1,6-diol mono-t-butyl-dimethylsilyl ether in 50 ml of methylene chloride was cooled to -20° C. and treated with 4.18 ml of triethyl amine and then 1.77 ml of methane sulfonyl chloride. After stirring 15 minutes at -20° C. the reaction mixture was diluted with water and extracted twice with 50 ml of methylene chloride. The organic layers were washed with brine, dried over sodium sulfate and evaported in vacuo to give the 3-hexyn-1,6-diol t-butyldimethylsilyl ether methyl sulfonate.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C(C)(C)C)=[CH:22][CH:21]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.[NH2:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51].[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]>>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:32])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:57][N:58]1[C@@H:75]2[CH2:76][C:63]3[CH:64]=[CH:65][C:66]([O:77][CH3:78])=[C:67]4[O:68][C@H:69]5[C:70]([CH2:72][CH2:73][C@@H:74]2[C@:61]5([C:62]=34)[CH2:60][CH2:59]1)=[O:71]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
Tyr-Tyr-Ile-Hydrocodone was prepared by similar methods except the amino acid starting material was Boc-Tyr(tBu)-Tyr(tBu)-OSu and the conjugate starting material was Ile-Hydrocodone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13](OCC)=[O:14])[CH2:9][CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[OH:14][CH2:13][CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[O:11]1
Reactant: CCOC(=O)C1CCc2cccc(OC)c2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CO)CC2
Reaction time: 8 h

Procedure:
59.0 g (0.25 mol) of ethyl 8-methoxy-chroman-2-carboxylate in 525 ml of anhydrous tetrahydrofuran are added dropwise in the course of 1 h, with stirring, at 20° C. to a suspension of 9.5 g (0.25 mol) of lithium aluminium hydride in 525 ml of anhydrous diethyl ether. The batch is stirred overnight and 9.5 ml of water, 9.5 ml of 15% strength sodium hydroxide solution and 28.4 ml of water are then successively added dropwise, with cooling. The organic phase is decanted off and evaporated. The residue is recrystallised twice from dichloromethane/petroleum ether. Yield: 38.0 g (87%) Melting point: 57°-58° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrBr
Reactant: Nc1nc(NCc2ccccc2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(NCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
6-Amino-9-benzyl-2-(N-benzylamino)purine (60 mg, 0.18 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (37 mg, yield 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[CH3:21].N>C(O)C.O.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:21])=[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:7][C:2]=2[CH3:1])[CH:17]=1
Reactant: CCC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2C)c(C)c1
Agent: [Fe]
Agent: N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(-c2cc(N)ccc2C)c(C)c1

Procedure:
2.2 g (7.8 mmol) of 1-(2,2′-dimethyl-5′-nitrobiphenyl-4-yl)-1-propanone are dissolved in a mixture of 80 ml of ethanol and 40 ml of water and 10 ml of acetic acid. The mixture is refluxed while 1.7 g (31 mmol) of iron powder are added. The medium is heated for 1 hour and then treated by addition of aqueous ammonia, cooled and filtered through Celite. The solution obtained is diluted in ethyl acetate and then washed with water, and the organic phase is dried and concentrated under reduced pressure. After chromatography on a column of silica (eluent: 60 heptane/40 ethyl acetate), a yellow oil is obtained (m=1.9 g; Y=96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7](=[O:8])[O:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:11]=[CH:12][C:4]=2[O:3]1.[OH-:23].[Na+:24]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C:10]2[CH:11]=[CH:12][C:4]([O:3][C:2]([CH3:22])([CH3:1])[C:7]([O-:6])=[O:8])=[C:5]([OH:23])[CH:9]=2)=[CH:16][CH:17]=1.[Na+:24]
Reactant: CC1(C)Oc2ccc(CNc3ccc(Cl)cc3)cc2OC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Oc1ccc(CNc2ccc(Cl)cc2)cc1O)C(=O)[O-]

Procedure:
To a solution of 158.7 mg of 3,3-dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one in 10 ml of ethanol is added 5 ml of a 1/10 N sodium hydroxide aqueous solution and the mixture is warmed to give clear solution. The solution is concentrated and the precipitated crystals are collected by filtration, washed with water and ether, and dried to give 140 mg of sodium 2-[4-(4-chloroanilinomethyl)-2-hydroxyphenoxy]-2-methylpropionate, mp 121° to 125° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[N:16][CH:17]=2)[S:6][C:5]=1[CH3:7]
Reactant: Cc1sc(Br)cc1C1OCCO1
Reactant: COc1ccc(B(O)O)cn1
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: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(C3OCCO3)c(C)s2)cn1

Procedure:
A mixture of 2-(5-bromo-2-methylthiophen-3-yl)-1,3-dioxolane (1.7 g), 2-methoxy-5-pyridineboronic acid (1.3 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine as an oil. The obtained 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine was dissolved in tetrahydrofuran (10 mL), 1N hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 75%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:26]([C:25]3[C:24]([CH3:23])=[N:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: Cc1ncccc1C(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-methylnicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.35 (m, 1H), 1.48-1.81 (m, 4H), 1.86 (m, 1H), 2.24 (s, 3H), 3.12 (m, 1H), 3.24 (m, 1H), 4.16 (m, 1H), 4.77 (t, 1H, J=9.8 Hz), 5.32 (m, 1H), 6.62 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=8.3 Hz), 7.27 (m, 1H), 7.47 (t, 1H, J=8.3 Hz), 7.66 (m, 1H), 7.93 (br s, 1H), 8.31 (br s, 1H), 8.47 (dd, 1H, J=5.1, 1.7 Hz), 10.92 (s, 1H). MS 430 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:39][S:40]([CH2:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:42])=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][CH:44]([CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CC1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-methanesulfonylmethyl-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C36H45N4O4SCl2 [(M+H)+] 699.2533, observed 699.2533.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.20 g, 0.73 mmol) in CH2Cl2 (5 mL) was added dropwise a solution of tert-butyl piperidin-4-ylcarbamate (0.19 g, 0.95 mmol) and triethylamine (203 μL, 147 mg, 1.46 mmol) in CH2Cl2. The reaction was stirred for 3 h and then quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain tert-butyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate. The residue was dissolved in 10 mL CH2Cl2 and 3 mL TFA. The reaction was stirred for 2 hours and neutralized with a 1.0 M aqueous NaOH solution. The mixture was partitioned between H2O/CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain 2-(4-(4-aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z 339.3 (M+H)+ at 1.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH2:45]([N:47]=[C:48]=[O:49])C>CC#N>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:48]([NH:47][CH3:45])=[O:49])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Reactant: CCN=C=O
Solvent: CC#N
Product: CNC(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 78.5 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) followed by CH3CN (15 mL) and ethylisocyanate (Chemservice, Inc.) (45.6 mg. 0.80 mmol). The reaction mixture was stirred at RT for 16 h, then the solvent was removed in vacuo. The resulting yellow oil was dissolved in EtOAc (20 mL) and washed with satd NaHCO3 (20 mL) and satd NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (397 mg). MS (ESI, pos. ion) m/z: 674 (M+1); MS (ESI, neg. ion) m/z: 672 (M−1). Calc'd for C37H44ClN5O0: 673.30.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].C(N)CN.ClCC1NC2C=CC=CC=2N=1.[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][N:34]=[C:35]=[S:36]>>[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][NH:34][C:35]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:36]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1nc2ccccc2[nH]1
Agent: ClCc1nc2ccccc2[nH]1
Solvent: NCCN
Product: CN(C)CCNC(=S)NCCNCc1nc2ccccc2[nH]1

Procedure:
N-(2-Benzimidazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 2-chloromethylbenzimidazole by the procedure of Example 40, is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](O)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:24][C:25]5[C:39]([O:40][CH3:41])=[CH:38][C:28]6[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:32][CH2:33][C:27]=6[CH:26]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Reactant: O=S(=O)(NC1CC1)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4cccc(S(=O)(=O)NC5CC5)c4)n3n1)CCN(CC(N)=O)CC2

Procedure:
This compound as a yellow solid, was prepared following the same procedure as described for the synthesis of Example 522 by coupling N-Cyclopropyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide. MP>150° C. (decomp.). LCMS (E/I+) 562.14 (M+H). 1H NMR (DMSO-d6) δ 9.00 (s, 1H), 8.60 (d, 1H, J=6.50 Hz), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (m, 2H), 7.70 (t, 1H, J=6.50 Hz), 7.20 (d, 1H, J=6.00 Hz), 7.00 (d, 1H, J=6.00 Hz), 6.80 (s, 1H), 4.30 (broad, 1H), 3.80 (s, 3H), 3.70 (broad, 1H), 2.80 (broad, 2H), 2.70 (broad, 2H), 2.60 (broad, 4H), 2.40 (broad, 2H), 2.10 (broad, 1H), 1.20 (broad, 1H), 0.50 (broad, 2H), 0.40 (broad, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:21][C:22]([N:24]([O:26][CH3:27])[CH3:25])=[O:23]>CN(C)C=O>[CH3:27][O:26][N:24]([CH3:25])[C:22]([C:21]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:9]=1[CH3:10])=[O:23]
Reactant: CON(C)C(=O)CCl
Reactant: CC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1oc2ccc(C)cc2c1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a solution (50 mL) of 1-(2-hydroxy-5-methylphenyl)ethanone (5.00 g) in N,N-dimethylformamide were added potassium carbonate (9.20 g), sodium iodide (9.98 g) and 2-chloro-N-methoxy-N-methylacetamide (5.04 g), and the mixture was stirred at 50° C. for 5 hr then at 80° C. overnight. The insoluble material was filtered off, 1,8-diazabicyclo[5.4.0]undec-7-ene (5.00 mL) was added to the filtrate and the mixture was stirred at 120° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (3.78 g, 49%) as a brown oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17](O)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:38][C:39]1[N:44]=[CH:43][C:42]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:41][CH:40]=1>ClCCl.C(OCC)(=O)C.O.N1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([NH:38][C:39]3[N:44]=[CH:43][C:42]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:41][CH:40]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(N)nc1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)nc1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (110 mg) in dichloromethane (3 mL) were added sequentially oxalyl chloride (0.03 mL) and a catalytic amount of DMF under ice-cooling, followed by stirring for 1 hour, and then ethyl (6-aminopyridin-3-yl)acetate (58 mg) and pyridine (0.05 mL) were added thereto under ice-cooling, followed by stirring for 2 hours. To the reaction mixture were added water and ethyl acetate. The organic layer was sequentially washed with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) as a pale yellow amorphous substance. To a solution of the obtained ethyl [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetate (57 mg) in THF (3 mL) was added 1 M aqueous sodium hydroxide solution (0.22 mL), and further added a drop of ethanol, followed by stirring at room temperature overnight. To the reaction solution was added 1 M hydrochloric acid (0.22 mL) to adjust the pH to 4, followed by dilution with saturated brine and dichloromethane for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. To a solution of the residue in ethyl acetate (3 mL) was added a 4 M hydrogen chloride/ethyl acetate solution (0.07 mL) under ice-cooling, followed by stirring for 10 minutes under ice-cooling, and the solvent was then evaporated under reduced pressure. To the residue was added ethyl acetate (3 mL), and the precipitate was collected by filtration and dried under reduced pressure to obtain [6-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)pyridin-3-yl]acetic acid hydrochloride (30 mg) as a colorless solid.
Reaction SMILES: C[C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:10][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[CH:2][C:8]=1[CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(O)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 2,3-dimethylhydroquinone (1.38 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), potassium iodide (0.83 g, 5 mmol) in 50 mL dry acetone was added benzyl bromide (1.88 g, 11 mmol). The resulting suspension was vigorously stirred for 48 at RT. The solid was filtered off and the liquid was concentrated. The residue was chromatographed to afford the benzyl derivative, 4-benzyloxy-3-methyl-phenol, as a light brown solid (1.15 g). 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.49-7.35 (m, 5H), 6.70 (d, J=8.7, 1H), 6.61 (d, J=8.7, 1H), 5.03 (s, 2H), 4.43 (s, 1H), 2.26 (s, 3H), 2.22 (s, 3H); MS (ESI) m/z: 229 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][C:3]=1[CH3:24].[Li+].[OH-].C1COCC1.Cl>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:24]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(C)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.6 %

Procedure:
Methyl 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinate (example BI; 4.8 g, 13.3 mmol) and LiOH (0.96 g, 40.0 mmol) were combined with THF (70 mL), water (14 mL) and methanol (7 mL) to give a yellow suspension. The reaction mixture was stirred for 22 h at room temperature, 15 mL water was added and the reaction mixture was heated to 45° C. and stirred for 3 h. After cooling to room temperature the reaction mixture was poured into 150 mL of 1 M HCl with ice (pH=1) and extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried with Na2SO4, filtrated and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 100% EtOAc in heptane to give 3.8 g (82%) of the title compound as a white crystalline solid; MS (ESI): 346.1 (M+H)+.