Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]3(O)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[C:10]([F:22])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[S:18]1[CH2:17][CH:16]=[C:15]([C:11]2[C:12]([F:14])=[CH:13][C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[CH:9][C:10]=2[F:22])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1cc(F)c(C2=CCSCC2)c(F)c1

Procedure:
A stirred solution of 4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,6-difluorophenyl]tetrahydro-2H-thiopyran-4-ol (Step 2, 1.617 g, 5.00 mmol) and p-toluenesulfonic acid monohydrate (0.107 g) in benzene (20 mL) is heated at reflux using a Dean-Stark trap for 5 h, during which additional p-toluenesulfonic acid monohydrate (0.342 g) is added. Solvent is then removed under reduced pressure, and the residue is taken up in CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (2×20 mL) and water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 2–5% EtOAc/Hexanes, affords the title compound, mp 118–119° C.; MS (ESI+) for C17H17F2NS m/z 306 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NC1CCCCC1
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CCCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of ethanol and 56 mg of cyclohexanamine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 92 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclohexylurea are obtained in the form of a pale yellow powder, the characteristics of which are as follows:
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CC/C=C\CCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C\CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
Cis-11-tetradecen -1-ol (1 g, 4.72 mmol) and carbon tetrabromide (1.56 g 4.72 mmol) were dissolved in dichloromethane (3ml) and the solution was cooled in ice bath. A solution of triphenylphosphine (1.24 g, 4.72 mmol) in 2 mL of dichloromethane was added dropwise. After stirring at 0° C. for 15 minutes and at room temperature for 3 h, the solvent was evaporated and the residue was diluted with ether. The ether solution was filtered and concentrated and purified using column chromatography on silica gel eluting with hexane:ethyl acetate (3:1) to give 0.23 g of (Z)-14-bromo-3-tetradecene.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[NH2:10])=[N:6][CH:7]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](N)=[C:35]([O:40][CH3:41])[CH:34]=1)[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:10][C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:11])=[C:35]([O:40][CH3:41])[CH:34]=1)[CH3:29]
Reactant: COc1cc(CN(C)C)ccc1N
Reactant: Cc1cnc(NC(N)=O)cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COc1cc(CN(C)C)ccc1NC(=O)Nc1cnc(C)cn1

Procedure:
144-Dimethylaminomethyl-2-methoxy-phenyl)-3-(5methyl-pyrazin-2-yl)urea. According to the diphenylphosphoryl azide method described above for compound 336, 4-dimethylaminomethyl-2-methoxy-phenylamine was converted to the (5-methyl-pyrazin-2-yl)-urea. The crude product was purified by preparative TLC, eluting with 5% MeOH in CH2Cl2. 1H NMR (400 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=7.83 Hz, 1H), 8.04 (s, 1H), 7.01 (s, 1H), 6.89 (d, J=7.83 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 2H), 2.26 (s, 3H), 2.24 (s, 6H). MS APCI-Pos, M+1=316.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Mg]Br)C.O1CCCC1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C(OCC)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccnc(B(O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-4-methylpyridine (0.5 g, 2.9 mmol) in diethyl ether (5 mL) was added a 1M solution of ethylmagnesium bromide in tetrahydrofuran (3.48 mL, 3.48 mmol) slowly at 0° C. over 10 minutes under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. To the above mixture was added tri-isopropyl borate (0.65 g, ˜0.8 mL, 3.48 mmol) dropwise at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for another 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (6 mL) at 0° C. and then extracted with diethyl ether (50 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methylpyridine-2-boronic acid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C@H:3]1[C:15]([O:17]C(C)(C)C)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Yield: 98.2 %

Procedure:
A mixture of 11.4 g of the product of Step B, 120 ml of toluene and 300 mg of p-toluene sulfonic acid was refluxed for 1 hour and was allowed to return to room temperature. The reaction mixture was washed with water, dried and evaporated to dryness to obtain 9.5 g of (1R,cis)2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylic acid which was used as is for the following step.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C(O[CH2:17][C:18]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=2[CH3:35])[C:22]2[N:36]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[S:38][C:21]=2[C:20](=[O:45])[N:19]=1)(=O)C.[C:46]1(=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48](=[O:55])[NH:47]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:35][C:26]1[C:27]([C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:23]1[C:22]2[N:36]=[C:37]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[S:38][C:21]=2[C:20](=[O:45])[N:19]=[C:18]1[CH2:17][N:47]1[C:48](=[O:55])[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]1=[O:56]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(C(F)(F)F)c1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Cn2c(CN3C(=O)c4ccccc4C3=O)nc(=O)c3sc(N4CCOCC4)nc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DEAD (0.035 mL, 0.221 mmol) was added to a solution of 5-(hydroxymethyl)-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (Example 113, 65 mg, 0.148 mmol), 1H-isoindole-1,3(2H)-dione (26.1 mg, 0.177 mmol) and triphenylphosphine (58.1 mg, 0.221 mmol) in Tetrahydrofuran (THF) (2 mL). The reaction was stirred at RT for overnight. The mixture was partitioned between DCM and NaCl solution, the organic layer was dried over MgSO4 and was concentrated. The residue was purified on a silica column eluting with 30% EtOAc/Hexanes to give the titled product, 60 mg (60%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>C1(C)C=CC=CC=1>[C:1]([O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
Decanoic acid (10.0 g, 58.1 mmol), vanillyl alcohol (8.05 g, 52.2 mmol), and lipase PS-C “Amano” I (enzyme immobilized on ceramic: 1.44 g) were measured and placed in a flask (500 ml), and toluene (200 ml) was added. Under an argon atmosphere, the mixture was heated with stirring in an oil bath at 40° C. for 2 hours. This reaction mixture was concentrated under reduced pressure, and dehydration was promoted by azeotropic effect. Toluene (150 ml) was further added to the concentrate, and the mixture was heated with stirring in an oil bath at 40° C. for 20 hours. The reaction mixture was again concentrated under reduced pressure, and heptane (200 ml) was added. The mixture was stirred at room temperature for 2.5 hours, and immobilized enzyme and precipitated vanillyl alcohol were removed by filtration. The filtrate was concentrated under reduced pressure to give a mixture (15.8 g) of vanillyl decanoate and decanoic acid. As a result of the analysis, the yield of vanillyl decanoate was 98% and the purity was 97.9 area % by HPLC. The mixture contained 8.6 wt % of decanoic acid relative to vanillyl decanoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:41]([N:43]([CH2:47][CH3:48])[CH2:44][CH2:45][NH2:46])[CH3:42]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:46][CH2:45][CH2:44][N:43]([CH2:47][CH3:48])[CH2:41][CH3:42])=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(Cl)cccc1Cl
Reactant: CCN(CC)CCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid (50 mg, 0.13 mmol), HOBT (21 mg, 0.156 mmol), and EDC (30 mg, 0.156 mmol) in DMF (2 mL) was added N,N-diethylethylenediamine (0.022 mL, 0.156 mmol). The reaction was stirred at room temperature for 24 hr, then diluted with EtOAc, and partitioned with H2O. The organic was separated and the aqueous was extracted with EtOAc. The organic layers were combined, washed with saturated NaHCO3, and concentrated to dryness under vacuum. The material was purified using column chromatography (silica gel, 99:1 to 95:5 CH2Cl2/MeOH) to give 4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide (45 mg, 72% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N-:14]=[C:15]=[O:16].C([NH+](CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([NH:13][C:15]([NH2:14])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [N-]=C=O
Reactant: CCCCCCCCCCCCN
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.1 g of dodecylamine (0.076 mol) dissolved in 20 ml of chloroform were added dropwise at room temperature with stirring to 100 ml of a solution of 10 g of triethylammonium isocyanate (0.069 mol) in chloroform, prepared according to Example 1. After completion of the addition, the mixture was subsequently stirred at room temperature for 24 hours and heated to reflux for 1 hour. The solvent was evaporated and the residue was recrystallized from chloroform. 9.45 g, i.e. 60% of theory, of dodecylurea were obtained in this way.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:25]([Cu])#[N:26].[C-]#N.[Na+]>Cl.O>[C:25]([C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7])#[N:26]
Reactant: Nc1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: N#Cc1cc(C[C@H](N)C(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 24.2 %

Procedure:
A solution of 5.70 g of 3-amino-L-tyrosine (Aldrich) in 35 mL of 2.15 N aqueous HCl was cooled to 0° C. and treated with a solution of 1.41 g of NaNO2 (Aldrich) in 5 mL of water followed by 2.97 g of Na2CO3. After stirring at 0° C. for 7 min, the solution was slowly added (via an addition funnel) to a stirred mixture of 3.58 g of CuCN (Aldrich), 5.88 g of NaCN (Aldrich) and 5.72 g of Na2CO3 in 40 mL of water maintained at 75° C. in a 250 mL 3-necked flask equipped with a condenser. During the addition, vigorous evolution of nitrogen occurred and the reaction mixture changed color to dark red-orange. The reaction mixture was stirred at 75° C. for 2 h, heated to 95° C., and stirred for additional 1 h. After cooling to RT, the reaction mixture was acidified to pH=2.0 by addition of concentrated HCl via the addition funnel. The evolved gas was scrubbed through a 20% aqueous NaOH trap followed by a 5% NaOCl (Chlorox) trap . The mixture was filtered and the pH of the filtrate was adjusted to 6.0 with concentrated NH4OH. The brown solution was mixed with 300 mL of water and stirred with 300 g of DOWEX 50WX-8 ion exchange resin (acid form). The resin was filtered, washed with 1 L of water, mixed with 500 mL of water, and the mixture was basified to pH 11 by addition of concentrated NH4OH. The mixture was filtered and the filrate concentrated in vacuo to dryness. The dark brown residue was suspended in 20 mL of water and treated with enough 1 N aqueous NaOH to dissolve the solid. The pH was then adjusted to 6.0 by addition of 1 N aqueous HCl. A precipitate formed which was collected by filtration and dried in vacuo to afford 1.45 g (35%) of 3-cyano-L-tyrosine as a chocolate brown solid, m.p. >250° C. 1H-NMR: (200 MHz, DMSO-d6) δ 9.60-7.20 (br s. NH2), 7.39 (s, 1 H, aromatic CH), 7.30 (m, 1 H, aromatic CH), 6.98 (m, 1 H, aromatic CH), 3.52 (m, 1 H, methine), 2.92 (m, 2 H, ArCH2).
Reaction SMILES: CO[C:3]([O:8][CH3:9])(OC)OC.[C:10]1([S:16]([NH:19][C:20](=[O:42])[C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][CH:31]=3)[CH:22]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C(O)(=O)C>[C:10]1([S:16]([NH:19][C:20]([C:21]2[CH:26]=[CH:25][C:24]3[N:27]=[C:3]([O:8][CH3:9])[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)[C:23]=3[CH:22]=2)=[O:42])(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: COC(OC)(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Tetramethoxymethane (0.250 g) was added to a solution of 0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 3 ml of acetic acid, and the mixture was stirred at 80° C. for 2 hours. Methanol was added to the reaction solution, and the crystals precipitated were collected. The crystals were washed with a mixed solvent of 1 ml of acetone and 8 ml of methanol, separated through filtration, and dried to give 0.280 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole (228).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](OC)(OC)[O:9]C>O>[CH3:8][O:9][N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1
Reactant: Nc1cccnc1
Reactant: COC(OC)OC
Solvent: O
Product: CON=C1C=CC=NC1
Yield: 90 %

Procedure:
A mixture of 3-aminopyridine (7.14 g, 0.076 mol) and trimethyl orthoformate (40 mL) was refluxed for approximately 60 hr. To the cooled reaction mixture was added water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine and dried with MgSO4. The suspension was filtered and concentrated to yield the 3-methoxyiminopyridine as a white solid (9.3 g, 90%).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:3]=1.[F:15][C:16](I)([F:21])[C:17]([F:20])([F:19])[F:18]>[Cu].CS(C)=O>[CH3:14][CH:9]([C:4]1[CH:3]=[C:2]([C:16]([F:21])([F:15])[C:17]([F:20])([F:19])[F:18])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: FC(F)(F)C(F)(F)I
Reactant: CC(C)CC(C)c1cc(I)ccc1N
Agent: [Cu]
Solvent: CS(C)=O
Product: CC(C)CC(C)c1cc(C(F)(F)C(F)(F)F)ccc1N
Temperature: 130 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
4-Iodo-2-(1,3-dimethylbutyl)aniline (1.35 g, 4.45 mmol), copper powder (0.85 g, 13.4 mmol) and pentafluoroethyl iodide (1.42 g, 5.77 mmol) were added to dimethyl sulfoxide (10 ml), and the resulting mixture was stirred at 130° C. for 4 hours. The mixture was filtered through Celite and the filtrate was diluted with ethyl acetate and washed 4 times with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 1.24 g of the desired compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([O:25][CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]=2)=[CH:23][CH:24]=1)[C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 56.3 %

Procedure:
Sodium hydride (95%, 36.2 g, 1.51 mol) was placed into a dry 5 liter 3-necked round bottom flask under an atmosphere of argon. Anhydrous dimethylformamide (DMF) (2.0 liters) was added via canula followed by the careful addition of N-Boc-5-hydroxyanthranilic acid (150 g, 0.59 mol). The reaction mixture was cooled with an ice/water bath and benzyl bromide (148 mL, 1.24 mol) was added via syringe keeping the reaction temperature below 50° C. After addition was complete, the reaction mixture was stirred at 45° C.-50° C. for 6 hours. At this time additional benzyl bromide (35 mL, 0.29 mol) was added and the reaction continued at 45° C.-50° C. for an additional 2 hours. Acetic acid (20 mL) was carefully added and the reaction mixture was transferred to a round bottom flask and concentrated to a volume of approximately 400 mL. Ethyl acetate (1.0 liters) was added and the resulting solution was decanted from any solids present. The flask was rinsed with additional ethyl acetate (2×500 mL), decanting after each rinse. The combined organics were washed with water (1.0 liter) and saturated NaCl (500 mL). The organics were filtered and concentrated in vacuo to yield crude N-Boc-5-benzyloxyanthranilic acid, benzyl ester as a reddish brown syrup. The crude product was transferred to boiling hexanes (3 liters) and refluxed an additional 10 minutes. The solution was filtered while still hot and allowed to cool for 48 hours to yield 72 g of product (28% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:63][CH2:64][CH3:65])[C@@H:5]([N:7]([CH2:52][C:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][CH:54]=1)[C:8](=[O:51])[C@@H:9]([NH:33]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:6])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:33][C@@H:9]([CH2:10][C:11]([NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:32])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:63][CH2:64][CH3:65])[CH2:52][C:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][CH:54]=1)=[O:51]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1,4-dioxo-4-(tritylamino)butan-2-ylcarbamate (Compound III-19) 23.4 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 13.6 g, (yield 78%).
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.COC(C(S(C)(=O)=O)(CC=CC(OC(=O)C)CCCCC)CCCCCCC(OC)=O)=O>>[CH3:32][S:29]([CH:5]([CH2:16][CH:17]=[CH:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C=CCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCCC(C=CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
This compound is prepared by the procedure of Example 3, Step D, except that the methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy-10-heptadecenoate.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][S:17][C:18]1[N:23]([CH3:24])[C:22](=[O:25])[C:21]([CH2:26][CH2:27]Cl)=[C:20]([CH3:29])[N:19]=1.[I-].[K+].C(N(CC)CC)C>C(#N)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH2:27][CH2:26][C:21]3[C:22](=[O:25])[N:23]([CH3:24])[C:18]([S:17][CH3:16])=[N:19][C:20]=3[CH3:29])[CH2:6][CH:5]=2)=[CH:8]1
Reactant: CSc1nc(C)c(CCCl)c(=O)n1C
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc(C)c(CCN2CC=C(c3c[nH]c4ccccc34)CC2)c(=O)n1C
Temperature: 80 °C

Procedure:
To a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)indole (1.0 g, 5 mmol) in acetonitrile (30 ml) was added 2-methylthio-5-(2-chloroethyl)-3,6-dimethyl-3H-pyrimidin-4-one (1.42 g, 6.1 mmol), potassium iodide (0.84 g, 5 mmol) and triethylamine (1.4 ml, 10 mmol). The mixture was heated at 80° C. for 8 hours, cooled, concentrated and purified by flash chromatografy (dichloromethane/methanol/ammonia=95/4.5/0.5)