Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C@@H:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([C@H:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.766 g, 1.996 mmol), (5-((1R)-1-(4-(tert-butoxycarbonyl)-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 146, Step 4) (0.705 g, 1.996 mmol), PdCl2AmPhos (0.071 g, 0.100 mmol), and KOAc (0.588 g, 5.99 mmol) in a mixture of dioxane (16.6 mL) and water (3.3 mL) was sparged with nitrogen and then heated at 100° C. for 2.5 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were then dried over Na2SO4 and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.570 g, 0.868 mmol, 43.5% yield) as light-yellow foam. m/z (ESI, +ve) 657.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.22 Hz, 1H); 8.18 (s, 1H); 7.18 (d, J=7.24 Hz, 4H); 6.82-6.89 (m, 5H); 4.75 (br. s., 4H); 3.79 (s, 6H); 3.60 (d, J=7.04 Hz, 1H); 3.43 (br. s., 4H); 2.63 (s, 3H); 2.30-2.53 (m, 4H); 1.44 (s, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.Cl.CNC>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for 5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH2:17])=[CH:11][CH:10]=1>C(O)=O>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH:17][CH:1]=[O:3])=[CH:11][CH:10]=1
Reactant: COc1nc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1nc(Br)ccc1NC=O
Reaction time: 0.42 h

Procedure:
Acetic anhydride (203 mL) was added dropwise to formic acid (204 mL) under ice-cooling, and the mixture was stirred at the same temperature for 25 minutes. 6-Bromo-2-methoxypyridine-3-amine powder (CAS #89466-18-2, 146 g) was put into the reaction mixture over 10 minutes, and then the reaction solution was stirred at the same temperature for 30 minutes. The water bath was removed. tert-Butyl methyl ether (300 mL) and n-heptane (500 mL) were sequentially added dropwise to the reaction solution, and then the reaction solution was stirred for 30 minutes. The precipitated powder was collected by filtration. The resulting powder was crushed with a mortar, washed with tert-butyl methyl ether and then dried under reduced pressure to obtain 137.4 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=Cc1ccccc1
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1ccccc1

Procedure:
Compound 165A was prepared from racemate 1G and benzaldehyde by procedures analogous to those described in Example 22A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][CH2:18][CH2:19]O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>ClC(Cl)Cl>[Cl:29][CH2:19][CH2:18][CH2:17][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][O:9]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1(c2ccc(F)cc2)OCc2ccccc21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C2(CCCCl)OCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 24.2 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-propanol in 8 parts of pyridine and 90 parts of trichloromethane were added dropwise 12.1 parts of thionyl chloride. Upon completion, the whole was heated slowly to 50° C. and stirring at this temperature was continued for 3 hours. The reaction mixture was poured onto ice-water. The organic phase was separated, washed with a sodium hydrogen carbonate solution (10%), dried and evaporated, yielding 20 parts of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran as a residue (intermediate 12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]2=[CH:11][C:10]=1[CH3:20].P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:12]2[N:13]([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: Cc1cc(O)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C

Procedure:
A solution of 7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (34.2 g, 111.5 mmol) and phosphorus tribromide (50 mL, 142.5 g, 526.4 mmol) in bromobenzene (500 mL) is refluxed for 1 h. After cooling to room temperature, the mixture is diluted with CHCl3. Saturated NaHCO3 solution is added at 0° C. to neutralize and the mixture is separated immediately. The aqueous layer is extracted with CHCl3 (2×). The combined CHCl3 solution is dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to dryness. The residue is subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to afford 38.8 g (93%) of light yellow solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=1.5 Hz, 1H), 7.29 (m, 2H), 6.64 (s, 1H), 6.49 (s, 1H), 2.28 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 136.8, 135.2, 134.3, 130.1, 129.3, 127.1, 125.6, 125.1, 124.2, 123.2, 114.8, 102.3, 22.0, 12.8; MS (EI) m/z 369 (M+), 371 (M+), 373 (M+); HRMS (FAB) calcd for C15H11BrCl2N2+H 368.9561, found 368.9572.
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>CCOCC>[CH:18]1([C:21]([O:11][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])[CH2:20][CH2:19]1
Reactant: CCCCCCCC#CCO
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCC#CCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a solution of 3.85 g. of 2-decyn-1-ol and 3.95 g. of pyridine in 100 ml. ether is added 3.0 g. of cyclopropanecarboxylic acid chloride. The mixture is stirred overnight under nitrogen. The reaction mixture is poured into distilled water, washed with dilute hydrochloric acid and then with sodium bicarbonate and solvent removed to yield 2-decynyl cyclopropanecarboxylate, b.p. 96°-97° (bath) at 0.1 mm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl-].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CO>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNCC[C@H](O)c1cccs1
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene to chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%);
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:4].Cl[CH:21]([F:23])[F:22].C(=O)=O>C1COCC1>[CH2:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:21]([F:23])[F:22])=[C:14]([F:19])[CH:13]=2)[CH2:10][CH2:11]1)[CH3:4]
Reactant: FC(F)Cl
Reactant: CCO[C@H]1CC[C@H](c2ccc(O)c(F)c2)CC1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@H]1CC[C@H](c2ccc(OC(F)F)c(F)c2)CC1
Reaction time: 1 h

Procedure:
11 g of NaOH (32%) are added to a solution of 8.2 (lacuna) of the resultant p-(trans-4-ethoxycyclohexyl)-o-flurophenol in 80 ml of THF and 13.8 g of chlorodifluoromethane are introduced (dry ice reflux condenser). After subsequently stirring for one hour, the solution is decanted off from the precipitate and concentrated to give a residue. Bulb tube distillation gives p-(trans-4-ethoxycyclohexyl)-o-fluorodifluoromethoxybenzene, b.p.1~ 220° C., Tg -62°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].O[CH2:11][CH2:12][CH2:13][C:14]1[C:15]2[C:16]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][C:17]=3[NH:18][C:19]=2[CH:20]=[CH:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:66]CCl>O1CCCC1.CO>[ClH:66].[CH2:27]1[C:16]2[C:15]3[C:14]([CH2:13][CH2:12][CH2:11][O:9][C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:22][CH:21]=[CH:20][C:19]=3[NH:18][C:17]=2[CH2:23][CH2:24][NH:25][CH2:26]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(CCCO)c3c2CC1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: N#Cc1ccc(OCCCc2cccc3[nH]c4c(c23)CCNCC4)cc1
Reaction time: 30 h

Procedure:
To a 25 mL scintillation vial containing a glass bead was added 4-cyanophenol (0.033 g, 0.277 mmol), a solution (0.250 M) of tert-butyl 10-(3-hydroxypropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3 (2H)-carboxylate (1.0 mL, 0.250 mmol) in tetrahydrofuran, a solution (0.275 M) of triphenylphosphine (1.0 mL, 0.275 mmol) in tetrahydrofuran, and diethylazodicarboxylate (43.5 μl, 0.275 mmol). The vial was capped and orbitally shaken for 30 h. The mixture then was diluted with dichloromethane (1 mL) and methanol (1 mL). DOWEX® ion exchange resin (5.2 meq/gram, 0.5-0.75 g) was added and the mixtures were capped and shaken orbitally at 40° C. for 3 h. The mixture was filtered and the resin was washed (2×each) with dichloromethane, methanol, water, and tetrahydrofuran. The product then was eluted using a 4 N solution of ammonium hydroxide in methanol. Evaporation provided a residue which upon treatment with methanolic hydrochloric acid and evaporation led to the title compound. MS (EI) for m/z 346 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1O.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.CCCCC>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:21][CH2:18][C:2]1[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)c(O)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 30 %

Procedure:
A mixture of 75.0 g. (0.397 mol.) of 4-bromoresorcinol, 95.1 ml. (0.80 mol.) of benzylbromide and 331 g. (2.4 mol.) of anhydrous potassium carbonate in 400 ml. of N,N-dimethylformamide is stirred for 12 hours at 25° C. and for 4 hour at 85° C. The reaction mixture is cooled and added to one liter of ice-200 ml. pentane-100 ml. ether. The organic phase is washed with three 500 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The oil is rapidly chromatographed on 400 g. of silica gel eluted with 20% ether-pentane to yield 80 g. of oil. The chromatographed oil is crystallized from pentane at 0° C. to yield 45.0 g. (30%) of the title compound, M.P. 37°-38° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C1COCC1>[NH4+].[Cl-].CCOCC.[Zn]>[C:2]1([CH:1]([OH:8])[CH2:11][CH:10]=[CH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
39 g (0.6 mol) of zinc powder were added at 0° C., a little at a time, to a solution of 53 g (0.5 mol) of benzaldehyde and 73 g (0.6 mol) of allyl bromide in 500 ml of saturated NH4Cl solution/100 ml of THF. The mixture was stirred for 4 hours at room temperature and diluted with ether, and the solid constituents were filtered off with suction. After washing with ether, the phases were separated, and the organic phase was washed with water (2×) and saturated NaCl solution. Drying and concentrating gave 65.2 g (88% of theory) of a colorless oil which was further employed directly.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][N:4]1[CH2:6][CH2:5]1.[N:13]#[C:14][SH:15]>O1CCOCC1>[S-:15][C:14]#[N:13].[NH:13]=[C:14]1[N:4]([CH2:3][CH:2]([OH:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][S:15]1
Reactant: OC(CN1CC1)c1ccccc1
Reactant: N#CS
Solvent: C1COCCO1
Product: N#C[S-]
Product: N=C1SCCN1CC(O)c1ccccc1
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 1-hydroxy-1-phenyl-2-ethyleniminoethane (16.3 g) in dioxan (35 ml) was added dropwise and with stirring at 0° C to an aqueous solution of thiocyanic acid (200 ml of 1N solution). After the addition the mixture was stirred in the cold for 1 hour. It was then heated under reflux for 1 hour and the solution cooled. The desired compound crystallised in 96% yield, m.p. 160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[C:13](CCC(Cl)=S)(=[O:15])[CH3:14].[SH:21][CH2:22][CH:23](SC)[C:24](N1[C@H](C(O)=O)CC2(C(=O)CCC2=O)C1)=[O:25]>>[C:13]([S:21][CH2:22][CH2:23][C:24]([N:6]1[CH2:7][C:3]([O:11][CH3:12])([O:2][CH3:1])[CH2:4][C@H:5]1[C:8]([OH:10])=[O:9])=[O:25])(=[O:15])[CH3:14]
Reactant: CSC(CS)C(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Reactant: COC1(OC)CN[C@H](C(=O)O)C1
Reactant: CC(=O)CCC(=S)Cl
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1

Procedure:
4,4-Dimethoxy-L-proline is reacted with 3-acetylthiopropionyl chloride according to the procedure of Example 3 (d) to yield 1-[3-(acetylthio)-1-oxopropyl]-4,4-dimethoxy-L-proline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)C.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: NCCCCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCCCCCO)c(OC)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 5-aminopentan-1-ol (194 mmol), 2,4-dimethoxybenzaldehyde (213 mmol) and acetic acid (213 mmol) in methanol (500 ml) was stirred at 10° C. for 0.5 h. NaBH4 (22 g) was added portionwise at −10° C. and the mixture was stirred for 10 minutes. Then the reaction mixture was allowed to warm to 10° C. and stirred for 1.5 h. Saturated NaHCO3 was added and the mixture was stirred for 0.5 h. The mixture was extracted by CH2Cl2 (3×100 ml). The combined organic phase was washed by saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. Yield: 46 g (69% purity, 65% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][O:18][CH2:19][C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])[C:21]=1[CH3:38]>CN(C)C=O>[ClH:26].[CH3:17][O:18][CH2:19][C:20]1[N:25]=[C:24]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:23]=[C:22]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])[C:21]=1[CH3:38]
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 45.2 %

Procedure:
After 2-methyl-4-fluoroaniline(0.62 ml, 4.5 mmol) and triethylamine (0.63 ml, 4.5 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.96 g, 3 mmol) in dimethylformamide(5 ml), 600 mg of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]2=[O:28])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(F)=C(C(F)=CC=1)OC1CN([C@@H](CC2CCCCC2)C([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][C:49]([OH:52])(C)C)[N:44]=2)=O)C(=O)C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:76]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:25])[F:27])=[CH:14][C:13]2=[O:28])[C:9]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH2:49][O:52][CH3:76])[N:44]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)ccc(Cl)c3F)=CC2=O)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2C(F)(F)F)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3ccccc3C(F)(F)F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared as in Example 32, 307 mg, 0.77 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in U.S. Pat. Appl. US2008021032 Example 72, 130 mg, 0.92 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (663 mg, 1.5 mmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 70% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide. This material was dissolved in dichloromethane (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The solid was filtered to give (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide hydrochloride (133 mg, 31%) as a light yellow solid: LR-ES-MS m/z calculated for C26H23F3N4O4 [M]+ 520, observed [M+H]+ 521; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-1.40 (m, 6H) 1.40-1.83 (m, 7H) 3.19 (s, 3H) 3.62 (t, J=5.2 Hz, 2H) 4.12 (t, J=5.2 Hz, 2H) 4.16 (d, J=18.7 Hz, 1H) 4.57 (d, J=18.7 Hz, 1H) 4.88 (dd, J=10.6, 5.4 Hz, 1H) 4.94 (s, 1H) 6.39 (d, J=2.1 Hz, 1H) 7.51 (t, J=7.2 Hz, 1H) 7.55 (d, J=2.1 Hz, 1H) 7.64 (d, J=7.8 Hz, 1H) 7.73-7.90 (m, 2H) 10.75 (s, 1H).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].[OH-].[K+]>C1COCC1.O>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Boc-Gly-Pro-Nleu-OEt (4.3 g, 0.0104 mol.) was dissolved in 80 ml THF/H2O (v/v, 1:1) and the solution was chilled to 0° C. on a water-ice bath. KOH (1.1 g dissolved in 20 ml H2O) was added while stirring the solution. After a while, the bath was removed and the stirring was continued for one more hour. The THF was removed under reduced pressure. The aqueous solution was extracted by ethyl acetate 2×50 ml. Then, the aqueous layer was chilled to 0° C. and was acidified to about pH=3 by addition of concentrated HCl while swirling the solution vigorously at the same time (the aqueous layer was covered by 50 ml ethyl acetate). The product was extracted from the aqueous layer by ethyl acetate 3×50 ml. The organic layer was combined and dried by Na2SO4. The ethyl acetate was removed under reduced pressure. Column chromatography (E/H:5:2) was carried out to obtain the pure product (white solid, 3.6 g, 92%). TLC Rf=0.44 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+ =386. Analytical RP-HPLC chromatogram, single peak, retention time RT=13 min. (25-60% B in 30 min.). 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ 12.50 (s, 1H, carboxyl), 6.62 (m, 1H, Gly-NH), 4.92 (d, Pro-α), 4.72 (d, Pro-α), 4.56 (d, Nleu-α), 4.48 (d, Pro-α), 4.12 (m, Nleu-α), 4.00-3.90 (m, Nleu-α), 3.83-3.66 (m, Nleu-α, Gly-α), 3.64-3.50 (m, Gly-α, Nleu-α), 3.50-3.33 (m, Pro-δ), 2.34-1.60 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 1.38 (s, 9H, Boc-CH3), 0.88 (dd, Nleu-δ), 0.75 (dd, Nleu-δ).