Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])=[O:3].[C:11]([O:15][C:16](=[O:44])[NH:17][C:18]([C:20]1[S:21][C:22]([S:42][CH3:43])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH2:41])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:44])[NH:17][C:18](=[NH:19])[C:20]1[S:21][C:22]([S:42][CH3:43])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[NH:41][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 24 h
Yield: 86.3 %

Procedure:
4-Methanesulfonyl-butyryl chloride (0.333 g, 1.81 mmol) [example 209, step a] was added to a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.468 g, 0.905 mmol) [example 25, step c] and triethylamine (1.83 g, 18.1 mmol) in dichloromethane at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.520 g, 78%) as a solid. ESI-MS (m/z): Calcd. for C29H35N3O7S4: 665.14; found: 665.8.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NS(C)(=O)=O)cc3F)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 34-1 (49 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in 2 mL of DCM, was added mesyl chloride (10 μL, 0.13 mmol). After 2 h, a second equivalent of triethylamine (17 μL, 0.12 mmol) and mesyl chloride (10 μL, 0.13 mmol) was added. After 1 h, the mixture was washed with brine, concentrated and purified on preparative HPLC to give 44-1: LC-MS 489.1 (MH), tR=7.31 (Method 2). EC50: 170 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:11]([CH3:13])[CH3:12])[O:8][C:9](=O)[C:4]=2[CH:3]=1.[CH3:16][NH2:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[N:6]=[C:7]([CH:11]([CH3:13])[CH3:12])[N:17]([CH3:16])[C:9]2=[O:8]
Reactant: CN
Reactant: CC(C)c1nc2ccc(Cl)cc2c(=O)o1
Product: CC(C)c1nc2ccc(Cl)cc2c(=O)n1C
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of 6-chloro-2-isopropyl-benzo[d][1,3]oxazin-4-one (2.75 g, 12.3 mmol) and methylamine (7.4 mL, 14.8 mmol, 2M solution in MeOH) were heated to 90° C. for 24 hours. The solvent was removed in vacuo and the residue was heated under reduced pressure to 160° C. for 2 hours. The reaction mixture was purified by column chromatography (0-30% ethyl acetate-hexanes) to yield the product (960 mg, 33%). 1H NMR H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.4 Hz, 1H), 7.65 (dd, J=8.7, 2.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 3.69 (s, 3H), 3.22 (septet, J=6.7 Hz, 1H), 1.39 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([C:13]([CH:15]([N:17]2[CH2:22][CH2:21][C:20]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[C:23]3=[O:32])[CH2:19][CH2:18]2)[CH3:16])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(C)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH:15]([N:17]2[CH2:18][CH2:19][C:20]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[C:23]3=[O:32])[CH2:21][CH2:22]2)[CH3:16])=[CH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC2(CC1)C(=O)N(C)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C(O)c1ccc(OCc2ccccc2)cc1)N1CCC2(CC1)C(=O)N(C)c1ccccc12

Procedure:
A mixture of 4.5 g of 1'-[1-(4-benzyloxybenzoyl)ethyl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, 5.6 g of sodium borohydride and 150 ml of isopropylalcohol was refluxed for 1 hour. The resulting mixture was poured into water and was extracted with ethylacetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was recrystallized from ethanol to give 1'-[1-(4-benzyloxyphenyl)-1-hydroxypropane-2-yl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[N:4][N:3]=1.[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[Cl:14][C:12]1[CH:13]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(N)c(Cl)c2)o1
Temperature: 40 °C
Yield: 49.2 %

Procedure:
To a mixture of 4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (0.220 g, 1.26 mmol) and anhydrous DMF (1.9 mL) was added N-chlorosuccinimide (0.168 g, 1.26 mmol). The reaction mixture was heated at 40° C. for 1.5 hours under argon before being allowed to cool to room temperature and partitioned between EtOAc (90 mL) and saturated aqueous NaHCO3 (15 mL). The organic layer was washed with saturated aqueous NaHCO3 (15 mL), dried (Na2SO4) and concentrated in vacuo. The brown residue was absorbed on silica gel (1.4 g), and purified using silica gel column chromatography eluting with a gradient of 0-30% EtOAc in CH2Cl2 to afford the title compound as a white solid (0.130 g, 49%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26].CCN(CC)CC>C(Cl)Cl>[F:15][C:16]1[C:21]([O:22][S:2]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)(=[O:4])=[O:3])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Preparation 2, 606 mg, 2.1 mmol, 1 eq) in DCM (35 ml) was added pentafluorophenol (412 mg, 2.2 mmol, 1.1 eq) and Et3N (540 mg, 5.4 mmol, 2.5 eq) and the reaction mixture stirred at room temperature until all of the starting material was consumed. The solvent was evaporated in vacuo and the residue redissolved in ethyl acetate (10 ml), washed with water (10 ml), saturated sodium hydrogen carbonate (10 ml), dried over sodium sulphate, filtered and evaporated to yiled the title compound as a white solid (690 mg, 1.8 mmol, 85%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2cc(F)ccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc(OCc2cc(F)ccc2F)cc1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 16.51 g, 47.4 mmol) in abs ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified with 1M HCl and concentrated in vacuo. The crude mixture was taken in chloroform and washed with water. The aqueous layer was washed one more time with chloroform. The combined organic layers were dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:11](O)=[O:12].S(=O)(=O)(O)O>>[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=1)[C:11]([O:4][CH2:3][C:2]([Cl:6])([Cl:5])[Cl:1])=[O:12]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(OCC(Cl)(Cl)Cl)c1cc(O)cc(O)c1
Temperature: 90 °C
Yield: 61.4 %

Procedure:
To freshly distilled 2,2,2-trichloroethanol (25 mL) was added 3,5-dihydroxybenzoic acid 4.50 g, 29.2 mmol) followed by concentrated sulfuric acid (1.0 mL), and mixture was stirred vigorously and heated at 90° C. for 48 h under nitrogen. The reaction mixture was cooled and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography eluting with CH2Cl2 gradually increasing to 1:10 diethyl ether/CH2Cl2, to give (2,2,2-trichloroethyl) 3,5-dihydroxybenzoate as a viscous oil (5.12 g, yield 61.4%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:35])[C:32](Cl)=[O:33])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:32](=[O:33])[CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH3:35])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc(C(C)C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NC(=O)C(C)c3ccc(OC)cc3)c(Cc3ccccc3)n2)cc1
Temperature: 55 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (8 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 2-(4-methoxyphenyl)propanoyl chloride (16) prepared above at room temperature, and the mixture was heated with stirring at 55° C. for 14 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified twice by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1, and silica gel 50 g, n-hexane/ethyl acetate=9/1→6/1) to give Compound 11w (942 mg, <quant.) as a colorless foamy solid containing some impurities.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:17]2[CH:18]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c2c(N)ncnc21

Procedure:
A solution of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 0.018 mmol), 3-biphenylboronic acid (18 mg, 0.091 mmol), K3PO4 (19.3 mg, 0.091 mmol) and Pd(PPh3)4 (12.5 mg, 0.011 mmol) in DMF (3 mL) was heated to 60° C. under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 301.1, found 301.3.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN.C[CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:20]([NH:35][CH3:34])=[O:22])[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (308 mg, 0.75 mmol), methylamine (40 wt % in water, 174 μL, 2.25 mmol), and DIEA (415 μl, 2.25 mmol) in DMF (7.5 mL) cooled to 0° C. was added HATU (569 mg, 1.5 mmol). The reaction mixture was allowed to warm slowly and stirring continued for 18 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in DCM (10 mL), dried over MgSO4 and evaporated. The crude product was purified by column chromatography to afford 226 mg (71%) of tert-butyl (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate. LCMS-ESI (m/z) calculated for C24H28N2O5: 424.2. found 447.1 [M+Na]+, tR=3.12 min. (Method 16).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:24]([O:27][C:28](Cl)=[O:29])[CH2:25][CH3:26]>ClCCl>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:28]([O:27][CH2:24][CH2:25][CH3:26])=[O:29])[CH2:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCOC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.0 g benzyl 1-piperazinecarboxylate in 100 ml dichloromethane were added 20.7 ml triethylamine. The solution was cooled to 0° C. and 8.4 ml propylchloroformate added dropwise at this temperature. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 19.3 g.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:15]1=[O:38])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:35])[F:36])[C:15]1=[O:38])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Reaction time: 2 h
Yield: 68.3 %

Procedure:
3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.21 g, 2.27 mmol) was added to 50 mL of a stirring solution of 15% TFA/methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 100 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1-5% methanol/methylene chloride) gave 670 mg (68%) of a light pink foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(O)c(Cl)c1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
The mixture of 3-chloro-4-hydroxybenzaldehyde (0.783 g, 5 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (2.72 g, 7.5 mmol) in anhydrous tetrahydrofuran (25 mL) was heated at 60° C. under nitrogen for 4 hours. The solvent was removed in vacuo and purified by silica gel chromatography (40% EtOAc in hexanes) to provide ethyl 3-(3-chloro-4-hydroxyphenyl)-2-methylacrylate (515) (1.11 g, 95.2%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[OH-].[K+]>CO>[F:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:4]([OH:24])=[O:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F
Yield: 88.6 %

Procedure:
1.9 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester is refluxed with 40 ml of potassium hydroxide in methanol (10%) for 2 hours. After the solvent is concentrated by evaporation in a vacuum, water is added, it is extracted with hexane, and the separated water phase is acidified with 6N hydrochloric acid. After extraction with ethyl acetate, the ethyl acetate phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized from hexane. 1.55 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid, melting point 102-104° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]([N:14]=[C:15]=[S:16])(=[O:13])[O:10][CH2:11][CH3:12]>O1CCOCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:9]([NH:14][C:15]([NH:8][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[S:16])=[O:13])[CH3:12]
Reactant: Nc1cc(Cl)ccn1
Reactant: CCOC(=O)N=C=S
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 4-chloropyridin-2-amine (2.16 g, 16.8 mmol, Eq: 1.00) in dioxane (70 ml) was added O-ethyl carbonisothiocyanatidate (2.2 g, 1.9 ml, 16.8 mmol, Eq: 1.00) at 25° C. The resulting mixture was stirred for 2 hours at 25° C. The mixture was diluted with ethyl acetate and washed with water and brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1-ethoxycarbonyl-3-(4-chloro-pyridin-2-yl)-thiourea (4.02 g/92.1%) as a green waxy solid. MS: m/e=257.9 (M−H+)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35]>>[CH3:30][O:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:16]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: COCC(C)(C)CN
Agent: Cl
Product: COCC(C)(C)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 54 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 3-methoxy-2,2-dimethylpropan-1-amine hydrochloride, the title compound as yellow solid (54%).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:23])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:23])=[O:19])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(c1ccccc1)c1ccc2n1CCCC2C(=O)O
Solvent: ClCCl
Product: COC(=O)C1CCCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A solution of 269 mg. of 3-benzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid in 10 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 3-benzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:21])[NH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.05 g of NaH (80% suspension in mineral oil), 9.5 g of 5-(4-chlorophenyl)-1-phenyl-4-imidazolin-2-one, 70 cc. of DMF, 8.3 g of 8-bromocaprylic acid methyl ester and 1.05 g of NaJ.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O-:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:18](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)[O-])CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5 g) in acetonitrile (22 ml) and methanol (2 ml) was treated with diisopropylethylamine (3.65 ml) and trimethylsilyldiazomethane (2M in hexane, 13.9 ml). After overnight stirring and evaporation of solvent, the crude product was chromatographed on silica gel (0–50% ethyl acetate/petrol) to give a yellow oil (4 g, 76%).