Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1.C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NCCCc1ccccc1
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NCCCc1ccccc1)NCc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of 3-phenylpropyl isocyanate (1.8 mmol) in anhydrous THF (10 mL) at 0° C. under an argon atmosphere was added 2-aminomethyl-pyridine (1.8 mmol). The reaction mixture was stirred at 0° C. for 10 min, the solvent was evaporated under reduced pressure, and the resultant solid was recrystallized from CH2Cl2/Et2O to give pure 59.1 in 92% yield. White solid. m p 89-90° C. When anhydrous benzene was used as solvent the product was directly crystallized out and isolated by filtration (93% yield).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:32])=[O:8])=[O:31])[CH3:30])=[O:29])[CH3:28])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of 0.015 moles of t-butyloxycarbonylalanylalanylproline benzyl ester in 50 ml of methanol is reduced with hydrogen at 40 lbs pressure in the presence of 1 gm of 10% Pd/C. The reaction mixture is filtered and concentrated in vacuo to give t-butyloxycarbonylalanylalanylproline.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[N:23]1[N:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]2=[C:25]([C:32](O)=[O:33])[CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[OH:22][CH2:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:32]([C:25]2[CH:24]=[N:23][N:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:26]=23)=[O:33])[CH:12]=1
Reactant: O=C(O)c1cnn2cccnc12
Reactant: COc1ccc(/C=C/CO)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(/C=C/CO)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of diisopropylethylamine (0.25 mL), (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol (90 mg), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (65 mg), HOBT (85 mg) and HBTU (0.20 g) in anhydrous acetonitrile (5 mL) was heated to 80° C. overnight. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/EtOAc, 3/97) to give an oil. This residue was triturated with ethyl acetate to give, upon standing for 1 hour, 20 mg of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol as a light brown solid which was collected by filtration. MS=325 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]([OH:27])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:48][CH2:47][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:45][CH2:44]1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[C:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:25]([N:43]2[CH2:44][CH2:45][CH:46]([O:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:48]2)=[O:27])=[CH:15][CH:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
11.14 g (30 mmol) of N-(benzyloxycarbonyl)-O-(1,1-dimethylethyl)-L-tyrosine were dissolved in 65 ml of ethyl acetate while warming to 40°. The solution was treated at 20° with 0.1 g (0.9 mmol) of N-hydroxysuccinimide. Subsequently, a solution of 7.5 g (36 mmol) of dicyclohexylcarbodiimide in 40 ml of ethyl acetate was added dropwise at 22° within 25 minutes. A white suspension formed during the addition and this was stirred for 30 minutes. A solution of 7.8 g (36 mmol) of t-butyl (4-piperidinyloxy)acetate in 100 ml of ethyl acetate was then added dropwise to the suspension within 30 minutes. A suspension formed and this was stirred at 22° for 3 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 2N hydrochloric acid, water and semi-saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. The residue was a viscous oil and weighed 18.5 g. The oil was diluted with a mixture of 10 ml of ethyl acetate and 60 ml of hexane and warmed to 50°. The insoluble solid was filtered off under suction and the filtrate was treated with 20 ml of hexane and seeded with a small amount of crystalline product at 30°. The mixture was cooled to 0° within one hour and stirred at this temperature for 30 minutes. The crystals were then filtered off under suction and washed on the filter with 20 ml of hexane. 14.5 g (85%) of benzyl [(S)-p-t-butoxy-α-[[4-[(t-butoxycarbonyl)methoxy]-piperidino]carbonyl]phenethyl]carbamate were obtained in this manner. Its content was 96% according to HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH:42][CH2:41][CH2:40][CH2:39][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: O=CCCCc1ncccn1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(C=CCCCc1ncccn1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To the 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (902 mg, 2.0 mmol) suspended in anhydrous THF (15 ml), under Nitrogen, cooled to between −20 and −30° C. was added sequentially Lithium bis(trimethylsilyl)amide (1.0M in THF, 4.0 ml), Chlorotrimethylsilane (217 mg, 2.0 mmol, 253 μl) and 4-pyrimidin-2-ylbutanal (300 mg, 2.0 mmol). The mixture was stirred at −20° C. for 1 hour, quenched with saturated ammonium chloride solution and allowed to stand at ambient temperature overnight. The solvents were removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (5 ml), the organics separated and chromatogrammed (50 g Silica Bond Elute, eluted with 0→100% Ethyl Acetate/Hexane gradient) to give the 2-(5-[4-(4-bromophenyl)piperazino]sulfonylpent-4-enyl)pyrimidine as a white crystalline material (759 mg, 84% Yield)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:42])[N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:32][C:33](=[O:42])[N:34]([CH:35]1[CH2:36][CH2:37][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:39][CH2:40]1)[CH3:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(N(C)C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction mixture is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and methyl-piperidine-4-yl-carbamic acid tert-butyl ester (773.2 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (470 mg; quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:15][C:16]4[NH:17][C:18]([CH3:21])=[N:19][C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C=O>[Si:34]([O:33][CH2:32][CH2:31][CH2:30][N:19]1[C:20]2[C:10]3[O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:22]([N:24]([CH3:25])[CH3:26])=[O:23])=[CH:15][C:16]=2[N:17]=[C:18]1[CH3:21])([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2[nH]1)CCC(c1ccc(F)cc1)O3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1CCCO[Si](C)(C)C(C)(C)C)OC(c1ccc(F)cc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 8-(4-fluorophenyl)-N,N,2-trimethyl-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (52.0 mg, 0.147 mmol, Step 8) in N,N-dimethylformamide (1.5 mL), was added sodium hydride (7.1 mg, 0.18 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Then (3-bromopropoxy)(tert-butyl)dimethylsilane (48.4 mg, 0.191 mmol) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature, stirred for 4 hours and left at the same temperature overnight. The reaction was quenched by saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine. It was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with hexane/ethyl acetate (1:1 and then 1:4) to afford the title compound as a brown oil (35.5 mg, 46%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]([C:1](=[O:3])[CH3:2])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CC(=O)Cl
Reactant: CCC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(CCN(C(C)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.57 g. (45.5 mmole) acetyl chloride in 50 ml. methylene chloride is slowly added dropwise to an ice-cold mixture of 16.0 g. (45.5 mmole) 4-chlorobenzenesulphonic acid-(4-propionylphenethylamide), 5.1 ml. (50 mmole) triethylamine and 200 ml. methylene chloride. The reaction mixture is then stirred for 3 hours at ambient temperature, extracted with 2N hydrochloric acid and several times with water, dried with anhydrous sodium sulphate and evaporated. After chromatography with silica gel/toluene +ethyl acetate (12:1 v/v), there are obtained 10.2 g. (57% of theory) of the desired product; m.p. 91°-92° C. (after recrystallisation from heptane +toluene).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:43]=[C:44]([Cl:46])[CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:38])=[C:4]([S:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[S:47]([C:42]3[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=3)(=[O:49])=[O:48])=[CH:16][CH:15]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)N(Cc1ccc(F)cc1)Cc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
To a solution of 3,5-dichloro-N-(4-fluorobenzyl)-N-(4-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (47 mg, 0.10 mmol) in CH2Cl2 (1 mL) were added 3,5-dichlorobenzene-1-sulfonyl chloride (25 mg, 0.10 mmol) and diisopropylethylamine (0.042 mL, 0.30 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated. The residue was dissolved in methanol and purified by prep HPLC to give the title compound (9.9 mg, 12%) as a white solid. 1H NMR (DMSO-d6) δ 11.17 (br s, 1H), 7.96 (t, 1H, J=5.1 Hz), 7.84 (d, 1H, J=2.1 Hz), 7.76 (d, 2H, J=2.5 Hz), 7.57 (d, 1H, J=2.1 Hz), 7.18-6.97 (m, 12H), 4.40 (s, 2H), 4.37 (s, 2H), 4.35 (s, 2H), 4.34 (s, 2H); MS (ESI) 786.8 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(OC)nn12
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(OC)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (134 mg) in tetrahydrofuran (10 mL), tetrahydro-2H-4-pyrancarbaldehyde (131 mg) and sodium triacetoxyborohydride (243 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the obtained reaction mixture, extraction was performed with ethyl acetate, and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (120 mg) was obtained from the n-hexane:ethyl acetate (4:1) fraction as a yellow amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34](=[N:36]O)[NH2:35]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: NC(=NO)c1c(F)cccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 17 mg (18% of theory)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:23]C1C=C(S(Cl)(=O)=O)C=CC=1>>[F:23][C:7]1[CH:2]=[C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1cccc(F)c1

Procedure:
Following the 14a synthetic method, using 3-fluorobenzenesulfonyl chloride (66.19 μL, 0.5 mmol) instead of 2-fluorobenzenesulfonyl chloride gave 15a as a colorless oil; (103.95 mg, 64.3%). [α]D25: −16.5 (c=0.31, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.49-7.32 (m, 3H), 7.25-7.20 (m, 4H), 7.10-7.08 (m, 2H), 5.45 (d, J=7.8 Hz, 1H), 4.25 (m, 1H), 3.19-2.91 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 163.89, 160.56, 141.51, 134.71, 130.88, 129.34, 128.68, 127.47, 122.75, 120.24, 119.96, 114.49, 114.17, 56.86 38.74; HRMS (ESI): calcd for: C15H14FNO4S [M−H]−=322.0555, obsd [M−H]−=322.0549.
Reaction SMILES: Br[CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:11][CH:12]=1)[C:3]([O-:5])=[O:4].[CH2:27]1CCN2C(=NCCC2)CC1.C1(C)C=CC=CC=1>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7](/[CH:6]=[CH:2]/[C:3]([O:5][CH3:27])=[O:4])=[CH:12][N:11]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(Br)C(=O)[O-])cn1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 2-bromo-3-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl]propionate (4.00 g), 1,8-diazabicyclo[5,4,0]-7-undecene (1.41 g) and toluene (80 ml) was stirred 2 hours at 90°-100° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual oily product was subjected to a silica gel chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v) was obtained methyl (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-pyridyl]acrylate (2.71 g, 83%). Recrystallization from diethyl ether-isopropyl ether gave colorless prisms, m.p. 116°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH2:5].[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH:5][C:13](=[O:14])[N:12]([CH3:16])[CH3:11]
Reactant: NOc1cc(Cl)ccc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)NOc1cc(Cl)ccc1Cl
Reaction time: 12 h
Yield: 61.9 %

Procedure:
5.00 g (28.1 mmoles) of 2,5-dichlorophenoxyamine was dissolved in 6.8 ml of pyridine, and then 3.02 g (28.1 mmoles) of dimethylcarbamoyl chloride was added. The mixture was stirred at a temperature of from 25° to 30° C. for 12 hours. After an addition of 200 ml of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and precipitated crystals were washed with hexane, whereby 4.33 g of the desired product was obtained as light yellow crystals (yield: 62%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1>C(O)C>[C:4]([C:3]1[CH:10]=[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][N:12]2[CH:2]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ncnc2ccccc12
Solvent: CCO
Product: CCOC(=O)c1cc2c3ccccc3ncn2c1

Procedure:
A solution of ethyl bromopyruvate (3.2g, 0.016 m) and 4-methylquinazoline (2.0g, 0.014 m) in dry ethanol (150 ml) was heated at reflux for two hours. During this time, a tan solid formed. Excess ethyl bromopyruvate was added (1.0g) and the reaction mixture was allowed to reflux overnight. After this time, the reaction was complete. The alcohol was removed in vacuo and the residue diluted with H2O. Sodium bicarbonate was added until effervescence ceased and the aqueous mixture extracted with ether. The ether extracts were combined, dried over Na2SO4, filtered and the solvent removed in vacuo to yield a tan solid. Crystallization from MeOH afforded the product as a white solid; m.p. 138°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:21]=[O:22])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:10](=[O:12])[CH:11]=1.[Br:28]NC(=O)CCC(N)=O>C(#N)C>[Br:28][C:11]1[C:10](=[O:12])[N:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:8]([CH:21]=[O:22])=[CH:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1c(F)cccc1F
Solvent: CC#N
Product: O=Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 ml one neck round bottom flask 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde (0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reaction mixture was cooled to 0° C. in ice bath and charged with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was allowed to stir at 0° C. for 2 hours under nitrogen atmosphere After 2 hours, the solvent was evaporated under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.73-7.67 (m, 2H), 7.62-7.54 (m, 1H), 7.35 (dt, J=10.40, 2.56 Hz, 1H), 7.27 (t, J=8.35 Hz, 2H), 7.19 (dt, J=8.60, 2.44 Hz, 1H), 5.72 (s, 1H), 5.50 (s, 2H); ES-MS m/z 455.9836 (M+H calcd for C19H11BrF4NO3, requires 455.9859).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH2:24])=[O:23])=[N:20][CH:21]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(F)cn1
Reactant: Oc1ccc(C2OCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2)cn1
Temperature: 25 °C

Procedure:
Dissolve 4-[1,3]dioxolan-2-ylphenol (Part C2, 0.471 g, 2.85 mmol) in DMF (89.5 mL). Add NaH (80% in mineral oil) (0.128 g, 4.28 mmol). Stir at room temperature for about an hour before adding 5-fluoropyridine-2-carboxamide (0.400 g, 2.85 mmol). Heat at 80° C. for 4.5 hours before concentrating to dryness to form 5-(4-[1,3]dioxolan-2-ylphenoxy)pyridine-2-carboxamide.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[CH3:14][O:12][C:11](=[O:13])[C@@H:8]1[CH2:7][C@@H:6]([OH:5])[CH2:10][NH:9]1
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Thionyl chloride (5.6 mL, 76.3 mmol) was added dropwise to dry methanol (76 mL) at −20° C., following by addition of trans-4-hydroxy-L-proline (5.0 g, 38.1 mmol). The resulting mixture was allowed to warm to rt and stirred for 20 h. The solvent was removed under reduced pressure, and the residue was further dried under high vacuum to provide trans-4-hydroxy-L-proline methyl ester 1 as a white solid: 1HNMR (300 MHz, DMSO-d6) δ 2.18-2.23 (m, 2H), 3.06 (m, 1H), 3.32-3.36 (m, 2H), 3.76 (s, 3H), 4.42 (br. s, 1H), 4.48 (dd, J=5.4, 8.1 Hz, 1H), 5.56 (br. s, 1H); EIMS m/z 146 ([M]++1).