Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][C:7](=O)[CH3:8])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:28]>C(OCC)(=O)C>[CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])/[CH:6]=[C:7](\[NH2:28])/[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Reactant: N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C/C(N)=C/C(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
N-Isopropyl-3-oxo-N-[4-(phenylamino)phenyl]butyramide (30.0 g, 0.0967 mol) and conc. acetic acid (1.4 g, 0.0233 mol) in ethyl acetate (140 g) were introduced into an autoclave. Ammonia (16.0 g, 0.9395 mol) was introduced in the course of 10 minutes and the temp. of the reaction mixture was increased to 35° C. during this period. After the introduction a pressure of 14 bar is present. The temperature of the reaction mixture was heated to 70° C. in the course of 30 min. In the course of this, the pressure rose to 17 bar. After 2.5 h under these conditions, the reaction mixture was cooled to 25° C. and ammonia was released. The reaction mixture was further cooled to 5° C. in order to crystallize the product. The suspension was filtered. The pale grey solid was washed with cold (0° C.) ethyl acetate (20 ml) and dried in vacuo (50 mbar) at 35° C. for 2 days. (Z)-3-Aminobut-2-enoic acid N-isopropyl-N-[4-(phenylamino)phenyl]amide (27.2 g, 91.0%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:14])(O)[C:11]#[N:12]>>[CH3:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:14])[C:11]#[N:12]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(O)C#N
Product: Cc1ccc(NC(C)(C)C#N)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of p-toluidine (1.07 g, 10 mmol) and acetone cyanohydrin (10 ml) was heated to 80° C. and stirred for 4 h. The medium was concentrated and dried under vacuum to yield 2-methyl-2-(4-methylphenyl)aminopropanenitrile, 5a (1.72g, 9.9 mmol, 99%) as brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]([C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=1)[C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:27]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: N#Cc1c(N)nc2ccccc2c1NCc1ccccc1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)N(C(=O)c2cccc(C)c2)c2nc3ccccc3c(NCc3ccccc3)c2C#N)c1
Temperature: 0 °C

Procedure:
To the solution of 5 g of 2-amino-3-cyano-4-benzylaminoquinoline in 30 ml of pyridine 6 ml of 3-methylbenzoyl chloride are dropped, under stirring at 0° C. The reaction mixture is stirred at 80° C. for 8 hour, then it is poured onto 150 ml of ice-water. The precipitate is filtered off, washed twice with 40 ml of water. The resulting white crystalline material is recrystallized from 200 ml of ethanol to give 9.2 g of the title compound, mp.: 234° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 104.4 %

Procedure:
A solution of (1R,2S,5S)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (200 mg, 0.4 mmol, obtained from Example 12b, Step 6 above), in methanol was treated with 60 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 130 mg of (1R,2S,5S)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=312.3.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH:23][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Reaction time: 8 h
Yield: 33.9 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (Example 437, Part B) (0.150 g, 0.617 mmol), 3,3-dimethylbutylamine (0.0624 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO®0 pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol, ethyl acetate and hexanes. After concentrating, take the product up in dichloromethane (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.0687 g, 33.8%): MS ES+ 329.1 (M+H)+, base peak 228.0 (M-C6H15N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.2 min, 100% purity.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[C:8]2[C:7](=[O:37])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1

Procedure:
A solution of cis-tert-butyl 2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (109 mg, 0.183 mmol) in TFA (5 mL) was heated at 60° C. for 2 h. After removal of the solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to give the title compound as a TFA salt. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.47 (br s, 2H), 1.57-1.75 (m, 3H), 1.84 (br s, 2H), 3.12-3.23 (m, 2H), 3.87-3.94 (m, 3H), 4.35-4.50 (m, 3H), 6.73 (br s, 1H), 7.71 (br s, 2H), 8.28-8.44 (m, 2H), 8.84 (d, J=3.91 Hz, 1H). [M+H] calc'd for C17H21FN6O, 345. found, 345.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].F[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
To a solution of 3-trifluoromethylphenol (29 g, 0.18 mol) dissolved in dimethylformamide (100 ml) was added finely-powdered potassium hydroxide (15 g, 0.19 mol). The reaction mixture was heated to approximately 60° C., with stirring, for one hour after which time 2,5-difluorobenzonitrile (25 g, 0.19 mol) was added and the temperature increased to 110° C. After approximately half an hour, the reaction mixture was allowed to cool and excess dimethylformamide was removed in vacuo before 500 ml of a 50:50 mixture of water and trichloromethane was added. The organic layer was separated, washed and dried and the residue purified by chromatography using a silica column with trichloromethane as eluant, followed by distillation and recrystallisation to yield the title compound as a solid.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:21]>C(OCC)(=O)C>[ClH:21].[C:8]1([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]2[CH3:1])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CNCCN1c1ccccc1
Reaction time: 0.25 h

Procedure:
(±)-tert-Butyl 3-methyl-4-phenylpiperazine-1-carboxylate (142 mg) was dissolved in 4N hydrogen chloride in ethyl acetate (5 ml). After stirring for 15 minutes, the solvent was removed under reduced pressure to give the title compound as a slightly yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:25][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
At a temperature of 0° C., p-toluenesulfonylchloride (6.0 g, 30.4 mol) was added portionwise to a stirred solution of (S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (4.9 g, 24.3 mmol) and pyridine (14.6 ml, 181 mmol) in dichloromethane (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. and then allowed to stand for 15 hours at ambient temperature. Then dichloromethane (50 ml) was added. The solution was washed with water (4×50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (9.83 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1) to afford 8.07 g (83.4% of theory) of (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil. 1H NMR (400 MHz, DMSO): δ 1.29 and 1.35 (s, 9H), 1.72 (m, 3H), 1.92 (m, 1H), 2.43 (s, 3H), 3.18 (m, 2H), 3.83 (m, 1H), 4.03 (m, 2H), 7.49 (d, 2H), 7.78 (d, 2H). MS [M+H]+ 256. [α]23D=−39.1 (c 5.98, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][O:1][C:2]3[CH:13]=[CH:12][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCCCc2ccc(O)cc21
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (20 ml) were added potassium carbonate (2.76 g, 20.0 mmol) and 4-phenylbenzyl bromide (2.72 g, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (30 ml) and THF (30 ml) were added to the residue and the resulting mixture was washed with water (10 ml, 5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was mixed with diisopropyl ether, and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain 3-(4-phenylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (3.00 g, 8.76 mmol, 88%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.CCOC(C)=O>>[C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCNCC1

Procedure:
1-Acetyl-4-tert-butoxycarbonylpiperazine was treated with 8 M HCl/EtOAc to afford the title compound in near quantitative yield.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:24]([CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11][N+:12]([O-:14])=[O:13])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][O:29][CH3:30])[N:17]=[C:16]([CH3:31])[N:15]=1>CN(C=O)C>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[C:16]([CH3:31])[N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: COCCOc1ccccc1-c1cc(Cl)nc(C)n1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Solvent: CN(C)C=O
Product: COCCOc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)nc(C)n1
Temperature: 90 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.1 g, 0.54 mmol) and 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidine (0.16 g, 0.0.57 mmol) in DMF (3 mL) was stirred at 90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding (3-{6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 83) as beige powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:13]([O:15][C:16]([C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][C@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21](Cl)=[O:22])=[O:17])[CH3:14]>O>[CH2:13]([O:15][C:16]([C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][C@H:20]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:21]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:22])=[O:17])[CH3:14]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solution of 1.5 g of 3-aminopropionic acid and 1.8 g of sodium carbonate in 30 ml of water at 0° is added to 2.2 g of 4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is extracted with ether, and the aqueous layer is acidified with 2N hydrochloric acid. The acidic solution is extracted with ethyl acetate, washed with saturated brine, dried (magnesium sulfate), filtered and concentrated. The residue is recrystallized from ether to yield N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, melting at 84°-86°; NMR (CDCl3) δ10.5 (1H, CO2H), 6.1 (t, 1H, J=6 Hz, NH), 4.1 (q, 2H, J=8 Hz, OCH2), 1.08 (t, 3H, J=8 Hz, CH3).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=2[CH3:37])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)cc2C)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methyl-phenylboronic acid, 5-(4-fluoro-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=72%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[N:54]1([C:59]([C:61]2[CH:69]=[CH:68][C:64]([C:65](O)=[O:66])=[CH:63][CH:62]=2)=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]1>ClCCl>[C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][C@H:3]([NH:2][C:65](=[O:66])[C:64]1[CH:63]=[CH:62][C:61]([C:59]([N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[O:60])=[CH:69][CH:68]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])#[N:24]
Reactant: N#Cc1cccc(OC[C@H](N)CC(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NC(=O)c2ccc(C(=O)N3CCCC3)cc2)c1

Procedure:
1.8 g (5.2 mmol) of benzyl (3R)-3-amino-4-(3-cyanophenoxy)butyrate hydrochloride (the compound in step 2 in Example 52), 703 mg (5.2 mmol) of 1-hydroxybenzotriazole (hydrate), 997 mg (5.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, 526 mg (5.2 mmol) of triethylamine, and 1.14 g (5.2 mmol) of 4-(1-pyrrolidyl carbonyl)benzoic acid were stirred in dichloromethane overnight. The reaction solution was washed with 1 N hydrochloric acid, 1 N aqueous sodium hydroxide and saturated saline and dried over sulfate magnesium anhydride, and the solvent was distilled off. The resulting residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[CH2:22]([O:24][C:25]([N:27]=[C:28]=[S:29])=[O:26])[CH3:23]>O1CCCC1>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][C:28]([NH:27][C:25](=[O:26])[O:24][CH2:22][CH3:23])=[S:29])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(5-amino-1,3,4-thiadiazole-2-yl)-2,6-bis(1,1-dimethylethyl)phenol (1.5 g, 0.005 mole) in tetrahydrofuran (10 ml) is added ethoxycarbonylisothiocyanate (0.64 g, 0.005 mole) dropwise. The resulting mixture is stirred 18 hours at room temperature, before concentrating in vacuo. The residue is recrystallized from ethanol/water to provide 1.7 g (2.2 g theor., 78%) of the title compound after drying in vacuo at 50° C., mp >250° C.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[N:17][CH:16]=2)[CH:12]=[N:11]1.O1CCOCC1.Cl>C(Cl)Cl>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4[C:18](=[N:17][CH:16]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)[N:20]=4)[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4ncc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCn1cc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (780 mg, 1.71 mmol) in CH2Cl2 (20 mL) was added the anhydrous HCl dioxane solution dropwise (4N, 1.07 mL, 4.27 mmol). A white solid was precipitated out. The reaction mixture was stirred for 1 hour and the LCMS showed the completion of the reaction. The reaction mixture was concentrated, and the residue was dissolved in distilled water (15 mL). The solution was adjusted to pH 7 with Na2CO3. An off-white solid was crashed out, which was filtered, washed with water, and dried on a high vacuum for 1 hour. The solid was re-crystallized from EtOH (50 mL) to provide 2-[4-(3-Quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (400, 63% yield) as a white crystalline solid with a melting point of 222° C. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H) 8.89 (dd, J=4.14, 1.70 Hz, 1H) 8.63 (s, 1H) 8.37 (dd, J=8.38, 1.04 Hz, 1H) 8.32 (s, 1H) 7.98-8.04 (m, 2H) 7.82 (dd, J=8.67, 2.07 Hz, 1H) 7.53 (dd, J=8.29, 4.14 Hz, 1H) 6.15 (s, 2H) 4.96 (t, J=5.27 Hz, 1H) 4.24 (t, J=5.46 Hz, 2H) 3.78 (q, J=5.46 Hz, 2H).
Reaction SMILES: C([O:8][C:9](=[O:33])[C@H:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:11][CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:27]([O:26][P:21]([CH:12]([NH:11][C@H:10]([C:9]([OH:33])=[O:8])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:28]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Yield: 98.7 %

Procedure:
To a solution of 445 mg of N-(1-diethoxyphosphoryl-3-phenylpropyl)-leucine benzyl ester in 10 ml of ethanol was added 100 mg of 10% Pd--C, after which the mixture was stirred vigorously under atmospheric pressure of hydrogen at room temperature for 24 hours. The Pd--C was filtered off, and the solvent was distilled off to yield the title compound as a light-yellow oil (356 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[CH:22][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[O:9][CH2:8][C:3]([C:4]([CH3:5])=[O:6])([CH3:7])[CH2:2][O:1]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2OCC(C)(C(C)=O)CO2)cc1

Procedure:
3,3-bis(Hydroxymethyl)butanone (39.6 g), benzene (200 ml), anisaldehyde (40.8) and toluene-p-sulphonic acid (200 mg) were heated under reflux in a Dean and Stark water trap until the theoretical amount of water had separated. The solution was concentrated in vacuo and the solid residue was crystallised from isopropyl acetate as a white crystalline solid m.p. 112°-114°, cis isomer.