Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][NH:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([O:3][CH2:4][CH3:5])=[O:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:11][C:10]1[C:9]2[C:8](=[CH:15][C:14]([F:16])=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CNc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2cc(F)ccc2c1N
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Dissolve 2-(Carbethoxy)methylamino-4-fluorobenzonitrile (220 mg, 1 mmol) in tetrahydrofuran (3 mL) and add dropwise with stirring to a solution of potassium tert-butoxide (1 mL of a 1M solution in 1 mL tetrahydrofuran) under a nitrogen atmosphere. After 1 hour, dilute with ethyl acetate, rinse with water, dry the organic phase and concentrate in vacuo to yield the title compound (170 mg, 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]2[CH:27]=[C:26]([CH:28]([NH2:30])[CH3:29])[CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C@@H:28]([C:26]2[CH:25]=[N:24][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:27]=2)[CH3:29])[N:7]=1)([CH3:15])[CH3:14].[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:26]2[CH:25]=[N:24][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:27]=2)[CH3:29])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1cnn(-c2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2cnn(-c3ccccc3)c2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2cnn(-c3ccccc3)c2)n1

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (96 mg, 0.40 mmol) and 1-(1-phenyl-1H-pyrazol-4-yl)ethanamine (387 mg, 2.97 mmol, 5.2 equiv) in DMSO (1.5 mL) was heated at 110° C. for 1½ h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 80%) provided (S)-4-isopropyl-3-(2-((R)-1-(1-phenyl-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(1-phenyl-1H-pyrazol-4-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[NH2:13])=[O:7].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH2:31]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:10]3[N:11]=[CH:12][C:8]([C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[O:7])=[C:9]3[N:13]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([CH3:30])(=[O:29])=[O:28])[C:32]#[CH:33]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: C#CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCN(c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1)S(C)(=O)=O
Yield: 77.1 %

Procedure:
0.1 g (0.33 mmol) of 4-thiophene-2-carbonyl-2H-pyrazol-3-ylamine and 0.063 g (0.33 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynyl-methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 8 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporate to dryness to yield an oil which, in the presence of ethyl acetate gave a yellow solid, 111 mg (yield=78%) N-2-propynyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: C(OC(=O)[C:5](=[N:7][O:8][CH2:9][CH2:10][CH3:11])[CH3:6])C.[OH-].[Na+].C(Cl)(=O)[C:16](Cl)=[O:17].C(N(CC)CC)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36]/[N:37]=[C:38](\[C:45]2[N:49]([CH3:50])[N:48]=[N:47][N:46]=2)/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:30]=1>CO.C(Cl)Cl>[CH2:9]([O:8][N:7]=[CH:5][CH2:6][C:16]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:36]/[N:37]=[C:38](\[C:45]2[N:49]([CH3:50])[N:48]=[N:47][N:46]=2)/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:30]=1)=[O:17])[CH2:10][CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCON=C(C)C(=O)OCC
Reactant: Cn1nnnc1/C(=N\OCc1cccc(N)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCON=CCC(=O)Nc1cccc(CO/N=C(/c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
0.12 g (0.70 mmol) of 2-n-propoxyimino-propionic acid ethyl ester was dissolved in 2 ml of methanol and 0.035 g (0.91 mmol) of sodium hydroxide was added to the resulting solution, followed by stirring for 1 hour at room temperature. The solvent was distilled off under reduced pressure, and neutralized with 2N hydrochloric acid, and extracted with chloroform. The organic layer was dried by adding magnesium sulfate, and concentrated tinder reduced pressure to obtain a white solid substance. The white solid substance was dissolved in 5 ml of methylene chloride, and stirred for 40 minutes at room temperature after adding 0.11 g (0.84 mmol) of oxalyl chloride, and concentrated tinder reduced pressure. The residue was dissolved in 5 ml of methylene chloride and stirred for 1 hour at room temperature after adding 0.10 g (0.99 mmol) of triethylamine and 0.14 g (0.45 mmol) of (Z)-(1-methyl-1H-tetrazol-5-yl)phenyl methanone-O-[2-aminopyridin-6-yl methyl]-oxime. The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1 (v/v)) to obtain 0.10 g of the target compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH3:37])=[CH:35][CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: Cc1ccc(CBr)cc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccc(C)cc3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 4-methylbenzyl bromide. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18]C)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C(#N)C>[O:18]=[C:16]1[CH2:15][C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][N:20]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3CC2=O)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
Potassium carbonate (1.4 g, 10 mmol) was added to a solution of methyl 2-(2-(chloromethyl)phenyl)acetate (940 mg, 4.7 mmol) in acetonitrile (20 mL). 4-Amino-N-Boc-piperidine (1.13 g, 5.6 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated in vacuo. Residue was treated with toluene (29 mL). Acetic acid (1.5 ml) was added to the mixture. Reaction was heated at reflux for 2 hours. Mixture was concentrated in vacuo. Residue was treated with ethyl acetate (50 mL). Mixture was washed successively with aqueous sodium bicarbonate (2×30 mL), 1N hydrochloric acid (30 mL), and brine (20 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography gave the title compound as lightly colored oil in 40% yield. MS m/e (M+H)+=331.2.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([Cl:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(Cl)c1N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(Cl)cccc2c1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-chlorobenzamide (780 mg, 2.30 mmol) in THF (20 mL) was treated with bis(trichloromethyl) carbonate (1.02 g, 3.45 mmol) and the solution stirred at room temperature for 21 h. The mixture was diluted with DCM and washed sequentially with saturated aqueous NaHCO3, water and brine. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 25-50%), to give 3-(3-bromo-2-methylphenyl)-8-chloroquinazoline-2,4(1H,3H)-dione as a white solid (800 mg, 95% yield). Mass spectrum m/z 365, 367 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH2:36])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH:36][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=3[Cl:39])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl]-2,4-dihydro- 4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv) according to the procedure of Example 51 to give an 88% yield of the desired material as a white solid after flash chromatography, mp 98°-101° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 693 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]([C:14]1C=C(C)C=C(C(C)(C)C)[C:15]=1[OH:25])(C)(C)C.C(Cl)(=O)C=C.Cl>O.N1C=CC=CC=1.CC(N(C)C)=O>[C:15]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:25])[CH:14]=[CH2:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(O)CCCCCO
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CC(=O)OCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6-hydroxyhexanoic acid (10 g), 2,6-di-tert-butyl-4-methylphenol (0.5 g), and dimethylacetamide (57 mL) was cooled to 0° C. Acryloyl chloride (17.2 g) was then added dropwise. After stirring for 3.5 hrs, pyridine (12 mL) and water (12 mL) were slowly added. After stirring for another 2 hrs, the solution was acidified with dilute HCl and extracted with ethyl acetate. The combined organic layer was washed with water, dried, filtered, and concentrated to afford 6-acryloyloxyhexanoic acid. 1H NMR (CDCl3, 500 MHz) δ 1.46 (m, 2H), 1.70 (m, 4H), 2.37 (t, J=7.3 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 5.82 (d, J=10.4 Hz, 1H), 6.12 (dd, J=17.3, 10.5 Hz, 1H), 6.39 (d, J=17.3 Hz, 1H), 11.59 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])[OH:11])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([OH:15])=[O:14])[OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(O)CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (44.0 g, 0.18 mol), 1N sodium hydroxide (180 mL) and absolute ethanol (280 mL) was stirred for 18 h at room temperature. The mixture was concentrated in vacuo, diluted with H2O and extracted with diethyl ether. The aqueous phase was acidified (pH 3) with dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid as an amber oil (37.7 g, 100%; Note: This compound spontaneously dehydrated upon standing at room temperature to a mixture of olefins unless immediately reacted with trifluoroacetic acid);
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.N#N.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1>N1C=CC=CC=1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CN(C)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino -2-butynoic acid (0.9 g, 3.8 mmol ) and N-methylmorpholine (0.384 g , 3.8 mmol ) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol ) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; : mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).
Reaction SMILES: N#N.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[NH2:26][C@@H:27]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:28]([OH:43])[C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30]>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]([NH:26][C@@H:27]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@H:28]([OH:43])[C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])=[O:18])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.5 g (43.9 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine and 7.33 g (72.3 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 12.7 g (36.6 mmol) of 1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide [prepared as described in step (c) above] in 100 ml of dimethylformamide, and the mixture was stirred overnight at room temperature. At the end of this time, the reaction mixture was poured into ice-water, after which it was extracted with methylene chloride. The organic extract was then washed with a 1N aqueous solution of sodium hydroxide, with a 10% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order. The extract was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixture of methylene chloride and hexane, to give 17.6 g of the title compound as a colorless powder, melting at 113°-115° C.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:9](Cl)(=[O:13])[CH:10]([CH3:12])[CH3:11]>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)(C)OO
Reactant: CC(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)OOC(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type E with a downstream reactor of type C. Before the start of the reaction, the first reactor is filled with a solution of 24.4% by weight of tert-butyl hydroperoxide and 12.7% by weight of potassium hydroxide in water. 33.6 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 27.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 38.0 kg/h of water and 18.4 kg/h of isobutyroyl chloride are then fed to the first reactor. Cooling with cooling water keeps the internal temperature in the first reactor at 11° C. and in the second reactor at 12° C. The reaction mixture withdrawn from the second reactor is mixed with 8.0 kg/h of isododecane and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with a 1% by weight solution of sodium hydrogencarbonate in water, and then dried by stripping in a packed column at 20° C. and 47 mbar. 33.4 kg/h of a 75% by weight solution of tert-butyl peroxyisobutyrate in isododecane are obtained (92.8% based on isobutyroyl chloride). The space-time yield is 2.69 kg/l·h.
Reaction SMILES: [Mg].BrCCBr.CC1(C)C[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=N1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>O1CCCC1.O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:9][OH:10]
Reactant: Cc1ccccc1Br
Reactant: CC1(C)COC(c2cccc(Br)c2)=N1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: O
Product: Cc1ccccc1-c1cccc(CO)c1
Reaction time: 16 h

Procedure:
3-(2-Methylphenyl)benzyl alcohol was prepared as follows: Under a nitrogen atmosphere a stirred mixture of magnesium turnings (3.0 g, 0.12 mole) and 10 ml of 1,2-dibromoethane in 100 ml of dry tetrahydrofuran was heated to 30°. To the stirred mixture was added dropwise 4,5-dihydro-4,4-dimethyl-2-(3-bromophenyl)oxazole (26.9 g, 0.11 mole) in 50 ml of dry tetrahydrofuran. Upon complete addition, the reaction mixture was heated at reflux for 1.5 hours. The so-prepared Grignard reagent was cooled, placed in a dropping funnel, and added dropwise at 0° to a stirred solution of 2-bromotoluene (18.1 g, 0.11 mole) and 0.5 g of bis(1,3-diphenylphosphino)propanenickel(II) chromate in 150 ml of dry tetrahydrofuran. The temperature of the reaction mixture was maintained at 0° throughout the addition. Upon complete addition, the temperature was allowed to rise to 15°, and the reaction mixture was stirred for 16 hours, then heated under reflux for approximately 24 hours. The reaction mixture was cooled and poured into 500 ml of water. The resultant emulsion was broken by pouring small amounts of the mixture into 1000 ml portions of water. Each portion was extracted with two 200 ml portions of toluene. The combined toluene extracts were evaporated under reduced pressure to afford 25 g of oily residue. The combined water layers were divided into three parts, and to each part was added 10 ml of 6 N hydrochloric acid. Each part was extracted with toluene. The combined extracts were evaporated under reduced pressure to give an additional 8.8 g of oily residue. The residues were combined and impurities removed by distillation using a Kugelrohr distilling system. The residue was purified by column chromatography on silica gel, producing 4,5-dihydro-4,4-dimethyl-2-[(2'-methyl[1,1'biphenyl]-3-yl)oxazole (7.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:11][CH3:12])[C:6]=1[C:7]([O:9]C)=O.C(O)(=O)C.[CH:17](N)=[NH:18].CCN(C(C)C)C(C)C>C(O)CCC>[CH2:11]([N:5]1[C:6]2[C:7]([OH:9])=[N:18][CH:17]=[N:1][C:2]=2[CH:3]=[N:4]1)[CH3:12]
Reactant: CCn1ncc(N)c1C(=O)OC
Reactant: N=CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCn1ncc2ncnc(O)c21
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A mixture of methyl 4-amino-1-ethyl-1H-pyrazole-5-carboxylate (1.75 g), formamidine acetate (1.615 g), n-butanol (20 mL) and DIPEA (20 mL) was stirred at 120° C. for 3 h. The mixture was concentrated under reduced pressure, and the residual crystals were washed with AcOEt/hexane to give the title compound (1.47 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:15]([NH:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:18]([CH:15]([CH3:17])[CH3:16])[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: O=C(O)COc1cc(F)c(F)cc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1Br
Yield: 52.9 %

Procedure:
A solution of (2-bromo-4,5-difluoro-phenoxy)-acetic acid (985 mg, 3.68 mmol) and benzoic acid N′-isopropyl-hydrazide (787 mg, 4.416 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.6 mL, 9.2 mmol) and PyBroP (2.57 g, 5.52 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (832 mg, 34%).