Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([O:39]CC1C=CC=CC=1)=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:26])[O:18]CC1C=CC=CC=1)=[O:13])[CH2:3][O:4]CC1C=CC=CC=1.CO.O>CC(O)=O>[NH:1]([C:47]([CH3:49])=[O:48])[C@H:2]([C:12]([NH:14][C@H:15]([C:27]([NH:29][C@H:30]([C:32]([NH:34][C@H:35]([C:37]([OH:39])=[O:38])[CH3:36])=[O:33])[CH3:31])=[O:28])[CH2:16][C:17](=[O:18])[OH:26])=[O:13])[CH2:3][OH:4]
Reactant: CC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O
Yield: 86.3 %

Procedure:
Ac-Ser(Bzl)-Asp(OBzl)-Ala-Ala-OBzl (0.6 g, 0.888 mmol) was hydrogenated in a Parr apparatus at 50 psi in the presence of 0.62 g catalyst (5% Pd on BaSO4) in a solvent mixture consisting of 35 ml MeOH, 15 ml H2O, and 1 ml HOAc for 4 hours. The catalyst was filtered off and the filtrate concentrated to a smaller volume and lyophilized to give 0.38 g crude material. Tlc showed two minor contaminants in addition to the major component. The compound was then purified on a Bio-Rad AGl × 2 column (3 × 24 cm) which was washed with 0.2M NaOH, H2O, 0.2 M HOAc, and equilibrated with pH 8.5 buffer of 0.025 M ammonium acetate. The sample was applied at this pH and the column eluted with 250 ml each of the following acetic acid solution in the order of: 0.25M, 0.5M, 1.0M, 1.5M, 2.0M, 2.5M, 3.0M, 3.5M, 4.0M, and 4.5M. The flow rate was adjusted to approximately 50 ml/hr and each 10 ml fraction was collected into an LKB fraction collector. The compound was located by spotting a 5 μl portion from each tube on silica gel tlc plate (Merck 60, F-254) and developed in the solvent system of n-BuOH:HOAc:EtOAc:H2O (1:1:1:1) and then stained with chlorine-tolidine reaction. The fractions containing the major component were pooled and lyophilized twice to give 310 mg (86.3%) of the desired product; [α]D25 =-77.01° (c 1, 10% HOAc).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[SH:12].[C:13]([O:16][CH2:17][Cl:18])(=[O:15])[CH3:14]>CO>[ClH:18].[CH3:17][O:16][C:13]([C:14]1[S:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:2]=1[NH:3][CH2:4][CH2:5][NH2:1])=[O:15]
Reactant: Sc1ccccc1C1=NCCN1
Reactant: CC(=O)OCCl
Solvent: CO
Product: COC(=O)c1sc2ccccc2c1NCCN
Product: Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of 2-(4,5-dihydro-1H-imidazol-2-yl)benzenethiol (1.00 g, 5.62 mmol) [Hegen H., Fleig H. Justus Liebigs Ann. Chem. 11:1994 (1975)] and chlormethyl acetate (610 mg, 5.62 mmol) in 15 mL of methanol is heated at reflux for 90 minutes. The reaction is cooled to room temperature and filtered. The filtrate is concentrated to dryness and the residue dissolved in hot chloroform. After several hours the resulting precipitate is collected and dried. The mother liquor affords a second crop of crystals giving 3-(2-aminoethylamino)benzo[b]thiophene-2-carboxylic acid methyl ester hydrochloride in an overall yield of 61%, mp 219°-220° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[C:11]([N:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2/[CH:42]=[CH:43]\[CH2:44]O)(=[O:34])=[O:33])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][CH2:17][C:16]1[O:20][CH:21]=[CH:22][C:15]2=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:23]([C:11]2[C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:19]3[C:14]([C:15]4[CH:22]=[CH:21][O:20][C:16]=4[CH2:17][O:18]3)=[CH:13][CH:12]=2)[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])(=[O:33])=[O:34])=[C:36](/[CH:42]=[CH:43]\[CH2:44][N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:37]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Methanesulfonyl chloride (0.100 g) was added to an ice-cooled, stirred solution of methyl-7-{N-[4-fluoro-2-((Z)-3-hydroxyprop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxymethyl)amino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 48, 1.57 g) and diisopropylethylamine (0.859 g) in DCM (25 mL) and the mixture was stirred in an ice bath for 20 minutes. Morpholine (0.689 g) was added and the reaction mixture was stirred at room temperature for 90 minutes. It was washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-80% to give methyl 7-{N-[4-fluoro-2((Z)-3-{morpholin-4-yl}prop-1-enyl)benzenesulfonyl]-N-(2-trimethylsilanylethoxy-methyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (1.15 g) as a yellow gum.
Reaction SMILES: [CH2:1]([P:3]([OH:22])([O:5][C@@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8])=O)[CH3:2].[Ca]>>[C:16]1([CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][NH:9][C:7](=[O:8])[C@@H:6]([O:5][PH:3]([CH2:1][CH2:2][O:5][CH2:6][CH3:7])=[O:22])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCP(=O)(O)O[C@@H](Cc1ccccc1)C(=O)NCCC(=O)O
Agent: [Ca]
Product: CCOCC[PH](=O)O[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
N-[(S)2-[(ethylhydroxyphosphinyl)oxy]-1-oxo-3-phenylpropyl]β-alanine, calcium salt thereof;
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(CO)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1CO
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To a solution (2 mL) of 2-chloro-4-fluoro-3-(hydroxymethyl)benzonitrile (150 mg) in dimethyl sulfoxide were added (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (167 mg) and lithium carbonate (66 mg), and the mixture was stirred at 140° C. for 10 min in a microwave reaction apparatus. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) and recrystallized from ethyl acetate-isopropyl ether to give the compound as a pale-yellow solid (yield: 85 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH2:15][C@H:14]([CH3:17])[N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[N:10]=[N:9]2)=[N:6][CH:7]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH2:15][C@H:14]([CH3:17])[NH:13][CH2:12][C:11]=3[N:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate (0.711 g, 2.13 mmol) in CH2Cl2 (10 mL) was added 4M HCl in dioxane (2.66 mL, 10.6 mmol). After stirring overnight at rt, the reaction was concentrated in vacuo to give the desired product as a light yellow solid (0.580 mg, 100%). MS (ESI) mass calcd. C10H11FN6, 234.23. m/z found, 235.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.97-9.69 (m, 1H), 9.15 (s, 2H), 4.58-4.35 (m, 2H), 3.80-3.47 (m, 2H), 3.21-3.03 (m, 1H), 1.46 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([CH3:47])[C@@H:18]([C:30](=[O:46])[N:31]([CH3:45])[C@@H:32]([C:40]([NH:42][NH:43][CH3:44])=[O:41])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:49](OC(=O)C)(=[O:51])[CH3:50].N1C=CC=CC=1>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:48])[N:17]([C@@H:18]([C:30](=[O:46])[N:31]([C@H:32]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]([NH:42][N:43]([C:49](=[O:51])[CH3:50])[CH3:44])=[O:41])[CH3:45])[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH3:47])[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: CC(=O)OC(C)=O
Reactant: CNNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 110 %

Procedure:
To a solution of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-1-(N'-methylhydrazinocarbonyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid ((9H-fluoren-9-yl)methyl) ester (0.18 g, 0.28 mmol) in methylene chloride (2 ml) was added acetic acid anhydride (0.053 ml) and pyridine (0.027 ml) and the mixture was stirred overnight. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.21 g (110%) of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid ((9H-fluoren-9-yl)methyl) ester as a colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([CH2:12]SC)[C:8]([NH2:9])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[C:8]([NH2:9])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCc1cc(C(C)(C)C)cc(Cl)c1N
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C(C)(C)C)cc(Cl)c1N

Procedure:
4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3 g) was dissolved in methanol (50 ml) and Raney nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all starting material had reacted (ether-hexane, 1:10). The Raney nickel was removed by filtration through celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using hexane--5% ether in hexane as eluant to afford the product as a yellow liquid. 1H NMR (360 MHz, CDCl3) δ1.26 (9H, s, (CH3)3), 2.19 (3H, s, CH3), 3.97 (2H, s, NH2), 6.97 (1H, d, J=2.0 Hz, ArH), 7.14 (1H, d, J=2.0 Hz, ArH).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:54]CC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:54])=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O)cc2)=CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-1(5,6-dihydro-5,5- dimethyl-8-(4-.((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1)50.0 mg (0.095 mmol) in 1.0 ml of THF at room temperature was added 73.2 mg (0.29 ml, 0.29 mmol) of tetrabutylamonium fluoride (1 M solution in THF). After stirring overnight, the solution was diluted with EtOAc and washed with H2O and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure, followed by column chromatography (4:1, Hexanes:EtOAc) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.98 (2H, d, J=8.2 Hz), 7.52 (2H, d, J=8.3 Hz), 7.41-7.20 (5H, m), 6.88 (2H, d, J=8.4 Hz), 5.96 (1H, t, J=4.5 Hz), 4.37 (2H, q, J=7.1 Hz), 2.34 (2H, d, J=4.5 Hz), 1.39 (3H, t, J=7.1 Hz), 1.34 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([C:36]([N:12]3[CH2:13][CH:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:10]([N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)[CH2:11]3)=[O:37])[CH2:34][CH2:35]2)[CH2:27][CH2:28]1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4RS)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 1-cyclopropylmethyl-piperidine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 546.3 [M]+.
Reaction SMILES: ClC1C=CC2N3C(C4CC4)=NN=C3[CH2:9][N:8]=[C:7](C3C=CC=CC=3Cl)C=2C=1.O.NN.[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH:44]1CC1>C(O)COCCO>[NH2:29][CH:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[N:38]1[C:42]([CH3:43])=[N:41][N:40]=[C:39]1[CH2:44][N:8]([CH3:9])[CH3:7]
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C3CC3)n1-2
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: Cc1nnc(CN(C)C)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A solution of 7.38 g. of 8-chloro-6-(o-chlorophenyl)-1-(dimethylamino)methyl-4H-s-triazolo[4,3 -a][1,4] benzodiazepine (III) (20.0 mmol.) and 5.0 ml. of hydrazine hydrate in 50 ml. of diethylene glycol is heated to about 140° C. for about 18 hours. The reaction is quenched in a cold aqueous 5% sodium hydroxide solution, and the product extracted with chloroform. The extracts are dried and concentrated in vacuo to yield 8.5 g. of oil, which is crystallized from ethyl acetate/hexane mixtures to give 4.0 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-[(dimethylamino)methyl]-5-methyl-4H-1,2,4 -triazole (I), isomer A, m.p. 142°-144° C., an analytical sample of which melts at 148°-150° C. and has infrared (mull) spectral absorptions at 3380, 3270, 3200, 3070, 2770, 1610, 1590, 1570, 1530 and 1520 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Cl:7][CH2:8][C:9]([OH:11])=[O:10].C(O)C>CC(C)=O>[Cl-:7].[C:9]([CH2:8][N+:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)([OH:11])=[O:10]
Reactant: O=C(O)CCl
Reactant: Cc1cscn1
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1csc[n+]1CC(=O)O
Product: [Cl-]
Reaction time: 120 h
Yield: 67 %

Procedure:
15.6 g of 4-methylthiazole was dissolved in 50 ml of anhydrous acetone. The mixture was added with 15 g of chloroacetic acid, stirred for 5 d, filtered to obtain a solid, and a white solid was then obtained by recrystallization from ethanol, dired to obtain 20.4 g product with a yield of 66.9%, mP=262.3-263.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14].Br[CH:20](C1C(C(N)=O)C1(C)C)C(Br)(Cl)Cl.F[B-](F)(F)F.C[O+](C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13](=[NH:15])[O:14][CH3:20]
Reactant: CC(C)C(C(N)=O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC1(C)C(C(N)=O)C1C(Br)C(Cl)(Cl)Br
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC(=N)C(c1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
In like manner, each of 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutyramide and 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropaneamide is reacted with trimethyloxonium tetrafluoroborate, giving methyl 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutanimidate and methyl 2-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanimidate, respectively. Each of these imidates is then reacted with 3-phenoxybenzyl alcohol to yield, respectively, 3-phenoxybenzyl 2-(2-chloro-4-trifluoromethylphenyl)-3-methylbutanimidate and 3-phenoxybenzyl 2-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanimidate.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([O:22]C)=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1(C)C=CC=CC=1>[CH:1]1([C:4]([NH:6][C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][C:17]4[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=4)[C:20]([OH:22])=[O:21])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzooxazol-6-yl}oxy)benzoate (8.2 g) in methanol (300 mL) was added 8N aqueous sodium hydroxide solution (50 ml), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 6N hydrochloric acid to adjust the pH to about 6.0, and the reaction mixture was concentrated under reduced pressure to about 100 mL. Ethyl acetate (200 mL) was added to the residue, and the mixture was washed with water (150 mL×2). The collected aqueous layer was extracted with ethyl acetate (100 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a brown amorphous substance. The obtained crude product was dissolved in toluene (150 mL) and 2-methylpropan-2-ol (100 mL), and the solvent was evaporated under reduced pressure. An azeotropic operation with toluene and 2-methylpropan-2-ol was further repeated twice to remove water from the crude product. The obtained brown amorphous substance (8.6 g) was used as the title compound in the next operation without a further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[CH3:32][N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29]
Reactant: CI
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
In 10 ml of dimethylformamide was dissolved 0.84 g (2.0 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.34 g (2.4 mmol) of methyl iodide was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol=10:1) to obtain 0.44 g of the desired compound.
Reaction SMILES: C([OH:5])CCC.C(O)(=O)C.O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[NH2:24][C@@H:25]([C:33](N1CCC[C@H]1C(N[C@H](C(CCl)=O)CCCNC(=N)N)=O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>Cl>[NH2:24][C@H:25]([C:33]([OH:34])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCO
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)CCl
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Thin layer chromatography on silica gel plates (Merck) with butanol:acetic acid:water (4:1:1) indicated a single spot, Rf 0.37, by uv and by ninhydrin and Sakaguchi stains. Amino acid analysis of the D-Phe-Pro-ArgCH2Cl. 2HCl following hydrolysis in 2 ml of 6.0 N HCl for 24 hr. at 110° C. gave Phe=0.98 and Pro=1.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.C([O:23]O)(C)(C)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[OH:23][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Agent: [Mo]
Agent: [C-]#[O+]
Product: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1O

Procedure:
A sample of 25.2 g (0.1 mole) of N-(2,2,6,6-tetramethylpiperidine-4-yl)-ε-caprolactam is refluxed for 2 hours with 50 ml of 4M tert-butylhydroperoxide in the presence of 0.2 g of molybdenum hexacarbonyl, Mo(CO)6 as described in Example 1, to provide 26.6 g of red solid (99% crude yield). Crystallization from hexane gives orange crystals, m.p. 152°-159° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:14]=1>C(O)CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:14]=1
Reactant: Cc1cc(-c2cccs2)nc(Cl)n1
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccs2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 25.8 %

Procedure:
Part C; 2-Bromo-4-(1-methylethyl)aniline (0.26 g) and 2-chloro-4-methyl-6-(2-thienyl)pyrimidine (0.21 g) in ethylene glycol were heated at reflux for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with aq. sodium hydroxide solution (10% , 3×100 mL) and the organic phase was dried. Solvent removal gave a crude brown oil, which was purified on silica gel using 20% ethyl acetate in hexanes (Rf 0.5) as eluent to provide N-(2-bromo-4-isopropylphenyl)-4-methyl-6-(2-thienyl)-2-pyrimidinamine (0.1 g) as a solid, mp 98-101° C. Mass spec (NH3-CI/DDIP): 390 (M+H)30 .