Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.CO>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: CCC[C@H](N)CO
Reactant: COc1ccc(N=C=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@@H](CO)NC(=O)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 105.3 %

Procedure:
A solution of (2S)-2-aminopentan-1-ol (500 mg) in THF (6 mL) was cooled in a dry ice-acetone bath under nitrogen atmosphere, and a solution of 4-methoxyphenyl isocyanate (657 mg) in THF (4 mL) was added dropwise thereto. After the mixture was stirred for 17 hr while gradually warming to room temperature, methanol was added thereto, and the solvent was distilled off under reduced pressure to afford 1-[(2S)-1-hydroxypentan-2-yl]-3-(4-methoxyphenyl)urea (1.17 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:11][C:7]1[C:6]2[C:2]([NH2:1])=[N:3][O:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Nc1noc2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
94.37 mg (0.63 mmol) of 3-amino-1,2-benzisoxazol-4-ol (from example V), 100 mg (0.63 mmol) of 3,4-difluoronitrobenzene and 95.56 mg (0.69 mmol) of potassium carbonate are suspended in 3 ml of anhydrous dimethylformamide and stirred at room temperature for 16 hours. The reaction solution is then diluted with water, and the precipitate is filtered off. The product is dried under high vacuum.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>O1CCCC1>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1cccnc1
Reactant: CC(O)CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)CNC(=O)c1cccnc1
Temperature: -4 °C
Reaction time: 2 h

Procedure:
To 4.29 g (0.039 mol) of nicotinic acid suspended in 120 mL of dry tetrahydrofuran, 4.04 g (0.039 mol) of freshly distilled triethylamine was added in one portion. The resultant clear solution was cooled to -4° C. in an ice bath under argon. Ethyl chloroformate (4.33 g, 0.039 mol) in 25 mL of tetrahydrofuran was added at such a rate that the temperature of the solution did not exceed 0° C. Then, 3 g (0.039 mol) of 1-amino-2-propanol were added directly to the cold reaction mixture. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The oily residue was washed several times with anhydrous ether and allowed to stand. The title compound was obtained as a white, hygroscopic, low-melting, waxy solid melting at 40° C. (6.11 g, 85%) and having the formula ##STR115##
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6]1>[Pd].C(O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:8]2[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:6][N:5]([CH3:4])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Yield: 101.9 %

Procedure:
Hydrazine hydrate (3 ml, 60% solution) is added to a well stirred mixture of 1-methyl-4-(p-nitrophenoxy)-3,5-diphenylpyrazole (2.56 g, 0.0069 mole), 5% Pd on carbon (0.4 g) and absolute ethanol (40 ml). Gas bubbles form immediately and an exotherm (ca. 50° C) is observed. After the reaction subsides, the reaction mixture is refluxed for 2 hours. The reaction mixture is cooled slightly and filtered to remove the catalyst. The filtrate is stripped in vacuo to give a white solid 2.4 g (100%), m.p. 167° to 169° C. Recrystallization from benzene (20 ml) affords a white solid, m.p. 167° to 168° C.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:6]=2[CH:5]=1)(O)=O.CN1CCN(C)C1=O.N12CCCN=C1CCCCC2>Cl>[Cl:13][C:12]1[C:6]2[CH:5]=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: Cl
Solvent: CN1CCN(C)C1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1cccc2sccc12
Temperature: 177.5 °C
Reaction time: 6 h

Procedure:
A mixture of 2-carboxy-4-chlorobenzo[b]thiophene (50.00 g), 1,3-dimethyl-2-imidazolidinone (DMI; 200 ml), and 1,8-diazabicyclo[5.4.0]-undec-7-ene (140.7 ml) was heated at 160 to 195° C. with stirring for 6 hours. After the mixture was cooled to 10° C., the mixture was added to 3N-hydrochloric acid (350 ml) cooled to 10° C. After the mixture was extracted with toluene (500 ml), the toluene layer was washed with 3N-hydrochloric acid, water, aqueous sodium bicarbonate solution, water, saline, and water in this order, and then concentrated to obtain 4-chlorobenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33]>C(#N)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:36])=[CH:3][CH:4]=1)#[N:18]
Reactant: CCCCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C#N)cc23)cc1
Yield: 55 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (150 mg) was added to 2.5 ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated to reflux. After then adding n-butyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 110 mg of the title compound as light brown crystals (55% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(O)c1ccc(COc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)phenoxymethyl)benzoic acid.
Reaction SMILES: [O:1]([CH3:21])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][CH:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH2:11]3)[N:6]([CH3:7])[CH2:5]1)=[O:3].B(F)(F)F.CCOCC.S(Cl)([Cl:34])(=O)=O>C(Cl)Cl>[Cl:34][CH:11]1[NH:12][C:13]2[C:20]3[CH:10]1[CH2:9][C@@H:8]1[C:18]([C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:19][C@@H:4]([C:2](=[O:3])[O:1][CH3:21])[CH2:5][N:6]1[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)[C@@H]1C=C2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1C=C2c3cccc4c3C(C[C@H]2N(C)C1)C(Cl)N4

Procedure:
885 mg. of methyl dihydrolysergate were dissolved in 50 ml. of methylene dichloride. 0.95 ml. of boron trifluoride etherate were added and the reaction mixture cooled to a temperature in the range 0°-5° C. A solution of 0.27 ml. sulfuryl chloride in 20 ml. of methylene dichloride was added in dropwise fashion. The reaction mixture was stirred and cooled for about 15 minutes and then quenched by pouring into an ice-dilute ammonium hydroxide mixture. D-2-chloro-6-methyl-8-carboxyergoline, methyl ester or methyl 2-chlorodihydrolysergate formed in the above reaction was isolated and purified by the procedure of Example 1. Chromatography over fluorosil using 2 percent methanol in chloroform yielded 730 mg. (74 percent yield) of crystalline material melting at 206°-8° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ncccn4)CC3)nc2c1
Yield: 80 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H), 3.87-3.96 (m, 7H), 4.12-4.15 (m, 4H), 6.54 (t, J=4.8 Hz, 1H), 6.92 (s, 1H), 7.04-7.36 (m, 3H), 7.62 (m, 1H), 8.34 (d, J=4.8 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:37]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:29][CH:30]=1)(=[S:37])[NH2:2]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (611 mg), pyridine (70 ml), triethylamine (10 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (660 mg) as a yellow solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.76 (1H, dd), 6.83 (1H, d), 7.76 (1H, d), 7.95 (2H, d), 8.05 (2H, d), 9.67 (1H, br s), 10.06 (1H, br s), 10.55 (1H, s), 11.12 (1H, s); Mass Spectrum m/Z 466 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:8]=2[N:7]=1
Reactant: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Product: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Example 228e, 4.3 g of methyl 2-(3-methoxypropyl)-3H-benzoimidazole-4-carboxylate and 3.54 ml of (2-chloromethoxyethyl)trimethylsilane are reacted. The title compound is obtained as a brown solid. Rf=0.33 (95:5 dichloromethane-methanol); Rt=4.26.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1
Product: CCc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-ethylphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(p-ethylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:15])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1([N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:17]1([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:27][CH2:28]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CCN(c2ccccc2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pyridine (24 μL) and phenyl chlorocarbonate (32 μL) were added to a solution of 1-phenyl-4-piperidylamine (35 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1/1) to give the title compound (37 mg).
Reaction SMILES: [CH:1]1([C:7](=[O:11])[CH:8]=[N+:9]=[N-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([O:14][P:15]([C:20]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13]>CCOCC>[CH2:24]([O:23][P:22]([C:20]1([P:15](=[O:19])([O:14][CH2:12][CH3:13])[O:16][CH2:17][CH3:18])[CH2:21][C:8]([C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:11])=[N:9][NH:10]1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: [N-]=[N+]=CC(=O)C1CCCCC1
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)C2CCCCC2)=NN1

Procedure:
1-Cyclohexyl-2-diazoethanone (I, PREPARATION 2, 3.1 g) and ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 6.00 g) are stirred in ether (20 ml) for 24 hrs at 22°. The precipitate is filtered, washed with ether, then recrystallized from ethyl acetate to give the title compound, mp 166°-165°; MS (m/e) 452, 341, 315, 287, 259, 241, 223 and 205; IR (mineral oil mull) 3186, 1656, 1552, 1449, 1267, 1253, 1241, 1162, 1041, 1019, 995 and 969 cm-1 ; NMR (CDCl3) 6.77, 4.24, 3.45, 3.24 and 1.9-1.2 δ.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@H:24]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]2)[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 97.9 %

Procedure:
A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (647 mg, 1.98 mmol), tert-butyl (3R)-3-aminomethyl-1-pyrrolidinecarboxylate (preparation 80), (398 mg, 1.98 mmol) and triethylamine (830 ml, 5.95 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled mixture was washed consecutively with water, 1N citric acid solution, brine, then dried over MgSO4, and evaporated under reduced pressure to give the desired compound as a gum, (952 mg, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:34])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:11]2=[N:10]1
Reactant: BrBr
Reactant: Cc1ccc(O)c(-n2nc3ccc(C(C)(C)C)cc3n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-butylbenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-butylbenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-butylbenzotriazole was 6.8 g (84%).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]1=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:20][CH:21]=1)[NH:19][C:3]1[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C1CCCCC(Br)C1=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Yield: 53.4 %

Procedure:
Methyl 3-bromo-2-oxocycloheptanecarboxylate (16.8 g, 67.4 mmol) and 4-chloroaniline (18.4 g, 98%, 2.13 eq, 143.6 mmol) were added to flask with thermometer, nitrogen inlet and mechanical stirring machine. As the temperature of the mixture passed 140° C. a relatively rapid exotherm and vigorous evolution of gas occurred. The reaction was cooled with water immediately. The reaction mixture was dissolved in DCM (200 mL). The material was transferred into a separatory funnel and washed with water (2×50 mL), 3HCl (3×50 mL), water (2×50 mL), brine, dried over Na2SO4, and the solvent was removed by vacuo. The crude residue was applied to a Biotage and eluted with 9/1 heptane/ethyl acetate to afford product 10 g (53%) as an off white solid, which was used for next reaction without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]3[CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]4[O:28][C:11]=3[CH:10]=2)O1.CC1C=CC(S(NCl)(=O)=O)=CC=1.[I-:42].[Na+]>C1COCC1.O>[I:42][C:9]1[CH:14]=[CH:13][C:12]2[CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3[O:28][C:11]=2[CH:10]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC2C1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reaction time: 20 h

Procedure:
Tert-butyl 7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (20 g, 0.05 mol) was dissolved in THF (0.4 L) and a solution of Chloramine T (28.1 g, 0.1 mol) in H2O (0.2 L) was added, followed by a solution of sodium iodide (15 g, 0.1 mol) in H2O (0.2 L) over 20 min. After 20 h stirring, of chloramine T (2.8 g, 0.01 mol) and sodium iodide (1.5 g, 0.01 mol) were added. The reaction mixture was stirred for 20 h, the solvent was evaporated, ethyl acetate and H2O were added. The layers were separated, and the organic layer was washed with H2O.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14]1[CH2:16][O:15]1>[OH-].[Na+].O>[OH:15][CH:14]([CH3:16])[CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(C)O)cc1C
Temperature: 140 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 2-methyloxirane (0.22 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was stirred at 140° C. for 4.0 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2-hydroxypropoxy)-2,6-dimethylphenyl)ethanone (445.9 mg. 2.1 mmol) as yellow oil in 66% yield: 1H NMR (CDCl3, 500 MHz) δ 6.57 (s, 2 H), 4.10-4.20 (s, 1 H), 3.90-3.93 (m, 2 H), 3.75-3.79 (m, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 1.25-1.28 (m, 3 H); ESI-MS: m/z 223.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:4]
Reactant: O=C(NCCCCCCO)C(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=CCCCCCNC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To 2.1 gm (10.1 mmole) of the 6-trifluroacetamido-1-hexanol in 40 ml of methylene chloride was added 3 gm (10.64 mmole) of pyridinium dichromate and 4.4 gm of 3 Angstrom molecular sieves, and the reaction was allowed to proceed with stirring for 3 hours at 23° C. After addition of 250 ml of ethyl acetate, the reaction mixture was filtered through a small bed of silica gel 60 and concentrated in vacuo. Flash chromatography using 50% (v/v) ethyl acetate in hexane afforded 1.48 gms (70%) of 6-trifluroacetamido-1-hexanal. ##STR16##