Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8].Cl.N1CCCCC1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])([O-:9])=[O:8]
Reactant: C1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 0.07 h

Procedure:
15 ml. of piperidine are added at once to 13 g. of 3-nitro-4-chloro-benzophenone under stirring. Due to the highly exothermic reaction the mixture warms to 98° to 100° C within 4 to 5 minutes, thereafter piperidine hydrochloride starts to separate from the homogeneous reaction mixture. The mixture is stirred for 10 minutes at 98° to 100° C, thereafter cooled, the product is triturated with 30 ml. of n-hexane, and filtered. The crystalline substance is washed on the filter with 2×30 ml. of n-hexane, suctioned well, and suspended several times in distilled water to remove piperidine hydrochloride. The obtained product is dried until constant weight. 15.5 g. of crystalline 3-nitro-4-piperidino-benzophenone are obtained; m.p.: 77° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=2[CH:13]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[S:9][C:8]([C:10]([N:17]([O:18][CH3:19])[CH3:16])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: CNOC
Reactant: O=C(O)c1cc2cc(F)cc(F)c2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cc(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-difluoro-1-benzothiophene-2-carboxylic acid (synthesized by the method of WO2003/055878, 1.95 g, 9.10 mmol), N,O-dimethylhydroxyamine hydrochloride (977 mg, 10.0 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g, 10.0 mmol) and N-hydroxybenzotriazole (1.35 g, 10.0 mmol) in dichloromethane (20 mL) was added triethylamine (1.90 mL, 13.7 mmol) at room temperature. The mixture was stirred at room temperature overnight, and then to the reaction solution was added 10% hydrochloric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a crude 5,7-difluoro-N-methoxy-N-methyl-1-benzothiophene-2-carboxamide (2.48 g) as a colorless solid. The resultant was used in the next step without further purification.
Reaction SMILES: Cl.C(OCC)(=[O:4])C.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@H:16]3[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[C@@H:17]3[C:11]=2[CH:10]=1>C1(C)C(C)=CC=CC=1>[ClH:8].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]2[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C@@H:16]([CH2:20][NH:19][CH3:21])[C@H:17]([C:18]([OH:22])=[O:4])[C:11]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1=O
Agent: Cl
Solvent: Cc1ccccc1C
Product: CNC[C@@H]1c2ccccc2Oc2ccc(Cl)cc2[C@H]1C(=O)O
Temperature: 65 °C

Procedure:
HCl (55.5 g) and silica gel (55 g) were suspended in xylene (550 mL). The suspension was heated to reflux for 1 night. The reaction mixture was cooled to 65° C. and ethyl acetate (550 mL) was added. The silica gel was filtered off and washed with ethyl acetate (550 mL). The organic phase was evaporated. The crude product was dissolved in methanol (750 mL). The methanol was partly evaporated upon which crystallization of the product takes place. After cooling to 5° C. for 3 hours, the product was obtained by filtration. This yielded trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (IV) (47.8 g, 86%); mp 150.6° C.; 1H-NMR (400.13 MHz in CDCl3 relative to TMS) δ 3.03 (d, 3H), 4.03 (m,1H), 3.53-3.65 (m, 2H), 3.82 (m,1H), 7.01-7.28 (m, 6H), 7.87 (dd, 1H).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[C:5](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1>CCN(CC)CC>[NH2:14][C:11]1[C:12]([CH3:13])=[C:4]2[C:5](=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])[C:6](=[O:8])[N:43]([CH:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)[C:3]2=[O:18]
Reactant: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester (1.3 g, 5.12 mmol), EDCI.HCl (1.07 g, 5.63 mmol) and HOBt (0.69 g, 5.12 mmol) was added Et3N (3.64 mL, 25.6 mL) and stirred at room temperature for 10 min. 4-Amino-1-methylpiperidine dihydrochloride (1.04 g, 5.63 mmol) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was evaporated in vacuo, the residue was dissolved in CHCl3 (200 mL), washed with water (2×100 mL). The organic layer was filtered over Na2SO4 and concentrated in vacuo to afford 5-Amino-4-methyl-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (1.7 g, quant), which was used as such for further reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:8](Cl)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.C(N(CC)CC)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCCOCCO
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCOCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a cooled solution of 11 g of 2-(2-aminoethoxy)-ethanol in 75 ml of dichloromethane and excess triethylamine was added dropwise 13 g of dodecanoyl chloride in 25 ml of dichloromethane. After stirring at room temperature for 3 hours the reaction mixture was concentrated and then diluted with 100 ml of ethyl acetate and 100 ml of water. The organic layer was washed with 2×50 ml of water and brine, dried, filtered and concentrated to give 13.7 g of crude product. Recrystallization from ethyl acetate/hexane gave 11.2 g of product, m.p. 62°-64° C.
Reaction SMILES: [CH3:1][Si:2]([N:5]=[C:6]=[O:7])([CH3:4])[CH3:3].[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH3:29]>N12CCCN=C1CCCCC2.ClCCl>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:6]([NH:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CONCCCCn1c(C)nc2c(N)nc3ccccc3c21
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CON(CCCCn1c(C)nc2c(N)nc3ccccc3c21)C(=O)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Trimethylsilyl isocyanate (1.62 mL, 12.0 mmol) and 1,8-diazabicyclo[5.4.0]undec-7ene (one drop) were added to a solution of 1-[4-(methoxyamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (3.00 g, 10.0 mmol) in dichloromethane (100 mL). The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure to afford 4.1 g of crude N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxy-N′-(trimethylsilyl)urea, which was used without purification in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: Sc1ccccc1Cl
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and 2-chlorothiophenol (190 mg, 1.31 mmol) in 5 ml of dimethylformamide was added potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the combined organic extracts were washed with brine, and dried over sodium sulfate. The solution was filtered and then concentrated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent followed by crystallization gave the title compound as a pure white crystalline solid (147 mg): mp (DSC) 153° C. Anal. Calc'd. for C23H18Cl2N2O2S2 (MW 489.44): C, 56.44; H, 3.71; N, 5.72. Found: C, 56.51; H, 3.54; N, 5.57.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[N+:22]([O-])=O.C(OCC)(=O)C>CS(C)=O>[CH2:2]1[C:1](=[O:9])[NH:22][C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:3]1=2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 0 °C
Yield: 85 %

Procedure:
Under ice cooling, diethyl malonate (500 g) was added dropwise into a suspension of sodium hydride (125 g) in dimethyl sulfoxide (800 ml). After the solution became homogeneous, the resultant mixture was heated to 100° C. and a solution of 2,5-dibromonitrobenzene (500 g) in dimethyl sulfoxide (400 ml) was added dropwise thereinto followed by stirring the resultant mixture at 100° C. for 5 hr. Then the reaction solution was diluted with ice water (2 l), mixed with ethyl acetate (8 l), and the layers were separated. The organic layer was washed successively with water (2 l) four times and brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was diluted with ethanol (2.5 l) followed by the addition of tin (380 g). Under ice cooling, conc. hydrochloric acid (1.5 l) was added dropwise into the reaction mixture. After the completion of the addition, the resultant mixture was heated under reflux for 3 hr and diluted with ice water (8 l). The resulting crystalline precipitates were collected by filtration, washed with water and hexane, and air dried at 50° C. for 24 hr to give the title compound (321 g) (yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]([CH3:7])[N:6]=1.Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[N:14][CH:15]=1>C(#N)C>[Cl:16][C:13]1[N:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]([CH3:7])=[CH:4][S:3][C:2]2=[N:1][CH2:9][C:10]2[CH:15]=[N:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: CC1CSC(N)=N1
Solvent: CC#N
Product: Cc1csc(=NCc2ccc(Cl)nc2)n1Cc1ccc(Cl)nc1
Temperature: 90 °C
Yield: 42.4 %

Procedure:
A mixture of 228 mg (2 mmol) of 2-amino-4-methylthiazoline and 1.03 g (5 mmol) of 5-bromomethyl-2-chloropyridine in 30 ml of acetonitrile was heated for 8 hours at 90° C. under refluxing. Then, the reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The resulting residue was mixed with dichloromethane and saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The water layer was extracted with dichloromethane, and combined organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel 60 (Merck Co., Ltd.) column chromatography (eluent; dichloromethane:ethyl acetate=from 9:1 to 4:1) to give 600 mg (yield; 82.1%) of crude product as yellow oil. Then, this crude product was purified again by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; dichloromethane), and the eluted product was crystallized by treatment with ether-isopropyl ether to give 310 mg (yield; 42.4%) of 3-(6-chloro-3-pyridyl)methyl-2-[(6-chloro-3-pyridyl)methyl]imino-4-methyl-2,3-dihydrothiazole as milky white crystalline. 200 mg (0.548 mmol) of this product was dissolved in methanol and to this solution was added 64 mg (0.551 mmol) of fumaric acid, and the mixture was concentrated under reduced pressure. The resulting residue was treated with acetonitrile to give crystalline. The crystalline was collected by filtration and dried in vacuum to give 213 mg of fumarate of the title Compound 9.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[C@@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH2:3]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:6]1[C@H:2]([CH3:1])[CH2:3][C@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[C:5]1=[O:7])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-7 (355 mg, 1.67 mmol) and THF (10 mL) at −78° C. was added NaN(TMS)2 (1.83 mL, 1.83 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.203 mL, 1.84 mmol) was added and the reaction was warmed to 0° C. After 30 minutes, the reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4), and concentrated to give 11-8 as a yellow oil.
Reaction SMILES: N1C(F)=NC(F)=NC=1F.[C:10]([O:14][C:15]([N:17]([CH3:30])[C@@H:18]([CH3:29])[C:19]([NH:21][C@@H:22]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:25])=O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][C@H:38]1[C:46]([O:48][CH2:49][CH3:50])=[O:47].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:49]([O:48][C:46]([C@@H:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:37]1[C:23](=[O:25])[C@@H:22]([NH:21][C:19](=[O:20])[C@@H:18]([N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH3:30])[CH3:29])[CH:26]([CH3:28])[CH3:27])=[O:47])[CH3:50]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 51.3 %

Procedure:
Cyanuric fluoride (3.25 g, 2.08 mL, 24.1 mmol) was added to a solution of (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid (5.4 g, 17.9 mmol) and pyridine (1.95 mL, 24.1 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at 23° C. for 2.5 h. The resulting precipitate was filtered off and the mother liquor was concentrated. The residue was dissolved in EtOAc (250 mL), and the solution was washed with saturated NaHCO3, 0.5 M citric acid and brine. The organic layer was dried over Na2SO4, filtered, concentrated and dried under vacuum. The resulting yellow oil was taken up in CH2Cl2 (35 mL) and cooled in a dry ice-MeOH bath. To this solution was added a solution of (S)-ethyl indoline-2-carboxylate (2.3 g, 12.0 mmol) and 2,6-di-tert-butylpyridine (4.6 g, 5.31 mL, 24.1 mmol) in 25 mL of CH2Cl2. The resulting mixture was stirred at rt overnight. The crude material was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.93 g), m/z=476 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[CH3:23][NH:24][CH3:25].Cl>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[N:24]([CH3:25])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
3.84 ml of triethylamine was added, at -15° to -20° C., to a solution of 5.8 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid dissolved in 85 ml of dry tetrahydrofuran, and then a solution of 2.63 ml of ethyl chloroformate in 25 ml of dry tetrahydrofuran was added to the resulting mixture at the same temperature. The reaction mixture was then stirred for 2 hours, after which 19.75 ml of 50% by volume aqueous dimethylamine was added to it at -20° to -25° C. The mixture was then stirred for 3 hours under ice cooling, after which it was allowed to stand overnight at room temperature. At the end of this time, the mixture was poured into a mixture of 30 ml of concentrated hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 9:1 by volume mixture of ethyl acetate and methanol) to afford 429 mg of the title compound.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[Cl:17][C:18]1[CH:36]=[CH:35][C:21]2[O:22][C:23]3[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=3[CH2:25][N:26]([C:27]([NH:29][NH2:30])=[O:28])[C:20]=2[CH:19]=1>>[C:10]1([S:7]([NH:6][CH2:5][CH2:4][C:3]([NH:30][NH:29][C:27]([N:26]2[CH2:25][C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[O:22][C:21]3[CH:35]=[CH:36][C:18]([Cl:17])=[CH:19][C:20]2=3)=[O:28])=[O:16])(=[O:8])=[O:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1
Product: O=C(CCNS(=O)(=O)c1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(phenylsulfonyl)amino]-1-oxopropyl]hydrazide (24) was prepared from N-(phenylsulfonyl)-β-alanine, methyl ester (23), prepared as described above in Example 23, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, on a two mmol scale in the manner described in Example 18 above to yield 0.44 g (44%) of product.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][C@@H:49]([CH2:63][C:64]1[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=1)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=1>C(Cl)Cl>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:48][C@@H:49]([CH2:63][C:64]3[CH:65]=[C:66]([F:71])[CH:67]=[C:68]([F:70])[CH:69]=3)[C@H:50]([OH:62])[CH2:51][NH:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[CH:55]=3)=[O:16])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1c[nH]c2ccc(C(=O)O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1c[nH]c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
To a mixture of 3-Butyl-1H-indole-5-carboxylic acid (0.145 g) in methylene chloride (15 mL) was added triethylamine (0.068 g), and HATU (0.255 g). The mixture was stirred at room temperature for 15 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.224 g) was added. The mixture was stirred at room temperature for 72 h then poured into methylene chloride (50 mL), washed with water then saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride with 0.15% HOAc as eluent to give 0.247 g of the title compound: MS (ESI+) for C32H37F2N3O2 m/z 534.3 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(CO[C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[CH:26]=[O:27])=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][N:24]1[C:20]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(C=O)c1N1CCN(c2ccccc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
A mixture of 1-phenylpiperazine (3.40 g), 5-[(4-chlorobenzyl)oxy]-1-methyl-1H-pyrazol-4-carbaldehyde (600 mg), triethylamine (1.20 mL) and dimethylformamide (7.0 mL) was stirred at 120° C. for 8 hours, and then at a room temperature for 17 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and water was then added thereto. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 10:90), so as to obtain the title compound (669 mg) in the form of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>CCCCCC>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:4][CH:3]=1
Reactant: Brc1ccc(NC2CCCCC2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(C)N(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9 g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me3SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me3SiCl was evaporated under reduced to yield 4-bromo-N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([N:21]1[CH2:25][C:24](=[O:26])[NH:23][S:22]1(=[O:28])=[O:27])=[CH:5]2.[CH3:29][C:30]([CH3:36])([CH2:33][CH:34]=[CH2:35])[CH2:31][OH:32]>>[OH:32][CH2:31][C:30]([CH3:36])([CH3:29])[CH2:33][CH2:34][CH2:35][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([N:21]1[CH2:25][C:24](=[O:26])[NH:23][S:22]1(=[O:27])=[O:28])=[CH:5]2
Reactant: C=CCC(C)(C)CO
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OC(=O)c2ccccc2)S(=O)(=O)N1
Product: CC(C)(CO)CCCc1ccc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 8, step A, from benzoic acid 6-bromo-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl ester and 2,2-dimethylpent-4-en-1-ol: Retention time=1.30 min (Method A); (M−H)−=495.