Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1ncccc1OC[C@@H]1CCN1
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
To 2-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 121a (469 mg, 1.66 mmol) was added TFA (5 mL) in methylene chloride (5 mL) at 0° C., and the mixture was stirred for 30 minutes. The volatile components were then removed under vacuum. The residue was treated with saturated K2CO3 solution, then extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with chloroform:methanol:NH4OH (10:1:0-10:1:0.5) to afford the free base of the title compound (217 mg). The base (156 mg) was dissolved in methylene chloride (3 mL) and then converted to the salt by treatment with saturated HCl in ether to give the title compound (142 mg). mp 155-156° C. MS (DCI/NH3) m/z 199, 201 (M+H)+, 216 (M+NH4)+. 1H NMR (D2O, 300 MHz) δ2.7-2.79 (m, 2H), 4.13-4.24 (m, 2H), 4.44-4.58 (m, 2H), 4.98 (m, 1H), 7.45 (dd, J=4.8, 8.1 Hz, 1H), 7.59 (dd, J=1.5, 8.2 Hz, 1H), 8.03 (dd, J=1.4, 4.5 Hz, 1H). Anal. Calcd. for C9H11N2OCl.1.0 HCl: C, 45.98; H, 5.14; N, 11.91. Found: C, 45.76; H, 5.09; N, 11.64.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.O.NN>C(O)C>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1S2
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To 400 mg of (10,11-dihydro-11-oxo dibenzo[b,f]thiepin-2-yl)-acetic acid were added 20 ml of ethanol and 1 ml of hydrazine hydrate, and the mixture was refluxed with stirring under a dry atmosphere for 5 hours. After cooling, the solvent was removed by distillation under reduced pressure, and to the resulting mixture were added 20 ml of diethylene glycol and 4.0 g of sodium hydroxide. Thereafter, the resulting mixture was stirred under a dry atmosphere at 130° C. for 2 hours. After subsequent cooling, water was added to the mixture which was then washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was chromatographed over 18 g of silica gel and eluted with n-hexane/acetone (5/1) to obtain pale yellow crystals. These crystals were recrystallized from acetone/n-hexane to give 321 mg (yield: 84%) of (10,11-dihydro dibenzo[b,f]-thiepin-2-yl)-acetic acid as colorless crystals having a melting point of 111°-112° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]=[C:27]=[O:28])=[C:18]([F:29])[CH:17]=1.Cl>C1(C)C=CC=CC=1.CN(C)C=O.O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([NH:26][C:27](=[O:28])[NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:18]([F:29])[CH:17]=1
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 10 ml of absolute toluene is added dropwise while stirring at 0° C. during 15 minutes to a suspension of 0.24 g of a 55% sodium hydride dispersion in 20 ml of absolute dimethylformamide and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is subsequently cooled to -30° C. and treated with a solution of 1.26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in 10 ml of absolute toluene. The temperature rises rapidly to -10° C. and the reaction mixture is thereafter stirred at room temperature for 2 hours. The reaction mixture is poured into a solution of 3 ml of 2N hydrochloric acid and 500 ml of water and the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. Via ethyl 3-[3-(4-chloro-2-fluoro-5 -isopropoxyphenyl)ureido]-4,4,4-trifluorocrotonate (m.p. 144°-146° C.), which is not isolated, there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: [N:1]#[C:2][C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:4][C:5](=O)[CH2:6][CH3:7].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>O1CCCC1>[NH2:1][C:2]1[S:23][C:5]([CH2:6][CH3:7])=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H](C#N)NC(=O)CC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CC)sc1N
Temperature: 70 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of ethyl 3-nitrilo-N-propionylalaninate (10 g), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (24.1 g) and tetrahydrofuran (150 mL) was stirred at 70° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After purification by silica gel column chromatography, the obtained residue was recrystallized from ethyl acetate-hexane to give the title compound as colorless crystals (3.8 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:6][C:5]2=O.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2nc(-c3ccccc3)[nH]c(=O)c2c1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3ccccc3)nc(Cl)c2c1

Procedure:
To a stirred slurry of 2.1 g of 6-methyl-2-phenylquinazolin-4(3H)-one and 35 ml of thionyl chloride was added dropwise 1.3 g of dimethylformamide. The mixture was maintained at reflux temperature for 90 minutes. The mixture was concentrated under reduced pressure, the residual solid was mixed with crushed ice and the washed solid collected. Two recrystallizations from petroleum ether (60°-110° fraction) gave 1.5 g of 4-chloro-6-methyl-2-phenylquinazoline, m.p. 111°-113°.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH2:9][N+:8]=2[O-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:23][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])(=[O:22])[CH3:21]
Reactant: O=C1C[N+]([O-])=C(C2CCCCC2)c2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1N=C(C2CCCCC2)c2ccccc2NC1=O
Temperature: 70 °C

Procedure:
To a suspension of 5-cyclohexy-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (0.70 g) in chloroform (10 ml) was added acetic anhydride (3.7 ml) at ambient temperature and the mixture was heated for 4 hours at 70° C. After cooling, the mixture was concentrated in vacuo. The residue was taken up with chloroform. The organic layer was washed with saturated aqueous sodium carbonate, dried over magnesium sulfate, filtered off and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography on silica gel with chloroform to give (3RS)-3-acetoxy-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: O[C:2]1([CH2:11]Cl)[CH2:6][S:5][C:4]([CH2:7][N:8]([CH3:10])[CH3:9])=[N:3]1.C1(C)C=CC=CC=1.[OH-:20].[K+]>O>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([CH2:11][OH:20])[N:3]=1)[CH3:10]
Reactant: CN(C)CC1=NC(O)(CCl)CS1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)Cc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 100 ml, three-necked, flask equipped with an agitator and condensor were added 3.0 g (0.014 mol) of 4-hydroxy-4-chloromethyl-2-(dimethylaminomethyl)thiazoline (prepared as in Example 1), 47 ml of toluene, 1 ml of water and 0.79 g (0.014 mol) of solid potassium hydroxide. The resulting solution was stirred at room temperature for 45 minutes. A 1 μl sample of the reaction mixture was then removed from the flask and diluted according to the procedure described in Example 4. The HPLC assay set forth in Example 3 indicated that 72.6% of the thiazoline substrate had converted to the desired titled product.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([Cl:35])[CH:34]=1)[N:31]([CH2:36][CH2:37][CH3:38])[C:30](=[O:39])[C:29]2=[O:40].C(N1C2C(=CC(C)=CC=2)[C:47](=[O:55])C1=O)C(C)C>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([Cl:35])[CH:34]=1)[N:31]([CH2:36][CH2:37][CH3:38])[C:30](=[O:39])[C:29]2([OH:40])[CH2:14][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:55][CH3:47])[N:17]=1)=[O:22]
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)cc(Cl)c21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CC(C)C
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2cccc(OC)n2)c2cc(Cl)cc(Cl)c21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5,7-dichloro-1-propylindoline-2,3-dione and 1-isobutyl-5-methylindoline-2,3-dione (purchased from Fisher Scientific). 1H-NMR δ 7.74 (dd, 1H), 7.65 (dd, 1H), 7.37-7.25 (m, 2H), 6.99 (dd, 1H), 5.31 (bs, OH), 4.04-3.96 (m, 6H), 3.53 (dd, 1H), 1.77 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>CC#N>[CH3:43][C:37]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([C:25]2[N:24]([CH3:32])[N:23]=[CH:22][C:21]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9]2[N:19]([CH:20]=[C:7]([C:5]4[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=[C:2]([CH3:1])[N:6]=4)[N:8]=2)[CH2:18][CH2:17][O:16]3)[CH2:27]1)([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)(C)N1CCCC(c2c(-c3ccc4c(c3)OCCn3cc(-c5nc(C)nn5C(C)C)nc3-4)cnn2C)C1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (60 mg, 0.127 mmol), ethyl 2-bromo-2-methylpropanoate (247.65 mg, 1.27 mmol), Ag2O (294 mg, 1.27 mmol), H2O (0.1 ml) and CH3CN (1.5 ml) in a seal tube was heated at 60° C. for 8 h. The solid was filtered off and the filtrate was purified by Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford ethyl 2-methyl-2-[3-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)piperidin-1-yl]propanoate (35 mg, 47% yield). LCMS (ESI) m/z: 589.3 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:16].C([O-])([O-])=O.[K+].[K+]>>[ClH:7].[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:26]1[CH2:27][CH2:28][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][CH3:16])[CH2:24][CH2:25]1
Reactant: CCc1ccccc1N1CCNCC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccccc1N1CCN(Cc2cc(OC)c(OC)c(OC)c2)CC1
Product: Cl
Yield: 76.5 %

Procedure:
8.3 g of 3,4,5-trimethoxybenzyl chloride and 3.8 g of N-(2-ethylphenyl)-piperazine and 3.5 g of K2CO3 are reacted and processed according to example 2. 6.5 g of N-(3,4,5-trimethoxy-benzyl)-N'-(2-ethylphenyl)-piperazine dihydrochloride is obtained. Mp.: 179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15]C(=O)[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28]([O:31][CH3:32])[O:29][CH3:30]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:28]([O:29][CH3:30])([O:31][CH3:32])[CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1C1CC(=O)CCN1C(=O)OCc1ccccc1
Reactant: COC(OC)OC
Solvent: CO
Product: COC1(OC)CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 132 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine were added 650 ml of methanol, 84 ml of trimethoxymethane and 2 g of strongly acidic resin IR-120 (manufactured by Japan Organo Co., Ltd.), and the mixture was stirred at room temperature for 3 days. From the reaction mixture was removed insoluble matters by filtration, and the solvent was removed by distillation under reduced pressure, to give 146 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine as shown in Table 125 below.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.[C:32](=[O:35])([O-:34])[O-].[Na+].[Na+].[OH-].[Na+]>CC1C=CC=CC=1C>[C:10]([OH:12])(=[O:11])[C:32]([OH:34])=[O:35].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([N:14]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(Nc2ccccc2)CCN(C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COC(=O)C1(N(C(=O)Cc2ccc(Cl)cc2)c2ccccc2)CCN(C(C)C)CC1
Product: O=C(O)C(=O)O
Yield: 48 %

Procedure:
a mixture of 5 parts of methyl 1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylate, 24 parts of 4-chlorobenzeneacetyl chloride, 4 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and refluxed for 32 hours. The reaction mixture is cooled, washed with a diluted sodium hydroxide solution and extracted with a diluted hydrochloric acid solution: three layers are obtained. The oil and the aqueous phase are combined and alkalized with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane, yielding 5 parts (48%) of methyl 4-[N-(4-chlorophenyl)acetyl-N-phenylamino]-1-(1-methylethyl)-4-piperidinecarboxylate ethanedioate; mp. 154.2° C.
Reaction SMILES: [NH:1]([CH2:6][CH2:7]C(NN)=O)[NH:2][C:3]([NH2:5])=[O:4].[N-:12]=[C:13]=[O:14].C[N:16](C)C=O>O>[NH:1]([CH:6]([CH3:7])[C:13]([NH:12][NH2:16])=[O:14])[NH:2][C:3]([NH2:5])=[O:4]
Reactant: CN(C)C=O
Reactant: NNC(=O)CCNNC(N)=O
Reactant: [N-]=C=O
Solvent: O
Product: CC(NNC(N)=O)C(=O)NN

Procedure:
8.63 parts of β-semicarbazido-propionic acid hydrazide dissolved in 17 parts of water and 450 parts of dimethylformamide were reacted with 215 parts of isocyanate prepolymer (prepared as in Example 2, isocyanate content 2.62% in the solid substance), and 210 parts of dimethylformamide and 4% TiO2 were added. The elastomeric solution had a viscosity of 640 poises. ηi- value 1.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.Br>[Br:21][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
To a mixture of methyl 4-methoxyphenylacetate (20 g, 0.11 mol) and NBS (0.11 mol) in CCl4 (0.2 l) were added 3 drops of 48% HBr and this mixture was heated to reflux for 8 h. The cooled solution was filtered through a pad of silica gel and the filtrate was evaporated in vacuo to give 29 g of the title compound as pale yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].[CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][NH:34]2)=O>>[NH:34]1[C:35]2[C:31](=[C:30]([CH2:28][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:21][CH2:20][C:19]5[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=5[O:17][C:16]([F:26])([F:27])[F:15])=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: FC(F)(F)Oc1ccccc1CNc1ccc2c(NCc3cccc4[nH]ccc34)cccc2n1

Procedure:
The title compound, MS: m/e=463.0 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 2-(trifluoromethoxy)benzylamine and 4-formylindole as described in example 26.
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(C1C=CC(S(N)(=O)=O)=CC=1)=O)(C)(C)C.C(C1C(=O)N(S(C2C=C(C=CC=2)C(O)=O)(=O)=O)CC(=O)NC1)C1C=CC=CC=1.C(OC(C1C=C(S(N)(=O)=O)C=CC=1)=O)(C)(C)C.ClC1C=CC(S(N2C(=O)/C(=C/C3C=C(Cl)C=CC=3OC)/CNC(=O)C2)(=O)=O)=CC=1C(OC)=O>>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([O:25][CH3:29])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C(=O)C(Cc2ccccc2)CN1
Agent: CC(C)(C)OC(=O)c1cccc(S(N)(=O)=O)c1
Agent: COC(=O)c1cc(S(=O)(=O)N2CC(=O)NC/C(=C\c3cc(Cl)ccc3OC)C2=O)ccc1Cl
Agent: O=C1CN(S(=O)(=O)c2cccc(C(=O)O)c2)C(=O)C(Cc2ccccc2)CN1
Product: COC(=O)c1ccc(S(=O)(=O)N2CC(=O)NCC(Cc3ccccc3)C2=O)cc1

Procedure:
4-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoic acid, synthesized by using 4-(tert-butoxycarbonyl)benzenesulfonamide instead of the starting material compound of Example 198, that is, 3-(tert-butoxycarbonyl)benzenesulfonamide for the similar procedure as in Example 198, was used instead of the starting material of Example 208, that is, the compound 196, for the similar procedure as with Example 208 to obtain the title compound.
Reaction SMILES: [H-].[Na+].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[N:12]=[CH:11]2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[CH:46]([N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:41]3=[N:42][CH:43]=[CH:44][CH:45]=[C:40]3[CH2:39][CH2:38][C:37]=2[CH:53]=1.C(N(CC)CC)C.Cl[C:62](Cl)([O:64]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1.ClCCl>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[CH:46]([N:47]3[CH2:48][CH2:49][N:50]([C:62]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]4[N:12]=[CH:11][NH:10][CH:14]=4)=[O:64])[CH2:51][CH2:52]3)[C:41]3=[N:42][CH:43]=[CH:44][CH:45]=[C:40]3[CH2:39][CH2:38][C:37]=2[CH:53]=1
Reactant: OCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCCCCc1c[nH]cn1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium hydride (200 mg of 60% dispersion; 5.0 mmol) in dry tetrahydrofuran (25 mL), was added portionwise alcohol hydrochloride (4) (1.05 g; 2.5 mmol) over a period of 10 min. The resultant suspension was stirred at room temperature for 3.5 h. The piperazine derivative (8) (706 mg; 2.25 mmol) was added, the mixture was diluted with dry tetrahydrofuran (25 mL), and the resultant suspension allowed to stir overnight at room temperature. Triethylamine (0.35 mL; 2.5 mmol) was added, followed by the addition over about 4 min. of a solution of triphosgene (252 mg; 0.849 mmol) in dry dichloromethane (2.5 mL) (mild exotherm). The resultant suspension was stirred at room temperature for 6 h; then the solids were filtered and washed with ethyl acetate. The filtrate and washings were combined, and solvent removed under reduced pressure. Chromatography of the residue on silica gel, eluting with a gradient of ethyl acetate-methanol (98:2→95:5), yielded the title tritylated product (31) as a white glassy foam. ESIMS: 722 (MH+; 85%); 243 (Ph3C+; 100%). [A more polar fraction corresponding to symmetrical urea (30) was also isolated.]
Reaction SMILES: [CH2:1]([C@H:5]1[O:7][C@@H:6]1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C(Cl)(=O)C(C)(C)C.[NH2:58][C@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]1[OH:65]>O1CCCC1>[OH:65][C@H:60]1[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:59]1[NH:58][C:8]([C@@H:6]1[C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:7]1)=[O:10]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)O
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H]1O[C@@H]1C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Under ice-cooling, to 20 ml of an anhydrous tetrahydrofuran solution containing 2.3 g (7 mmol) of (2S-trans)-3-butyl-oxirane carboxylic acid.dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 844 mg (7 mmol) of pivaloyl chloride, and the mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature and the mixture was further stirred for 2 hours. After removing insoluble material in the reaction mixture by filtration, the filtrate was added to 20 ml of an anhydrous tetrahydrofuran solution containing 806 mg (7 mmol) of (1S,2S)-2-aminocyclohexanol under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and then, a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.69 g (Yield: 100%) of the title compound.