Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1COCC1>[N:10]1([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCOCC1
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl bromoacetate (1.61 mL, 10.0 mmol) in THF (25 mL) was added morpholine (1.74 mL, 20.0 mmol); the resultant suspension was stirred for 1.5 h and then concentrated. The residue was dissolved in CH2Cl2 (50 mL)/saturated Na2CO3 (75 mL), the layers were separated, and the aqueous layer was extracted with additional CH2Cl2 (2×25 mL). The combined organics were washed with saturated Na2CO3 (20 mL) and brine (30 mL), dried and concentrated to give crude title compound. Tituration with EtOAc (15 mL), filtration, and concentration of the filtrate gave the title compound (2.01 g, 100%) as a colorless oil. TLC: Rf 0.45 (EtOAc). 1H NMR: δ3.79-3.73 (m, 4H, CH2OCH2), 3.11 (s, 2H, CH2), 2.61-2.55 (m, 4H, CH2NCH2), 1.46 (s, 9H, t-Bu). MS (DCI/CH4): m/z (rel intensity) 202 (MH+, 15), 201 (8), 200 (13), 174 (20), 146 (100), 100 (23). HRMS (C10H19NO3) (MH+): calcd, 201.1365; obsd, 201.1371.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]#[N:7].[NH3:16]>CO>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[C:6]([NH2:16])=[NH:7]
Reactant: CSCCC(C#N)OCCO[Si](C)(C)C
Reactant: N
Solvent: CO
Product: CSCCC(OCCO[Si](C)(C)C)C(=N)N

Procedure:
A solution of intermediate 18, 4-(methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile, (4.9 g, 0.02 mol) in 30 mL of methanol was saturated with ammonia. The flask was then sealed and heated in an oil bath at 80–90° C. for 16 hrs. After cooling, the flask was opened and the mixture concentrated in vacuo to give the title compound in essentially quantitative yield as a very viscous oil. 1H NMR (300 MHz, CDCl3) δ ppm: 3.94–4.02 (1H, m) 3.76–3.94 (3H, m) 3.68–3.77 (2H, m) 3.52–3.62 (2H, M) 2.53–2.67 (2H, m) 2.07 (3H, s) 1.89–2.01 (2H, m); LC/MS 193 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C1(S([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CCCCCC)(=O)=[O:22])C=CC=CC=1.[Na]>S(=O)(=O)(O)O>[C:7]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:1]1(=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1(=[O:24])[NH:13][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Agent: ON=C1CCCCC1
Agent: [Na]
Product: O=C1CCCCC1
Product: O=C1CCCCCN1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Take 200 ml of aqueous solution of 2.16N sulfuric acid in a round bottom flask. Dissolve in this solution 6.8 gm of sodium dodecyl benzene sulfonate (SDBS) and 1.3 gm of benzene by mild stirring. Keep the flask in a water bath maintained at temperature of 40° C. A macroemulsions of benzene in sulfuric acid is formed. To this macroemulsion, add 14.0 gm of cyclohexanone oxime and stir for 21/2 hours. Neutralize the excess acid using Whatman No. 1 filter paper to remove or recycle the the unreacted cyclohexanone oxime. Separate the organic and aqueous layers of the filtrate. Wash the aqueous layer with 3×10 ml benzene and add the benzene washing with the main organic layer. Analyze the benzene layer, the aqueous layer and the unreacted cyclohexanone oxime as obtained above by Gas Chromatography for the amount of cyclohexanone oxime, cyclohexanone and caprolactam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]3[C:21](=[O:22])[CH:20]4[CH:15]([CH:16]5[O:23][CH:19]4[CH2:18][CH2:17]5)[C:14]3=[O:24])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]3[C:14](=[O:24])[CH:15]4[CH:20]([CH:19]5[O:23][CH:16]4[CH2:17][CH2:18]5)[C:21]=3[O:22][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C2CC2)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.3 %

Procedure:
To a solution of 4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (100 mg, 0.18 mmol) in DCM (5 ml) and triethylamine (140 μl, 1 mmol) is added the cyclopropane carbonyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give cyclopropanecarboxylic acid-4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-5-oxo-10-oxa-tricyclo[5.2.1.0*2,6*]dec-3-en-3-yl ester (102 mg).
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]1[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][S:23]1
Reactant: ClCC[NH2+]Cc1ccccc1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2Cc2ccccc2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.80 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.60 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.44 g, 35.80 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere. Then the reaction was allowed to warm to ambient temperature and quenched with water (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.64 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 7.68 (dd, J=7.5, 2.1 Hz, 1H), 7.21-7.14 (m, 5H), 7.05-6.89 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:4].[NH4+:32].C([O-])(=O)C>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:7]3[C:6](=[CH:11][CH:10]=[C:9]([C:12](=[O:20])[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)[CH:8]=3)[NH:5][C:3](=[O:4])[N:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A mixture of intermediate 21 (0.0085 mol) and acetic acid, ammonium salt (0.0169 mol) in DMSO (42 ml) was stirred at 60° C. for 4 hours then cooled and poured out into ice water. The precipitate was filtered, washed with water, taken up in warm CH3CN, filtered off and dried under a vacuo, yielding 2.02 g (63%) of 4-(3-chlorophenyl)-6-(4-methylbenzoyl)-2(1H)quinazolinone (intermediate 22), mp. >260° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCc2ccccc2)CC1

Procedure:
1-(2-Phenylethyl)-4-piperidone oxime is prepared from 1-(2-phenylethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:7]=1)[O:8][CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Reactant: Oc1cc(Cl)ccc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(Cl)ccc1CCc1ccccc1

Procedure:
680 mg of 5-chloro-2-(2-phenylethyl)phenol (prepared as described in Preparation 9) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 360 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1 .38 g (yield 91%) of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCSc1ccc(Cl)nc1C#N
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N

Procedure:
6-Chloro-3-propylthio-2-pyridinecarbonitrile (12.8 g) was mixed with 10.6 g of 3,4-dichlorophenol in the presence of 7.3 g of t-BuOK in DMSO (10 ml) and THF (100 ml). The desired, 6-(3,4-dichlorophenoxy)-3-propylthio-2-pyridinecarbonitrile was recovered, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:8]2[C@@H:3]1[CH2:4][C:5]1[C:6]3[C:19]([NH:20][CH:21]=1)=[CH:18][CH:17]=[CH:16][C:7]=32.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:20]1[C:19]2[C:6]3=[C:7]([CH:16]=[CH:17][CH:18]=2)[C@H:8]2[C@H:3]([CH2:4][C:5]3=[CH:21]1)[N:2]([CH3:1])[CH2:15][C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2ccccc2[C@H]2c3cccc4c3c(cn4C)C[C@@H]21
Reaction time: 1 h

Procedure:
3 g of trans-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine are dissolved in 60 ml of dimethylformamide. The solution is cooled to -25°, and mixed whilst stirring with 280 mg of a 55% sodium hydride dispersion. The resultant suspension is allowed to warm to 0° over the course of 40 mins., and then 0.81 ml of methyl iodide, dissolved in 10 ml of dimethylformamide, are added in drops. The black reaction solution is stirred for a further 1 hour at 0°, and the dimethylformamide is subsequently removed under a high vacuum. The residue of evaporation is taken up in methylene chloride/methanol=95/5, extracted with water, and the combined organic phases dried, filtered and concentrated. The residue of evaporation is chromatographed on silica gel with methylene chloride/methanol=98/2 (methylene chloride 10% saturated with NH3). The title compound which crystallises from the solvent mixture used for chromatography is thus obtained. After washing with ether and subsequent drying, it melts at 184°- 185°.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
A mixture of 4-t-pentylbenzenesulfonyl chloride (0.13 g, 0.53 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.10 g, 0.44 mmol) in pyridine (1.0 mL) was heated at 80° C. for 3 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.11 g, 0.24 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J=1.6, 4.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.54 (dd, J=4.8, 8.4 Hz, 1H), 7.46-7.43 (m, 3H), 6.02 (s, 1H), 2.32 (s, 3H), 1.70 (q, J=7.2 Hz, 2H), 1.34 (s, 6H), 0.70 (t, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C24H27N4O2S [M+H]+ 435.2. found 435.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=CC(S(Cl)(=O)=O)=C[CH:18]=1.C([O-])(O)=O.[Na+]>CC(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:17]([CH3:27])([CH3:22])[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-Chloropyrimidine-4-carboxylic acid (500 mg, 3.154 mmol) was suspended in 2-methylpropan-2-ol (20 ml), followed by addition of pyridine (3 ml) and p-toluenesulfonyl chloride (1.2 g, 6.308 mmol), and then resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was neutralized by slow addition of a saturated aqueous NaHCO3 solution, and then concentrated under reduced pressure, followed by addition of distilled water (5 ml). The precipitated solid was filtered, followed by vacuum drying, to obtain 420 mg of pale yellow solid (62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:9].CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:9]1[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: NC(c1ccccc1)c1ccccc1F
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Fc1ccccc1C(c1ccccc1)n1cccc1
Yield: 69.3 %

Procedure:
To 100 ml of cooled (0° C.) acetic acid was added α-(2-fluorophenyl)benzenemethanamine (13.09 g). This mixture was then brought to room temperature and 2,5-dimethoxytetrahydrofuran (8.60 g) was added dropwise. The mixture was heated at reflux for 1.5 hours, after which time TLC (thin layer chromatography) showed absence of amine. The mixture was cooled and most of the acetic acid was removed by evaporation. The mixture was dissolved in ether and washed (3×H2O; 1×sat. NaHCO3), dried (sat. NaCl and anhydrous MgSO4), filtered and concentrated to yield a brown solid. Distillation (117° C.@0.15 mmHg) gave a slightly yellow solid (11.33 g). A sample was recrystallized from acetonitrile to give a white crystal, mp 81°-82.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31].[C:35](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:27]([O:28][C:29](=[O:34])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[O:21])[CH:14]=3)[NH:9]2)[CH:3]=1)([CH3:32])[CH3:31])[CH3:35]
Reactant: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N)c1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(C)Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 9.6 %

Procedure:
A mixture of N-[2-(3-Amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (0.37 g, 1 mmol), 2-bromo-2-methyl-propionic acid methyl ester (0.39 mL, 3 mmol) and potassium carbonate (690 mg, 5 mmol) in N,N-dimethylformamide (6 mL) was stirred at 25° C. for 96 h. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid ethyl ester (47 mg, 10%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O5S (M+H)+: 474.60, observed: 474.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[CH:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cn2)cc1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cn2)cc1
Yield: 28.7 %

Procedure:
Using a method similar to Example 455, step 3, using 2-thiophen-2-yl-ethylamine (0.027 mL, 0.227 mmol) and 4-(5-formyl-pyridin-2-yloxy)-benzamide (58 mg, 0.239 mmol) from step 1 (above) gives the title compound (23 mg, 27%). Mass spectrum (ion spray): m/z=353.9 (M+1); 1H NMR (DMSO-d6): 8.08 (d, J=2.1 Hz, 1H), 7.93 (bs, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.82 (dd, J=2.3 Hz, 8.3 Hz, 1H), 7.31 (bs, 1H), 7.27 (dd, J=1.0 Hz, 5.2 Hz, 1H), 7.12 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.90 (dd, J=3.5 Hz, 5.2 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 3.68 (S, 2H), 2.91 (t, J=7.1 Hz, 2H) 2.72 (t, J=7.1 Hz, 2H), 2.25 (bs, N—H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH2:22](N(CC)CC)C.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][NH:30][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4])=[O:34])[CH3:22].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: COC(=O)CCN
Reactant: CCN(CC)CC
Agent: Cl
Product: CCC(=O)[O-]
Product: CCOC(=O)CCNS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 32.7 %

Procedure:
This compound is prepared according to synthesis 25, from 115 mg (0.35 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2), 147 μL (1.05 mmol) of triethylamine and 59 mg (0.42 mmol) of methyl 3-aminopropanoate hydrochloride. After purification by chromatography on silica (eluent dichloromethane/methanol 96/4), 25 mg (18%) of 8-(2-ethoxycarbonyl-ethylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a gray solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C:26]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CNC(=O)OCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a suspension of diethyl 2-aminomalonate hydrochloride (10.6 g) in tetrahydrofuran are added N-(benzyloxycarbonyl)glycine (10.5 g) and triethylamine (5.1 g). The mixture is cooled to 0° to 5° C., and thereto is added N,N'-dicyclohexylcarbodiimide (10.8 g). The mixture is stirred at the same temperature for 2 hours and then allowed to stand at room temperature overnight. Insoluble substance is filtered off from the reaction mixture. The filtrate is distilled to remove the solvent, and to the residue is added ethyl acetate, and the insoluble substance is filtered off. The filtrate is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-isopropyl ether to give diethyl 2-[[N-(benzyloxycarbonyl)glycyl]amino]malonate (16.0 g), m.p. 94.5°-95.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22]([O:24]C(=O)CCl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([OH:23])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: O=C(CCl)OC(=O)CCl
Product: O=C([O-])CCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O

Procedure:
Following the procedure of the preceding paragraph react 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 4-oxide with chloroacetic anhydride to produce 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, chloroacetate.