Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]2[CH2:3][CH2:2]1.[C:15]1([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:31])=[CH:33][CH:34]=2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)CN1CCC[C@H]1CN2
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine prepared in Reference Example 28 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give (11aS)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11, 11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine. The resulting (11aS)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine was dissolved in ethyl acetate, a 4N hydrochloric acid-ethyl acetate solution was added thereto, the resulting precipitates were recovered through filtration and washed with a small amount of ethyl acetate to thus give the title compound. Yield 62.4%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:21])[CH2:11][O:12][CH:13]([CH2:19]O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:11][O:12][C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:19][O:21]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCCC(CO)OCC(O)c1ccc(OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(OCC)cc2)CO1

Procedure:
One boils a solution of 29.6 g. 1-p-ethoxyphenyl-4-hydroxymethyl-3-oxa-nonan-1-ol (obtainable by reaction of p-ethoxyphenacyl bromide with 2-hydroxyheptanoic acid ethyl ester to give 2-p-ethoxyphenacyloxyheptanoic acid ethyl ester and reduction with LiAlH4) and 1 g. p-toluenesulphonic acid in 400 ml. toluene for 1 hour with water separator, washes with NaHCO3 solution, dries, evaporates and obtains trans-2-p-ethoxyphenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C(N(C)C)=N.[CH2:43]=[O:44]>C(#N)C.C([O-])(O)=O.[Na+]>[C:31]([O:30][C:28]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([N+:14]([O-:16])=[O:15])[CH2:43][OH:44])[C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)[O-]
Reactant: C=O
Agent: CN(C)C(=N)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(CO)[N+](=O)[O-])C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol) in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueous solution). After stirring for 60 min, more formaldehyde (0.050 mL, 37% aqueous solution) was added. After stirring for an additional 60 min the mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (25%→75% ethyl acetate/hexanes) to give the title compound (1.44 g,). MS 409.1 (M+1-2 Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[CH3:26][CH:27]1[CH2:33][C:32](=[O:34])[O:31][C:29](=[O:30])[CH2:28]1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:32]([CH2:33][CH:27]([CH3:26])[CH2:28][C:29]([OH:31])=[O:30])=[O:34])[CH3:8]
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Reactant: CC1CC(=O)OC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(=O)O)CC(=O)NC(C)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
20 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 10 mg of 3-methylglutaric anhydride and 4 μl of triethylamine were added thereto. The mixture was stirred at room temperature for 3 hours. A saturated sodium carbonate aqueous solution and methylene chloride were added to the reaction solution, and the mixture was stirred for 30 minutes. Then, the organic layer was collected by separation, washed with 1N hydrochloric acid and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-200, 2 g; chloroform/methanol=20/1) to obtain 16 mg (yield: 74%) of the above-identified compound as colorless oily substance.
Reaction SMILES: CC([O-:5])(C)C.[K+].[OH2:7].[ClH:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C:34]([CH2:43][O:44][C:45](NCC)=[O:46])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O.O.[Cl:52][C:53]1[CH:54]=[C:55]([CH:60]([CH2:72][CH2:73][N:74]2[CH2:79][CH2:78][C:77]([C:87]3[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=3)([CH2:80][O:81][C:82](NCC)=[O:83])[CH2:76][CH2:75]2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=[CH:57][C:58]=1[Cl:59].Cl.Cl>CN(C=O)C>[OH2:5].[ClH:9].[C:45]([CH2:80][C:77]1([C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:78][CH2:79][N:74]([CH2:73][CH2:72][CH:60]([C:55]2[CH:56]=[CH:57][C:58]([Cl:59])=[C:53]([Cl:52])[CH:54]=2)[CH2:61][N:62]([CH3:71])[C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:75][CH2:76]1)([OH:46])=[O:44].[OH2:27].[OH2:7].[C:82]([CH2:43][C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:36][CH2:35]1)([OH:83])=[O:81].[ClH:8]
Reactant: CC(C)(C)[O-]
Reactant: CCNC(=O)OCC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(CCN1CCC(CC(=O)O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 80 °C
Yield: 136.9 %

Procedure:
1.8 g of potassium tert-butylate and then 1.5 g of the compound obtained in step C of EXAMPLE 15 are added to a solution of 2.3 g of the compound obtained in PREPARATION 1.22 in 20 ml of DMF, and the reaction mixture is heated to 80° C. for 2 hours. It is concentrated under vacuum, the residue is taken up in water, the mixture is neutralized to pH 7 by adding concentrated HCl solution, the product is extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/MeOH (95:5; v/v) mixture. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum. 0.96 g of the expected product is obtained after crystallization in iso ether.
Reaction SMILES: [CH2:1]([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S:24]=[C:25]([C:27](=[S:29])[NH2:28])[NH2:26]>>[CH2:1]([CH:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[S:24][C:25]2[N:26]=[C:14]([C:10]3[S:11][CH:12]=[CH:13][C:9]=3[CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[S:29][C:27]=2[N:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1C=O
Reactant: NC(=S)C(N)=S
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1-c1nc2sc(-c3sccc3CC(CCCCCC)CCCCCCCC)nc2s1
Temperature: 200 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, 3-(2-hexyldecyl)-2thiophenaldehyde (3.00 g, 8.91 mmol) (A3) and rubeanic acid (375 mg, 2.97 mmol) were added to a flask equipped with Dean-Stark, then heated to 200° C., and stirred for five hours. Then, the reaction mixture was extracted with chloroform, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and chloroform was used as a mobile phase, 2,5-bis(3(2-hexyldecyl)thiophene-2-yl)thiazolo[5,4-d]thiazole (A4) was obtained as a yellow solid (630 mg, 28% yield). The product (A4) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.34 (d, J=5.4 Hz, 1 H), 6.95 (d, j=5.4 Hz, 1 H), 2.93 (d, J=7.4 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([F:20])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:13]([F:20])[CH:12]=1
Reactant: O=Cc1cnccc1Br
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a mixture of 4-bromonicotinaldehyde (3.00 g, 16.13 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.81 g, 16.13 mmol), cesium carbonate (10.51 g, 32.3 mmol) and Pd(PPh3)4 (0.932 g, 0.806 mmol) was added THF (50 mL) and water (8 mL). Nitrogen gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under nitrogen atmosphere at 85° C. for 6 h. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate (30 mL) and washed with water (1×25 mL) and brine (1×25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to yield 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.5 g, 6.37 mmol, 39% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 9.18 (s, 1H), 8.86 (d, J=5.1 Hz, 1H), 7.30 (m, 4H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepentanoate(10.0 g), 2-methylimidazole(7.20 g), potassium carbonate(12.1 g) and N,N-dimethylformamide(80 ml) was stirred for 2 hours at 120-130° C. Water was added to the reaction mixture to give 30 ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanoate(9.97 g, 88%). This was recrystallized from ethyl acetate-isopropyl ether to give colorless prisms. mp 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:38][CH:39]([CH3:43])[C:40](=[S:42])[NH2:41]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([CH:39]([CH3:43])[CH3:38])=[N:41][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Reactant: CC(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.0 g, 2.3 mmol) in DMF (10 mL) was added NBS (0.49 g, 2.8 mmol). After stirring for 45 min at rt, 2-methylpropanethioamide (0.35 g, 3.4 mmol), was added and the reaction was stirred at rt. After 4 h, the reaction mixture was partitioned between ether and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous NaSCO4, filtered, and concentrated to generate 0.49 g (41% yield) as a yellow powder. MS (ESI) 525 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)C=C.[C:15]1(C)[CH:20]=C(C)C=C(C)[CH:16]=1>>[CH2:20]([C:13]1[C:12]([Cl:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:4])[CH:15]=[CH2:16]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc(Cl)cc2c1CCC2
Product: C=CCc1c(Cl)cc2c(c1O)CCC2
Yield: 56 %

Procedure:
Treatment of 4-(allyloxy)-6-chloroindane (8.0 g, 0.038 mol) in refluxing mesitylene (270 mL) generally according to the procedure described for Intermediate 1 afforded 4.5 g (56%) of 5-allyl-6-chloroindan-4-ol as a colorless oil which solidified into a white solid upon standing. mp 37-39° C.; Anal. calcd. for C12H13ClO.0.1H2O: C, 68.48; H, 6.32. Found: C, 68.54; H, 6.29.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[N:17][OH:18])[NH2:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)C(c1ccccc1)c1ccccc1
Yield: 30.5 %

Procedure:
A mixture of diphenylacetonitrile (7.0 g), hydroxylamine hydrochloride (3.03 g), and sodium acetate (6.67 g) in 150 ml of 5:1 ethanol-water was refluxed for 4 h. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtrated, and dried to give the title compound (2.5 g) having the following physical data.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1(O)[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:6]1[C:7](OC)=[O:8].O.Cl>CO.C[O-].[Na+]>[OH:3][NH:2][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:5]=1[OH:4]
Reactant: NO
Reactant: COC(=O)C1C=CC(C)=CC1(O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NO)c(O)c1
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
9.05 g of hydroxylamine hydrochloride was dissolved in 84 mL of methanol, to which 40.64 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this mixture was stirred for 10 minutes. Then, 21 mL of a solution of 7.00 g of methyl 2-hydroxy-4-methylsalicylate in methanol was added dropwise to the reaction mixture, which was stirred for one hour at room temperature and then another four hours while heating it under reflux. The reaction mixture was added to water, and adjusted to pH 5 with 6M hydrochloric acid, and then resultant precipitate was filtered out thereof. The resultant solid was washed with water and diisopropyl ether successively to yield 5.95 g of N,2-dihydroxy-4-methylbenzamide as light yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 140 °C
Yield: 90 %

Procedure:
A mixture of crushed phthalic anhydride (18.53 g, 0.125 mol) and 4-aminobutyric acid was heated for 30 minutes at 140° C. The reaction mixture was cooled, and resulting precipitate was recrystallized from methanol-water to give 26.26 g (yield 90%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 20, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[N:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:31])([CH3:32])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[CH:14][N:13]=1)=[O:5]
Reactant: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(N)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(NC(=O)c2ccccc2Cl)cn1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
To a 0° C. cooled and stirred, solution of 2-chlorobenzoyl chloride (43 μL, 0.34 mmol, 1.0 eq) in DCM (2 mL) was added drop wise a solution of Intermediate 1b, (100 mg, 0.34 mmol, 1.0 eq) in DCM (5 mL) followed by pyridine (47 μL, 0.44 mmol, 1.3 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM (10 mL), and washed with 10% hydrochloric acid (5 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane as eluent) to afford 50 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.80 (s, 1H, D2O exchangeable), 8.39 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.84 (dd, J=7.0, 1.5 Hz, 1H), 7.52-7.40 (m, 4H), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 435, 437 [(MH)+, Cl35,37].
Reaction SMILES: O.O.C([O-])(=O)C.[Zn+2:7].C([O-])(=O)C.[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2>CO>[CH:15]1[CH:14]=[C:13]([O-:12])[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=1.[CH:15]1[CH:14]=[C:13]([O-:12])[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:16]=1.[Zn+2:7]
Reactant: Oc1cccc2cccnc12
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: [O-]c1cccc2cccnc12
Yield: 89.4 %

Procedure:
Zinc acetate dihydrate (1.0 g) was dissolved in 75 ml. of hot methanol and 1.4 g of 8-hydroxyquinoline was added to the homogeneous solution. A yellow precipitate formed after a few minutes and the solution was stirred at reflux for 3 hours. The solution was allowed to cool and the precipitate was isolated by filtration and washed with methanol and petroleum ether. After air drying, 1.44 g of bis(8-hydroxyquinolinato)zinc was obtained as a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 7.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (170 mg, 0.76 mmol) and ethyl isocyanatoacetate (103 μL, 0.92 mmol) in 1.5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), followed by Gilson HPLC separation, gave the desired product (20 mg, 7%). LC-MS (m/z) 352.0 (M+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:25]([O-:27])=[O:26])[CH:8]=2)[N:3]=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>O>[CH2:28]([NH:31][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:25]([O-:27])=[O:26])[CH:8]=2)[N:3]=1)[CH:29]=[CH2:30]
Reactant: C=CCN
Reactant: CCCCCCCCCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCCCCCCCCCCCC)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To 170 mg (0.44 mmol) of 2-chloro-4-dodecylamino-6-nitroquinazoline was added 1.70 ml (22.66 mmol) of allylamine, and then the resulting mixture was stirred at room temperature overnight. After water was added to the reaction solution, crystals thus precipitated were filtered to give 170 mg (93.4%) of the title compound.