Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[CH3:11][N:12](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[NH2:7][C:6]1[CH:8]=[C:2]([Br:1])[C:3]([CH3:10])=[CH:4][C:5]=1[C:11]#[N:12]
Reactant: CN(C)C=O
Reactant: Cc1cc(I)c(N)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)c(N)cc1Br
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([OH:22])[CH2:11][P:12]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:23]1([O:14][P:12]([CH2:11][C@H:10]([OH:22])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (0.67 g, 2.0 mmol) in 10 mL THF at 0° C. was added 1-chloro-N, N-2-trimethyl-1-propenylamine (319 mg, 2.4 mmol). After stirring for 10 min at 0° C., a solution of phenol (188 mg, 2.0 mmol) and triethylamine (243 mg, 2.4 mmol) in THF (3 mL) was added dropwise. After addition the reaction mixture was stirred at 0° C. for 2 h and then room temperature for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column gave ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester (500 mg, 1.22 mmol). 1H-NMR (CDCl3, 300 MHz): δ 7.35 (m, 2H), 7.18 (m, 3H), 4.18 (br s, H), −33.21-3.09 (m, 2H), 2.01-1.58 (m, 10H), 1.43-0.95 (m, 15H). 31P NMR (CD3OD, 300 MHz): 57.90, 58.65.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1.[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: COC(=O)Cc1ccccc1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1OC1CCN(C(C)=O)CC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
Di-tert-butylazodicarboxylate (305 mg, 1.32 mmol) was dropped to a solution of 1-(4-hydroxy-piperidin-1-yl)-ethanone (259 mg, 1.8 mmol) in tetrahydrofuran (4 mL) under nitrogen atmosphere. Then (2-hydroxy-phenyl)-acetic acid methyl ester (200 mg, 1.2 mmol) and triphenylphosphine (347 mg, 1.3 mmol) were added. The yellow mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was purified on silica using hexane/ethyl acetate mixture of increasing polarity (from 70% to 100% ethyl acetate) as eluent to give 195 mg (55.6%) of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH:16]([CH3:18])[CH3:17])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH:16]([CH3:18])[CH3:17])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid (3.2 g) and 4-nitrophenol (2.2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.7 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, crystallization of the crude product from 2-propanol-hexane yielded 3.55 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid 4-nitrophenyl ester, mp 111.5°-113° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[C:57]2[N:56]=[C:55]([Cl:58])[N:54]=[C:38]([NH:39][CH2:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:37]=2[N:36]=[CH:35]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[NH3:34].[Cl:58][C:55]1[N:54]=[C:38]([NH:39][CH2:40][CH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:37]2[N:36]=[CH:35][N:34]([C:57]=2[N:56]=1)[C@@H:11]1[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 22 °C
Reaction time: 2 h
Yield: 186.1 %

Procedure:
2-Chloro-N-(2,2-diphenylethyl)-adenosine 2',3',5'-tribenzoate (71.2 g) in methanol (980 ml) was treated with potassium carbonate (52.1 g). The suspension was stirred at 22° C. for 2 h. It was then acidified to pH 8 with concentrated hydrochloric acid, evaporated and purified on flash silica (2 kg) eluting with dichloromethane:ethanol:0.880 ammonia (90:10:1) to give the title compound (40.2 g) as a white solid, nmr(δ,DMSO-d6) 3.58(m,1H), 3.65(m,1H), 3.84(br.s,1H), 4.0 to 4.2 and 4.4 to 4.65(2 m,5H), 5.04(t,1H), 5.22 (d,1H), 5.48 (d,1H), 5.82(m,1H), 7.1 to 7.4(m,10H), 8.33(s,1H), 8.42(t,1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:15]=O)([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.CO>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:15][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:10])[CH3:9]
Reactant: CC(C)Oc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1cc(CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.25 ml of 1-methylpiperazine are added to a solution of 3.06 g of 3-isopropoxy-4-nitrobenzaldehyde in 15 ml of toluene and 0.34 ml of acetic acid in a three-necked round-bottomed flask under argon. The reaction mixture is stirred at ambient temperature for 1.5 h and then 5 ml of toluene are added, followed by 4.9 g of sodium triacetoxyborohydride by spatula. The reaction mixture is stirred at ambient temperature for 16 h, and then treated with 4.5 ml of methanol and 75 ml of a saturated sodium hydrogen carbonate solution. After stirring at ambient temperature for 30 min, the mixture is extracted with 30 ml and then 2×50 ml of ethyl acetate. The organic extracts are combined, washed with water, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure, so as to give 4.24 g of 1-(3-isopropoxy-4-nitrobenzyl)-4-methylpiperazine in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[N:17][C:16]([CH3:19])=[N:15]1)[CH:2]=[CH2:3].CO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N:14]1[CH:18]=[N:17][C:16]([CH3:19])=[N:15]1)[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C=CCOc1cc(N)ccc1-n1cnc(C)n1
Temperature: 65 °C
Reaction time: 0.83 h
Yield: 61 %

Procedure:
Iron powder-325 mesh (565 mg, 9.6 mmol), was taken in a round bottom flask charged with a mixture of 1-(2-(allyloxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (500 mg, 1.921 mmol), absolute methanol (5 ml), water (1 mL) and ammonium chloride (517 mg, 9.61 mmol). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 65° C. with vigorous stirring for 50 min. The reaction mixture was filtered and washed with methanol. The solvent was removed in vacuo. EtOAc was added to the residue, and washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 3-(allyloxy)-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline. (270 mg, 61% yield). LC-MS (M+H)+=231.2 1H NMR (400 MHz, DMSO-d6) δ ppm 8.434 (s, 1H), 7.11 (d, 1H, J=8.8 Hz), 6.34 (s, 1H), 6.21 (d, 1H, J=8.4 Hz), 5.99-5.93 (m, 1H), 5.42 (s, 2H), 5.29-5.18 (m, 2H), 4.50-4.48 (m, 2H), 2.28 (s, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([OH:41])=O)[N:38]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([N:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54][CH2:53]2)=[O:41])[N:38]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)O)cs1
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)N2CCCc3ccccc32)cs1
Reaction time: 18 h
Yield: 63.6 %

Procedure:
HBTU (306 mg, 0.81 mmol) was added to a solution of tert-butyl(1-(4-carboxythiazol-2-yl)ethyl)carbamate (200 mg, 0.73 mmol) in DMF (5 ml) at room temperature. Diisopropylethylamine (0.26 ml, 190 mg, 1.5 mmol) and 1,2,3,4-tetrahydroquinoline (0.11 ml, 117 mg, 0.88 mmol) were added and the mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid and separated. The organic layer was washed with water and brine, dried and reduced. Chromatography (45% EtOAc/55% hexanes) afforded tert-butyl(1-(4-(1,2,3,4-tetrahydroquinoline-1-carbonyl) thiazol-2-yl)ethyl)carbamate (180 mg, 63%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(CC2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC2CCCCC2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.41 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(cyclohexylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25][OH:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][OH:26])[CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: O=C(CO)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: O=[C:2]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:3]([O:10][C:11](=O)[C@H:12]1[CH2:16][C@@H:15](O)[CH2:14][N:13]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:35]([O-:38])([CH3:37])=[O:36].[NH4+:39]>CC(O)=O>[C:35]([O:38][C@H:15]1[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:12]([C:11]2[O:10][C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:39]=2)[CH2:16]1)(=[O:36])[CH3:37]
Reactant: O=C(c1ccccc1)C(OC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)c1ccccc1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Temperature: 120 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
A mixture of cis-4-hydroxy-N-benzyloxycarbonyl-D-proline 2-oxo-1,2-diphenylethyl ester (7.0 g) and AcONH4 (11.8 g) in AcOH was stirred at 120° C. for 1 hour. The reaction mixture was evaporated, and the residue was dissolved in EtOAc, washed with water, 3N NaOH solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 1:1˜2:3 elution) to give first benzyl (2R, 4R)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (972.6 mg), then benzyl (2R, 4R)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (5.12 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1ccccc1

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([S:10][CH3:11])[CH:3]=1.Cl.[CH3:13][O:14][NH2:15].C([O-])(=O)C.[Na+].O>CCOCC.C1COCC1>[CH3:13][O:14][N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[S:10][CH3:11]
Reactant: CON
Reactant: CSc1cc(F)ccc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON=Cc1ccc(F)cc1SC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A 250 mL round bottom flask was charged with 4-fluoro-2-methylsulfanylbenzaldehyde (5.106 g, 30 mmol), O-methylhydroxylamine hydrochloride (3.758 g, 45 mmol), sodium acetate (6.124 g, 45 mmol), water (50 mL) and THF (75 mL). The reaction mixture was stirred at room temperature for 4 h and taken up into ether (300 mL), washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.892 g, 99%) as a white solid.
Reaction SMILES: ClC1C=C([CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])C=CC=1Cl.N1[C:33]2[C:28](=[CH:29][C:30]([S:34](N)(=O)=O)=[CH:31][CH:32]=2)CC1.C1(SCC(O)=O)C=CC=CC=1>>[C:30]1([S:34][CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:31]=[CH:32][CH:33]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=C(O)CSc1ccccc1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CSc1ccccc1
Yield: 45 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 64, indoline-5-sulfonamide (Intermediate 54A, 120 mg, 0.60 mmol) and 2-(phenylthio)acetic acid (117 mg, 0.70 mmol) were converted to the title compound (100 mg, 45%). 1H NMR (DMSO-d6) δ 8.09 (d, J=8.4 Hz, 1H), 7.67-7.62 (m, 2H), 7.43-7.40 (m, 2H), 7.34-7.30 (m, 2H), 7.22-7.19 (m, 3H), 4.29 (t, J=8.6 Hz, 2H), 4.17 (s, 2H), 3.23 (t, J=8.5 Hz, 2H); MS(ESI+) m/z 348.9 (M+H)+.
Reaction SMILES: CN(C=[O:5])C.Br[C:7]1[CH:16]=[CH:15][C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=1.[C:17]([Cu])#[N:18].[C-]#N.[Na+]>O>[OH:5][C:15]1[C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]#[N:18])[CH:16]=1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(O)c2[nH]c(=O)oc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of DMF (110 ml) was added 6-bromo-2(3H)-benzoxazolone (50 g, 0.234 mole) and CuCN (89.6 g, 0.398 mole) and the mixture heated to 150° C. for 6 h under nitrogen. The reaction was then cooled to 100° C., H2O (200 ml) and NaCN (36 g, 0.734 mole) added, the suspension stirred for 2 h at ambient temperature and partitioned with EtOAc at 70° C. The organic phase was washed with H2O (2×150 ml) and concentrated in vacuo to give the title compound as a tan solid (33.2 g, 88.5%); mp>220° C.; 1H NMR (DMSO-d6) δ 7.8 (s, 1 H), 7.6 (d, J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:23]=[CH:22][C:18]3[S:19][CH:20]=[CH:21][C:17]=3[CH:16]=2)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>O.C(O)C.CN(C)C=O>[CH2:4]([O:6][N:7]=[C:25]([C:10]1[C:11](=[O:24])[CH2:12][CH:13]([C:15]2[C:23]3[CH:22]=[CH:18][S:19][C:20]=3[CH:21]=[CH:17][CH:16]=2)[CH2:14][C:9]=1[OH:8])[CH2:26][CH3:27])[CH3:5]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3sccc3c2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2cccc3sccc23)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of sodium hydroxide (0.15 g) in water (2 ml) and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(benzo[b]thien-5-yl)-2-propionylcyclohex-2-en-1-one (1.05 g) in ethanol/dimethylformamide (5:2 v/v; (70 ml). The mixture was stirred at room temperature for 12 hr, and was subsequently poured into water. the dried (MgSO4) diethyl ether extract was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(benzo[b]thien-4-yl)cyclohex-2-en-1-one as a white solid, mp 76° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][Br:28]>>[Br-:28].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: COCCCBr
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: COCCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 41.3 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and 3-bromopropyl methyl ether (0.035 g, 0.229 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0277 g, 41.3%). EI-MS m/z 361 (M+) Rt (1.58 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[NH2:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O[C:24]([CH2:26][C:27]1[NH:31][C:30]2[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=2[N:28]=1)=O)C>C(Cl)Cl.C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][C:4]1[CH:17]=[CH:18][C:19]2[NH:20][C:24]([CH2:26][C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:29]=4[N:28]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]c(Cc3nc4cc(CN5C(=O)c6ccccc6C5=O)ccc4[nH]3)nc2c1
Temperature: 185 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A finely ground mixture of 2-(3,4-diaminobenzyl)isoindole-1,3-dione (2.0 g, 7.5 mmol) and 2-ethoxycarbonylmethyl-1H-benzimidazole-5-carboxylic acid (0.93 g, 3.75 mmol) was heated 1 hour at 185° C. under nitrogen. The mixture was suspended in 1:1 methylene chloride/ethanol (20 mL) and stirred vigorously for 1 hour. The solids were collected by filtration, washed with 1:1 methylene chloride/ethanol (3×20 mL) and dried to provide 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1H-benzoimidazole-5-carboxylic acid (0.98 g, 29% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.45 (broad s, 1H), 8.07 (s, 1H), 7.80-7.83 (m, 6H), 7.51 (d, 1H, J=7.5 Hz), 7.43 (s, 1H), 7.11 (d, 1H, J=7.2 Hz), 4.82 (s, 2H), 4.48 (s, 2H).