Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[F:21][C:11]([F:10])([F:22])[C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:66]2[CH2:65][CH2:64][N:63]([C:46](=[O:45])[CH2:47][NH:48][C:49]([C:51]3[CH:56]=[CH:55][C:54]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:53][CH:52]=3)=[O:50])[CH2:68][CH2:67]2)=[O:18])=[CH:19][CH:20]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-trifluoromethyl-benzoic acid (48.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 33 mg (25.9% yield) of biphenyl-4-carboxylicacid {2-[4-(4-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.96%, 1H NMR: (DMSO) δ 8.65 (t, 1H), 8.0 (d, 2H), 7.9-7.7 (m, 6H), 7.7-7.64 (d, 2H), 7.56-7.46 (t, 2H), 7.46-7.38 (t, 1H) 4.2 (s, 3H), 3.6 (d, 7H).
Reaction SMILES: [C-]#N.[K+].[C:4]([CH2:6]CC1C=C2C(=CC=1)NC(=O)C2)#N.Cl[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.CS(C)=[O:33]>>[C:20]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)(=[O:33])[CH2:19][CH2:4][CH3:6]
Reactant: CS(C)=O
Reactant: N#CCCc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: [C-]#N
Agent: [K+]
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 90 °C
Yield: 42 %

Procedure:
To 15 g aluminum chloride suspended in 30 mL 1,2-dichloro-ethane in an ice bath was added 7.5 g of 2-oxindole and then 12 g of butanoyl chloride. The resulting suspension was heated to 50° C. overnight. The mixture was poured into ice water and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness to give a brown solid. The solid was chromatographed on silica gel (50% ethyl acetate in hexane) to give 3 g (25%) of the title compound as a yellow solid. 5-Cyanoethyl-2-oxindole Potassium cyanide (2.0 g) was added to 15 mL of dimethyl-sulfoxide and heated to 90° C. 5-Chloroethyl-2-oxindole (3.0 g) dissolved in 5 mL dimethyl sulfoxide was added slowly with stirring, and the reaction heated to 150° C. for 2 hours. The mixture was cooled, poured into ice water and the precipitate collected by vacuum filtration, washed with water, dried and then chromatographed on silica gel (5% methanol in chloroform) to give 1.2 g (42% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[C:17]([C:20]4[CH:21]=[N:22][N:23]([C:25]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:44][C:45]1[S:46][CH:47]=[C:48]([CH3:50])[N:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:50][C:48]1[N:49]=[C:45]([NH:44][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([C:25]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:2]=2[F:1])[S:46][CH:47]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cn23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cn34)cc2F)n1
Yield: 84.9 %

Procedure:
170 mg 2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo-[1,2-a]pyridin-3-yl]benzoic acid (compound in Example 472) and 34.4 mg 2-amino-4-methyl-1,3-thiazole were allowed to react overnight with 146 mg benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 50 μL triethylamine in 6 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 169 mg of the title compound as colorless crystals (recrystallization solvent: ethyl acetate).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16]N[CH2:14][CH2:13]1.[C:18]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[N:12]1([CH2:11][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:18][CH2:14][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.2 %

Procedure:
1-Fluoro-4-nitro-benzene (1.00 g, 7.09 mmol) is dissolved in N,N-dimethylformamide (20 mL), and to this solution, is added 1-methyl-piperazine (0.944 mL, 8.51 mmol) followed by K2CO3 (1.47 g, 10.6 mmol). After stirring the mixture at room temperature for 18 h, the solvent is removed via high vacuum. The resulting residue is dissolved in EtOAc (100 mL) and washed with H2O (10 mL) and brine (10 mL) and then dried (Na2SO4). The solvent is taken off via high vacuum to afford the product as a solid (1.50 g, 96%); 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37-2.42 (m, 4H), 3.39-3.43 (m, 4H), 6.98 (d, J=9.6 Hz, 2H), 8.00 (d, J=9.5 Hz, 2H); mass spectrum [(+) ESI], m/z 222 (M+H)+.
Reaction SMILES: [CH:1]12[CH:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]3[S:17][C:16]([O:18][CH:19]4OC(C)(C)N(C(C)(C)C)[C:20]4=[CH2:30])=[N:15][CH:14]=3)=[O:12])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-:31].[Na+]>C(OCC)(=O)C>[CH:1]12[CH:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]3[S:17][C:16]([O:18][CH2:19][CH:20]([OH:31])[CH3:30])=[N:15][CH:14]=3)=[O:12])[CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: [OH-]
Reactant: C=C1C(Oc2ncc(C(=O)NCCC3C4CCC3CC4)s2)OC(C)(C)N1C(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(O)COc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reaction time: 0.5 h

Procedure:
This example illustrates methods of converting the compounds of formula E into the compounds of formula C. In this example 1 g. of 5-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)-methylene-N-t-butyl-2,2-dimethyloxazolidine is dissolved in 50 ml. of ethyl acetate and this solution is treated with aqueous 5% sodium hydroxide (20 ml.) at 20° C. The mixture is allowed to stand for 0.5 hours, washed three times with water, dried over magnesium sulfate and then evaporated to dryness affording 1-t-butyl-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[Cl:19][CH:20]([S:24]([CH3:27])(=[O:26])=[O:25])C(=O)C>O.CC(C)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][N:10]=[C:20]([Cl:19])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: CC(=O)C(Cl)S(C)(=O)=O
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)C(Cl)=NNc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
Part A. 3-Chloroaniline (5.00 g, 39.2 mmol) was added dropwise to an ice-cold 1N hydrochloric acid solution followed by the addition of 4 mL of 12M hydrochloric acid. To this solution was slowly added an ice-cold solution of sodium nitrite (3.00 g, 43.1 mmol) in 4 mL of water while maintaining the internal temperature to less than 5° C. This solution was stirred for 45 min at 0° C. during which time a precipitate formed. Glacial acetic acid (1 mL) was added and the precipitate dissolved. To this solution was added solid sodium acetate (approx. 2 g) to adjust the pH to 4 and then 10 mL ice cold acetone was added followed by an ice cold solution of 1-chloro-1-methanesulfonyl-propan-2-one in 10 mL acetone. The reaction was allowed to warm to ambient temperature and stirred for 14 h. A stream of nitrogen was passed over the solution to slightly reduce the solvent volume. The solid precipitate was collected by filtration, washed twice with water, and dried in vacuo at 40° C. to give 8.47 g (81%) of N-(3-chlorophenyl)-1-(methylsulfonyl)-methanehydrazonoyl chloride as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]1[CH2:12][CH:13]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:15][CH2:16][C:5]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:31][S:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1)(=[O:34])=[O:33]>O1CCCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:39][C:38]1[CH:37]=[CH:36][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:42][CH:41]=1)[C:6]1[CH2:12][CH:13]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:15][CH2:16][C:5]2=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(O)CC1CCCc2c([nH]c3c(F)cc(F)cc23)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Cn2c3c(c4cc(F)cc(F)c42)CCCC(CC(=O)O)C3)cc1
Reaction time: 0.17 h

Procedure:
To a cold solution (0° C.) of 3.5 g of acid from Step 2 in 75 mL of tetrahydrofuran was added dropwise 38.7 cc of a solution of KHMDS in toluene (0.684M) and the mixture stirred for 10 minutes. To the resulting cold (0° C.) solution was added dropwise 3.5 g of a solution of p-methylsufonylbenzyl chloride in 10 mL of tetrahydrofuran. The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was acidified with HCl (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of hexane/ethyl acetate (7:3) and filtered to yield the title product m.p. 200°-202° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.[CH2:23]=O>C(#N)C.N1CCC[C@H]1C(O)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:23][CH:18]1[C:19](=[O:20])[O:21][C:14]([CH3:22])([CH3:13])[O:15][C:16]1=[O:17])([O-:3])=[O:2]
Reactant: C=O
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)C(=O)O1
Yield: 78.5 %

Procedure:
An adaption of the procedure of Flaugh1 was used. Thus, a solution of 5-nitroindole (50.0 g, 0.32 mol), Meldrum's acid (46.0 g, 0.32 mol), 37% aqueous formaldehyde (26.0 mL, 0.32 mol) and proline (1.8 g, 0.016 mol) in 200 mL of acetonitrile was stirred at room temperature for 18 h. The resulting thick yellow slurry was filtered and the filtercake was washed with acetonitrile, then acetone and finally with ether. This material was dried in vacuo to give the title compound (80.0 g, 81%) as a bright yellow solid, mp 182° C. (dec). The mother liquor was concentrated and then diluted with H2O, and the resulting solid was collected, washed and dried as before to give a second crop of the product (7.0 g) as a darker yellow solid. Total yield=87.0 g (89%): IR (KBr) 3330, 1767, 1732 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 11.64 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 7.96 (dd, J=9.0, 2.2 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.33 (d, J=2.2 Hz, 1H), 4.84 (t, J=4.6 Hz, 1H), 3.45 (d, J=4.5 Hz, 2H), 1.78 (s, 3H), 1.55 (s, 3H). Anal. Calcd for C15H14N2O6 : C, 56.60; H, 4.43; N, 8.80. Found: C, 56.62; H, 4.41; N, 8.91.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-])=O)=[C:11]([CH3:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)CC.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:8][C:9]1[CH:10]=[C:11]([CH3:19])[C:12](=[CH:13][C:14]=1[CH3:15])[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Cl)c(C(C)(C)C)c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCCO
Product: Cc1cc(Oc2ccc(Cl)c(C(C)(C)C)c2)c(C)cc1N
Temperature: 25 °C

Procedure:
A solution of 40 g (119 mmol) of 4-(3-t-butyl-4-chlorphenoxy)-2,5-dimethylnitrobenzene in 30 ml of n-propanol was treated dropwise with hydrazine hydrate (17.3 ml, 356 mmol), then Pd/C was added (5% on charcoal, 400 mg, 0.2 mmol of Pd) and the mixture was heated to reflux for 10 hrs. After cooling to room temperature the mixture was filtrated, the residue was washed with methanol and the combined filtrates were evaporated. The residue was dissolved in dichloromethane, and the solution was extracted several times with water in order to remove remaining n-propanol. The organic phase was dried over Na2SO4, filtrated and evaporated. Yield: 32 g (87%); log P (pH 2.3)=4.38.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[Br:18][CH2:19][C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5])=[O:21]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To an iced solution of 266 g (1 mol) of 2-amino-2',5-dichlorobenzophenone in 3 liters of ethyl ether there are added, drop by drop, 90 cc (1.1 mol) of bromacetyl chloride dissolved in 500 cc of ethyl ether. The batch is allowed to come to room temperature, whereupon it is evaporated to dryness and the crystalline residue extracted with petroleum ether and filtered. In this manner, 371 g of crystals are recovered.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([NH2:24])([CH2:22][CH3:23])([CH3:21])[CH3:20]>>[CH3:20][C:19]([NH:24][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:21])[CH2:22][CH3:23]
Reactant: CCC(C)(C)N
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Product: CCC(C)(C)Nc1c(-c2ccc(OC)cc2)c(=O)c1=O
Yield: 84.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and tert-amyl amine (0.48 mL, 4.11 mmol) were converted to the title compound (0.14 g, 84%) m.p.: 133-135° C.; 1H NMR (DMSO-d6) δ8.28(br s,1H), 8.04(m,2H), 7.11(m,2H), 3.83(s,3H), 1.80(q,2H), 1.42(s,6H), 0.85(t,3H); IR (KBr) 2980, 1765, 1725, 1600, 1423, 1310, 1260, 1175, 1030, 850 cm−1; MS (m/z) 273 [M+].
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: COc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.09 g, 54.76 mmol) in DMF (300 mL) was added NaN3 (4.27 g, 65.71 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 19.43 g, 83.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 7.75 (d, 1H), 7.27 (m, 5H), 7.02 (m, 4H), 4.07 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)([O-])O[C:24](CC)([CH2:33]C)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.CN(C)C=O.C[O-].[Na+]>O.C(O)(=O)C>[C:16]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11]([CH:33]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:14][CH:15]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc(OC)cc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A mixture of 54.6 g (0.2 mol) of 4-diphenylaminobenzaldehyde, 51.6 g (0.2 mol) of diethyl-4-methoxybenzyl phosphonate, and 250 ml of dimethylformamide was placed in a 500 ml four-neck flask. 57.9 g of 28% sodium methylate was added dropwise to the above mixture with stirring at room temperature over a period of 15 minutes. Thus, the reaction was carried out at 50° to 60° C. for five hours. The thus obtained reaction mixture was diluted with 500 ml of water, and then made acid with the addition of acetic acid. Then the mixture was filtrated to obtain a wet cake. The thus obtained wet cake was washed with 100 ml of methanol three times, and recrystallized from a mixed solvent of ethanol and dioxane, whereby 46.2 g of 4-diphenylamino-4'-methoxystilbene was obtained as yellow crystals in the form of needles in a yield of 61.3%. The melting point of the obtained compound was 170° to 171.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=O.[CH:14]([NH2:16])=O>CC(C)=O>[O:13]=[C:11]1[C:3]2[C:2](=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[N:1]=[CH:14][NH:16]1
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Reactant: NC=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 4-amino isophthalic acid (2 g, 11.04 mmol) and formamide (10 mL) was heated at 180° C. for 5 h. The reaction mixture was cooled to RT and acetone was added. The solid precipitate thus obtained was stirred for 2 h, filtered and dried to give 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid in 50% yield.
Reaction SMILES: [CH2:1]([C:3]1[N:11]2[C:6]([CH2:7][O:8][C:9]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:10]=32)=[C:5]([C:19]([OH:21])=[O:20])[N:4]=1)[CH3:2]>CO>[CH2:1]([C:3]1[N:11]2[C:6]([CH2:7][O:8][C:9]3[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:10]=32)=[C:5]([C:19]([OH:21])=[O:20])[N:4]=1)[CH3:2]
Reactant: CCc1nc(C(=O)O)c2n1-c1cccc([N+](=O)[O-])c1OC2
Solvent: CO
Product: CCc1nc(C(=O)O)c2n1-c1cccc(N)c1OC2

Procedure:
Ethyl 6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine was reduced shaken in MeOH under 40 p.s.i. H2 with 20 weight percent of 10% Pd/C (Degussa) for 1 h then filtered and the solvent evaporated. The compound was purified directly by column chromatograph (EtOAc/hexane) to yield Ethyl 6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine 1H (DMSO-d6) 8.41 (s, 1H), 6.98 (m, 1H), 6.82 (m, 1H), 6.43 (m, 1H), 5.28 ((s. 2H), 4.23 (q, 2H, J=6.2 Hz), 1.27 (t, 2H, J=6.2 Hz) purity 92% MS (m/e): 232 (MH+).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:13][C:14]([OH:16])=[O:15]>C(O)C.O>[C:1]([S:8][CH2:13][C:14]([OH:16])=[O:15])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CI
Reactant: OC(=S)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.8 %

Procedure:
To a purged stirring solution at 0° C. of (5.74 g, 41.6 mmoles) thiobenzoic acid in (100 mL) ethanol was added (27.8 mL, 3N, 83.2 mmoles) potassium hydroxide followed by (7.70 g, 41.6 mmoles) iodoacetic acid in (30 mL) ethanol. The solution stirred for 10 hours at room temperature under argon. The ethanol was rotavapped and the orange solid product was dissolved in (40 mL) water. The solution was acidified to pH 2.0 where an orange precipitate formed. This was filtered, washed with water, and dried in vacuo to give (7.98 g, 99% yield) benzoylmercaptoacetic acid.