Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].CI.O>C(O)C>[CH3:12][S:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
2-Nitro-4-thiocyanato-aniline (17.6 g.) was added portionwise to a stirred solution of potassium hydroxide (13.4 g.) in ethanol (210 ml.) cooled below 15° C. After 5 minutes, methyl iodide (12.8 g.) was added to the purple solution and the mixture was allowed to stand overnight at room temperature. The mixture was then poured into water (1100 ml.) and the deep red solid was filtered off, washed with water, and dried to give 4-methylthio-2-nitroaniline (15.8 g.), m.p. 72°-73° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][OH:22]>ClCCl>[CH3:10][S:11]([O:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][O:22][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: OCCSSCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (4.35 ml) and 1.70 ml of methanesulfonyl chloride were added to a suspension of 1.22 ml of 2-hydroxyethyl disulfide in 30 ml of dichloromethane at −40° C. under an argon atmosphere. The mixture was stirred at that temperature for 30 min. The reaction solution was then diluted with dichloromethane, and the diluted solution was washed with an dilute aqueous hydrochloric acid solution, an aqueous sodium hydrogencarbonate solution, and water in that order, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to prepare 3.08 g of 2-methanesulfonyloxyethyl disulfide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)/[N:9]=[CH:10]/N(C)C.C[Si]([CH:27]=[C:28]=[O:29])(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[C:28](=[O:29])[CH:27]=[CH:10][N:9]=1
Reactant: C[Si](C)(C)C=C=O
Reactant: Cc1ccc(N=C(/N=C/N(C)C)c2ccccc2Br)cc1F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2c(-c3ccccc3Br)nccc2=O)cc1F
Temperature: 23 °C
Reaction time: 120 h

Procedure:
A solution of 2-bromo-N-[(1E)-(dimethylamino)methylidene]-N′-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-3, 500 mg, 1.38 mmol, 1.0 equiv) in ethyl acetate (5 mL) was treated with a solution of (trimethylsilyl)ketene (0.39 mL, 2.76 mmol, 2 equiv) in toluene (5 mL). The reaction mixture was stirred at 23° C. for 5 days. The resulting mixture was concentrated, and the residue was purified via reverse-phase HPLC (Acetonitrile:H2O gradient with 0.1% TFA present) to afford 2-(2-bromophenyl)-3-(3-fluoro-4-methylphenyl)pyrimidin-4(3H)-one (1-4) as a dark orange solid. 1H NMR (500 MHz, CD3OD) δ 8.12 (d, 1H, J=6.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.46 (d, 1H, J=7.6 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.20-7.08 (m, 3H), 6.67 (d, 1H, J=6.6 Hz), 2.19 (s, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccs2)CC1

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4.4 g of 2-bromo-1,3-thiazole and 7.4 g of K2CO3 in 50 ml of EtOH is heated at reflux for 4 days. Water is added to the reaction mixture, the EtOH is evaporated under vacuum, the resulting aqueous phase is extracted with AcOEt, the organic phase is washed with saturated K2CO3 solution and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (98/2; v/v) mixture. This gives 5 g of the expected product following cold precipitation from a DCM/hexane mixture and isolation with suction; m.p.=114-116° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1ccc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N[C@@H]2C[C@H]3CC[C@@H]2N3)nc1
Reaction time: 8 h

Procedure:
To the title compound of step A (319 mg, 0.89 mmol) in DCM (8.7 mL) was added 4M HCl in dioxane (1.1 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step B that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(F)c1
Product: O=C(NCCc1ccc(Cl)c(Cl)c1)c1cccc(F)c1

Procedure:
N-[2-(3,4-Dichloro-phenyl)-ethyl]-3-fluoro-benzamide was prepared in analogy to Example 40 from 3-fluoro-benzoic acid and 2-(3,4-dichloro-phenyl)-ethylamine: yellow solid,
Reaction SMILES: C([O:3][C:4]([C@:6]12[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2)=O)C.[NH3:12]>CO>[C@:6]12([C:4]([NH2:12])=[O:3])[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2
Reactant: N
Reactant: CCOC(=O)[C@]12C[C@H]1CCN2
Solvent: CO
Product: NC(=O)[C@]12C[C@H]1CCN2

Procedure:
A mixture of (1S,5R)-2-aza-bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (2.5 g, prepared by the procedure of Hercouet Tetrahedron Assymmetry 1996, 7, 1267-1268.) and 7M ammonia in methanol (20 ml) are heated in a sealed vessel at 80° C. for 5 days. The cooled reaction mixture is evaporated and triturated with hexanes/dichloromethane to give the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.O1CCCC1.[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([Br:22])[CH:24]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
First, 13.8 g of 2,6-dimethylaniline, 17.3 g of triethylamine, and 150 mL of tetrahydrofuran (THF) were put in a 500 mL three-neck flask, and stirred. This mixed solution was cooled in ice, and a mixed solution of 25 g of 3-bromobenzoyl chloride and 30 mL of THF was dripped through a dropping funnel, and then, the temperature was increased to room temperature and the mixture was stirred for 24 hours. After the stirring, chloroform was added to this mixture, the mixture was washed with water and then saturated saline, and anhydrate magnesium sulfate was added for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with hexane, so that N-(2,6-dimethylphenyl)-3-bromobenzamide was prepared as a white solid with a yield of 53%. The synthetic scheme of Step 1 is shown by (a-17).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C#N.[CH3:12][N:13](CC1C=CC=CC=1)C.[C-]#N.[Na+]>C(Cl)Cl.O>[C:1]([C:12]#[N:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(=O)c1ccccc1
Reaction time: 2 h
Yield: 91 %

Procedure:
140.5 grams (1.0 mole) of benzoyl chloride were dissolved in 600 ml of methylene chloride. This solution was treated simultaneously with 27 grams (1.0 mole) of hydrogen cyanide and 1.83 grams (0.014 mole) of N,N-dimethyl benzyl amine. Then within 20 minutes there were fed in 171 grams of a 29.8 percent aqueous sodium cyanide solution (1.04 moles of sodium cyanide). The temperature of the reaction mixture meanwhile and for a further 2 hours was held at 15 to 35° C. Then there were added 60 grams of water and the phases separated. After removal of the hydrogen cyanide and the methylene chloride there were obtained by distillation 136 grams of crude, 91 percent benzoyl cyanide. In fractional distillation there were obtained 122 grams of pure benzoyl cyanide. This corresponds to a yield of 93% base on the benzoyl chloride employed.
Reaction SMILES: F[B-](F)(F)F.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:9][C:8]=1[N+]#N.[OH2:29]>>[Cl:6][C:7]1[C:8]([OH:29])=[CH:9][C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:11]([F:13])[CH:12]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+]#N)c(Cl)cc2F)c1=O
Reactant: O
Agent: F[B-](F)(F)F
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0 23 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo -3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzenediazonium tetrafluoroborate is added to a solution of 75 g of cupric nitrate trihydrate in 50 ml of water. 67 mg of cuprous oxide are added thereto and the reaction mixture is stirred at room temperature for 10 minutes. The mixture is subsequently filtered, the filtrate is extracted with 50 ml of ethyl acetate and the organic phase is washed and evaporated under reduced pressure. The resulting crude product is crystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.Cl[CH2:8][CH2:9][CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][CH2:8][O:12]2)[S:5][CH:6]=1
Reactant: O=C(CCCCl)c1cccs1
Reactant: Cc1cscn1
Product: Cc1csc(C2(c3cccs3)CCCO2)n1

Procedure:
The title compound was prepared from 4-methylthiazole and 4-chloro-1-(2-thienyl)-1-butanone, using the general method of Example 36.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:22])[NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:23][C:2]1([F:1])[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)Nc1cnccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cnccn1)[C@@H]1CC(F)(F)CN1
Reaction time: 4 h

Procedure:
To a stirred solution of (S)-tert-butyl 4,4-difluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 116B (1.6 g, 4.87 mmol) in CH2Cl2(30 mL) was added trifluoroacetic acid (7.24 mL, 97 mmol). The mixture was stirred for 4 hrs, the solvent was evaporated to dryness and the residue 116C was used in the next reaction without further purification. LC/MS [M+H]+: 229; Ret time (Method F): 0.61 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reaction time: 4 h

Procedure:
Combine 2-methyl-5-nitrobenzoic acid (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf =0.61 (silica gel, ethyl acetate/hexane 1/1).
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N[C@H](C(N[CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])[C@H:18]([CH2:20]C)[CH3:19])=[O:15])=O)C(C)C)=O.Cl.O1CCOCC1.[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57]CC(O)=O)=[O:56].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:53]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:54][C:55]([NH:57][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])=[O:56]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
III (6.0 g, 0.0148 mole) was deblocked with HCl/Dioxane and solvent removed under reduced pressure. The residue was triturated with ether, filtered, washed with ether, then pet. ether and dried. A very hygroscopic material was obtained (4.2 g, 0.0123 mole) which was coupled in DMF with II (2.86 g, 0.0123 mole) in the presence of 10% excess of EDCI (2.60 g) and HOBt (2.07 g). The reaction was worked up as described for I to obtain IV as a white foam in a quantitative yield, no sharp m.p. 54°-62° C. Rf2, 0.42; Rf3, 0.74. Anal. Calcd. for C26H38N4)7 ; C, 60.21; H, 7.38; N, 10.805. Found: C, 60.0; H, 7.46; N, 10.81%,
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[N:2]1.[CH2:8]1[O:13][C@:12](O)([CH2:14][NH2:15])[C@@H:11]([OH:17])[C@H:10]([OH:18])[C@@H:9]1[OH:19]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:7][C:12]([C@@H:11]([OH:17])[C@H:10]([OH:18])[C@H:9]([OH:19])[CH2:8][OH:13])=[CH:14][N:15]=2)=[N:2]1
Reactant: NC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: N#Cc1ccon1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)c1cnc(-c2ccon2)[nH]1

Procedure:
which comprises: combining isoxazole-3-carbonitrile with a solvent and a first base to provide a first reaction mixture; combining the first reaction mixture with fructosamine to provide a second reaction mixture; and isolating (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-5-yl)butane-1,2,3,4-tetraol from the second reaction mixture.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([O:34]CC)=[O:33])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([C:31](=[O:37])[C:32]([OH:34])=[O:33])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Yield: 46.7 %

Procedure:
{1-Benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[3,5-bis(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.737 g, 1.42 mmol), potassium hydroxide (0.260 g, 4.63 mmol) in THF (9 mL) and water (9 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 88° C. furnished the title compound as a white solid (0.326 g, 47%), mp: 206-207° C. Mass spectrum (+APCI, [M+H]+) m/z 492; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.3 (br s, 1H), 8.75 (s, 1H), 8.5 (s, 1H), 8.25 (s, 2H), 8.1 (s, 1H), 7.75 (s, 2H), 7.25-7.35 (m, 5H), and 5.6 ppm(s, 2H).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].C(OCC)C.C[O-].[Na+].S(=O)(=O)(O)O>CO.CCCCCC.CCOC(C)=O.C(Cl)Cl.CC(C)=O>[C:13]([C:12]1[C:11](=[O:16])[NH:10][C:5]2[C:4]([C:3]=1[OH:17])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:15])[CH3:14]
Reactant: COC(=O)c1ccccc1NC(=O)CC(C)=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Temperature: 40 °C
Yield: 75.5 %

Procedure:
2-(3-Oxo-butanoylamino)-benzoic acid methyl ester (383 mg, 1.63 mmol) was combined with diethyl ether (10 mL) and methanol (5 mL) and the mixture was stirred rapidly while a solution of sodium methoxide (25% solution, 1.63 mmol, 0.45 mL) in methanol (3 mL) was added over 10 minutes. The reaction then was heated at 40° C. overnight. Progress of the reaction was monitored by TLC (silica gel, hexane:EtOAc:CH2Cl2:acetone (3:3:3:1)) and analytical HPLC and upon its completion the mixture was acidified with 1 N sulfuric acid to form a solid. The solid was collected by filtration and then crystallized from hot acetic acid/acetonitrile/water to provide 3-acetyl-4-hydroxy-1H-quinolin-2-one (250 mg, 76%) as small colorless prisms, mp 258-262° C. (dec) (lit., 259° C.). LCMS MH+ 204.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([O:14]CC)=[O:13])=[CH:8][N:7]=[C:6]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[I-].[Li+]>N1C=CC=CC=1>[CH3:23][O:22][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]=[C:6]1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cnc(-c2cccs2)n(CC(OC)OC)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COC(Cn1c(-c2cccs2)ncc(C(=O)O)c1=O)OC
Temperature: 110 °C

Procedure:
To a solution of ethyl 1-(2,2-dimethoxyethyl)-2-(2-thienyl)pyrimidin-6(1H)-one-5-carboxylate in pyridine (33 mL) was added lithium iodide (3.32 g) and the resulting mixture was heated at 110° C. overnight. The pyridine was evaporated and residual traces of pyridine were removed by evaporation with toluene. The residue was dissolved in 1N hydrochloric acid and the product was extracted into ethyl acetate. The solution was dried and evaporated to give an oil which crystallized from ether to provide 1-(2,2-dimethoxyethyl)-2-(2-thienyl)pyrimidin-6(1H)-one-5-carboxylic acid as a brown solid; MS: m/z=311(M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH+]1C=CC=CC=1>CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:13][C:12]1=[S:17]
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: O=C1C(=Cc2ccccc2)SC(=S)N1N=c1sc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2.0 g of 3-[(1,3-benzodithiol-2-ylidene)amino]-2-thioxo-4-thiazolidinone (see example 37), benzaldehyde (20 ml, excess) and pyridinium acetate (5 ml) is prepared and heated at 120° C for 3 days under nitrogen with stirring. The mixture is then cooled, diluted with ether and filtered. The residue is washed with water and recrystallized from dimethylformamide to yield 2.2 g of the title compound, melting point 288°-289° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2=[C:15]3[C:24](=[CH:25][CH:26]=[C:13]2[C:12]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:11][CH:10]=1)[CH:23]=[C:22]1[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]1)=[CH:16]3.C(O)C>CN(C=O)C>[Br:1][C:23]1[C:24]2[C:15]([CH:16]=[C:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)=[C:14]1[CH:9]=[CH:10][CH:11]=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([CH:31]=[O:32])=[CH:33][CH:34]=3)[C:13]1=[CH:26][CH:25]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2cccc3c2ccc2c(Br)c4ccccc4cc23)cc1
Reaction time: 3 h

Procedure:
29.4 g (165 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 49 g (150 mmol) of 4-benz[a]anthracen-4-ylbenzaldehyde in 800 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried. Yield: 49.3 g (119 mmol), 79%.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[CH3:28])[C:13]1=[O:29])=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:26])[CH3:27])[CH3:24])[CH2:19][C@H:18]2[CH3:28])[C:13]1=[O:29]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](C)C1
Reaction time: 4 h
Yield: 95.8 %

Procedure:
(S)-3-Benzyloxycarbonylamino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-methylcyclohexyl)pyrrolidin-2-one (47 mg) in MeOH (5 mL) was charged with 20% Pd(OH)2 (70 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 4 h and then filtered and concentrated to provide (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-methylcyclohexyl)pyrrolidin-2-one (30 mg). MS (ES+)=268.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH:10]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[C:13]3[N:12]([C:22](=[O:23])[NH:20][C:18](=[O:19])[C:17]=3[C:16]([CH3:21])=[N:15]2)[CH2:11][CH:10]=1
Reactant: Cc1nn2c(c1C(N)=O)NCC=C2c1cc(Cl)ccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: Cc1nn2c3c1c(=O)[nH]c(=O)n3CC=C2c1cc(Cl)ccc1Cl

Procedure:
To a 3.0 g amount of 7-(2,5-dichlorophenyl)-4,5-dihydro-2-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 9) suspended and stirred in 100 ml of dry p-dioxane, under nitrogen is added 8.0 g of 1,1'-carbonyldiimidazole. The mixture is evaporated to dryness in vacuo and the residue is treated with water to decompose the excess 1,1'-carbonyldiimidazole. The remaining solid is collected by filtration, then stirred with 50 ml of tetrahydrofuran. The solid is collected and dried to give 1.6 g of the desired product as a white solid. The product is recrystallized from ethanol-acetonitrile and gives mp 205-209° C.