Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)[OH:17].C([BH3-])#N.[Na+]>>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH:16]([C:18]1[CH:26]=[C:22]([C:23]([NH2:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)[OH:17])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Reactant: CC(=O)CCOCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(CCOCc1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
Combine 4-benzyloxy-2-butanone (2.6 g, 15 mmol) with 5-(2-amino-1-hydroxyethyl)salicylamide (15 mmol in methanol, 50 ml) and treat with sodium cyanoborohydride (0.9 g, 15 mmol). Let stand 16 hours, evaporate the solvent and extract the residue in ethyl acetate/ 1N sodium bicarbonate solution. Separate the organic phase, dry over sodium sulfate and evaporate in vacuo.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:17]([CH3:19])[C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(Nc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 33.6 %

Procedure:
388 mg of 4-fluoronitrobenzene, 500 mg of L-alanine tert-butyl ester and 0.9 ml of Et3N were added to a solution of 10 ml of N-methylpyrrolidinone. The reaction medium was heated at 70° C. for 20 hours and, after cooling to room temperature, then poured into a water and ice mixture. The yellow precipitate formed was filtered off, re-slurried in water and then dried over P2O5. 246 mg of tert-butyl 2-(4-nitrophenylamino)propionate (10) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH:22][C:23]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CS(C)=O.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:25][C:24]4[CH:27]=[C:28]([Cl:32])[CH:29]=[C:30]([Cl:31])[C:23]=4[OH:22])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
After dissolving 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester (20 mg, 0.055 mmol) in dimethylsulfoxide-acetic acid (10:1), 2-hydroxy-3,5-dichlorobenzaldehyde (32.0 mg, 0.166 mmol) and sodium triacetoxyborohydride (35.0 mg, 0.166 mg) were added and the mixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added to the reaction mixture, and then after stirring for 1 minute, it was purified by SCX solid phase extraction (Bond Elute SCX500MG). The product was further purified by preparative HPLC to obtain 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:36][N:34]([CH3:35])[C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CN(C)c1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (67 mg, 1.68 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (300 mg, 1.53 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-dimethylaminophenethyl)homopiperidine (470 mg, 1.68 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with hexane and ethyl acetate (4:1) and finally with hexane and ethyl acetate (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl) piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (224 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]Cl.[CH2:14]([NH2:17])[CH2:15][CH3:16]>O>[CH2:14]([NH:17][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:8]=1[Cl:13])[CH2:15][CH3:16]
Reactant: ClCCOc1c(Cl)cc(Cl)cc1Cl
Reactant: CCCN
Solvent: O
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
N-n-propyl-N-2-(2,4,6-trichlorophenoxy)-ethylamine is prepared by selectively chlorinating 2-phenoxy ethanol by reacting it with chlorine either in the presence of hydrogen chloride at a temperature of from -10° C. to 50° C. or in the presence of urea at a temperature of from 20° C. to 55° C. in a water/carbon tetrachloride solvent mixture to form 2-(2,4,6-trichlorophenoxy)ethanol; reacting the 2-(2,4,6-trichlorophenoxy)ethanol with thionyl chloride in the presence of a catalytic amount of tetraalkyl ammonium chloride, optionally in the presence of a solvent to form 2-(2,4,6-trichlorophenoxy)ethyl chloride; and reacting the 2-(2,4,6-trichlorophenoxy) ethyl chloride with n-propylamine at a temperature of from 20° C. to 150° C., optionally in the presence of water to form N-n-propyl-N-2-(2,4,6-trichlorophenoxy) ethyl amine.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([NH2:17])[N:13](C)[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:18](Cl)(=O)C.C(=O)(O)[O-].[Na+].C(Cl)Cl.[CH:30](O)([CH3:32])[CH3:31]>O>[CH3:31][C:30]1[C:32]2[N:13]3[CH:14]=[CH:15][N:17]=[C:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=[C:3]([CH3:2])[CH:18]=1
Reactant: CC(C)O
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)N(C)C(N)c1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c2c(c1)c1ccccc1c1nccn12
Yield: 40 %

Procedure:
3,5-Dimethyl-6-phenanthridinamine (8.6 g, 39 mmol), a 50% solution of acetyl chloride (4.6 g, 58 mmol) in water, sodium bicarbonate (6.5 g, 77.4 mmol) in 258 mL of isopropyl alcohol were heated to reflux for 40 hours. After cooling the crude product was dissolve into methylene chloride and vacuum filtered. The filtrate was concentrated and the crude product was crystallized in methylene chloride and ethyl acetate mixture. The pure product was collected by vacuum filtration to give 5,7-dimethyl-imidazo[1,2-f]phenanthridine) (3.8 g, 40% yield) as determined by NMR.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([NH:12][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.07 g (30.6 mmol) of succinic anhydride was suspended in 30 ml of dichloromethane. 4.1 ml (34.5 mmol) of t-butylamine was dropped into the suspension, and the resultant mixture was stirred at room temperature for 1 hour. White crystals thus formed were washed with ethyl acetate and then dissolved in 40 ml of 1 N aqueous sodium hydroxide solution. The resultant solution was stirred at room temperature for 2 hours and then acidified with 1 N aqueous hydrochloric acid solution under cooling with ice. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Sn](Cl)Cl.Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2OC)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cc(N)ccc2OC)cc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (57b), 2.0 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(2-methoxy-5-nitrophenyl)-(4-methoxyphenyl)methyl]amine [prepared as described in step (a) above], 3.54 g of tin (II) chloride and 40 ml of a 1:1 mixture of concentrated aqueous hydrochloric acid and ethanol were reacted, to obtain 370 mg of isomer A and 591 mg of isomer B of the title compound as yellow oils, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1C=CC([C@@H](N2CC[C@](CC(C)=C)(C3C=CC=CC=3)OC2=O)C)=C[CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:9]2[CH2:29][CH2:28]2)[N:10]2[CH2:15][CH2:14][C:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=C(C)CC1(c2ccccc2)CCN(C(c2ccc(Br)cc2)C2CC2)C(=O)O1

Procedure:
The stereochemical assignments of the diastereomers are based on the comparison of the 1H NMR data with the data of the known analogs 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one and 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[Br:10].[CH3:11][C:12]([O:15][C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:17])([CH3:14])[CH3:13].[H-].[Na+]>O1CCCC1>[C:22]([O:21][C:19]([N:18]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([Br:10])[CH:4]=1)[C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(CBr)cc1Br
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-methyl-3-bromobenzylbromide (1.63 g, 6.2 mmol, prepared according to the procedure described in International Patent Application No. WO 0009475) and di-tert-butyliminodicarboxylate (1.48 g, 6.8 mmol) in anhydrous tetrahydrofuran (15 ml) was treated portionwise with sodium hydride (0.27 g of 60% dispersion in mineral oil, 6.8 mmol). The mixture was stirred at ambient temperature for 18 hours then partitioned between saturated aqueous ammonium chloride solution (20 ml) and ethyl acetate (3 lots of 80 ml). The combined organic layers were washed with brine (80 ml), then dried over magnesium sulfate and concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of cyclohexane and diethyl ether (9:1, v/v) to give 4-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-2-bromo-toluene as a pale yellow oil (2.4 g). 1H NMR (CDCl3, 500 MHz): δ 7.45 (s, 1H), 7.18 (m, 2H), 4.71 (s, 2H), 2.38 (s, 3H), 1.43 (s, 18H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C@:8]12[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].BrC[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32].[C:33]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:33][C:29]1[CH:30]=[CH:31][CH:26]=[C:27]([F:32])[CH:28]=1)[C:9](=[O:14])[C@@:8]12[CH2:16][C@@H:15]1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[O:4]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1ccc2c(c1)[C@]1(C[C@H]1c1ccc(F)cc1)C(=O)N2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(1S,2R) and (1R,2S)-methyl-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylate (500 mg, 1.61 mmol), 1-bromomethyl-2-fluoro-benzene (456 mg, 2.14 mmol) and Cs2CO3 (785 mg, 4.2 mmol) were mixed in anhydrous DMF and stirred at room temperature for 8 hours. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 15-25% ethyl acetate in petroleum ether) to give title compound as white solid (405 mg, 60%). LC/MS m/e calcd. for C25H19F2NO3 420, observed (M+H)+: 420.5.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[C:53]1[N:57]([CH3:58])[N:56]=[CH:55][CH:54]=1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[C:53]2[N:57]([CH3:58])[N:56]=[CH:55][CH:54]=2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH:18]1C=CC=C[CH:19]=1.[CH3:24][CH2:25]O>>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:18][CH3:19])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:24][CH3:25])=[O:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C(=O)OCC)nc1
Reaction time: 5 h

Procedure:
To a suspension of 100 g (0.6 mol) of 2,5-pyridinedicarboxylic acid in 300 mL of absolute EtOH was added 100 mL of concentrated H2SO4 over a period of 1.5 h. During this time, the solid gradually all went into solution. The brown reaction mixture was refluxed for 16 h. Then 200 mL of benzene was added and the benzene/EtOH/H2O azeotrope was removed at the rate of 30 mL/30 min, with more 1:1 benzene/EtOH mixture added at 30-min intervals. After 5 h, the reaction mixture was poured onto 30 L of ice-water. Solid NaHCO3 was then added until the mixture was neutralized. The product was extracted into EtOAc. The EtOAc layer was washed with brine, dried (Na2SO4), and concentrated to 99.8 g of a yellow solid, which was purified on 400 g of silica gel (25% Et2O/hexane and 50% Et2O/hexane) to give 95 g of solid. Recrystallization from Et2O/hexane gave 90 g of the diethyl ester, diethyl pyridine-2,5-dicarboxylate, as pale yellow crystals, mp 46°-47° C.; IR (mull) 1730, 1710, 1600, 1375, 1280, 1250, 1100, 1030, 750 cm-1 ; 1H NMR (CDCl3) δ1.47 and 1.50 (2 t, J=7.5 Hz, 6, CO2CH2CH3), 4.55 and 4.62 (2 q, J=7.5 Hz, 4, CO2CH2CH3), 8.17 (d, J=8 Hz, 1, 3'--H), 8.47 (dd, J=2.5 Hz, J=8 Hz, 1, 4'--H), 9.33 d, J=2.5 Hz, 1,6'--H).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32]C2C=CC(C#N)=CC=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:43].[K+].Cl>C(O)CC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:31][CH2:32][C:5]2[CH:42]=[CH:41][C:8]([C:9]([OH:10])=[O:43])=[CH:7][CH:6]=2)=[CH:41][CH:42]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCCO
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 135.1 %

Procedure:
A solution of 430 mg (0.77 mmol) of methyl 4-{(3E)4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate in 20 ml of 1-propanol is mixed with 1.73 g (30.84 mmol) of potassium hydroxide and stirred at 110° C. for 5 hours. The mixture is adjusted to pH 2 with 1 M hydrochloric acid and evaporated. The resulting residue is purified directly by preparative HPLC. 290 mg (0.52 mmol, 53% yield) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.S1C(CN)=CC2C=CC=CC1=2.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30](=[O:43])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH:8][CH2:7][C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30](=[O:43])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(CN)s1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Agent: NCc1cc2ccccc2s1
Product: Cc1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)s1
Yield: 43 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylthiophen-2-yl)methanamine in replace of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.30 (m, 5H), 6.73 (d, J=3.3 Hz, 1H), 7.59-6.57 (m, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.43 (d, J=5.8 Hz, 2H), 2.53 (s, 3H), 2.34 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: CS[S:3][CH3:4].Br[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]>N1C=CC(C)=CC=1C.[Cu]>[CH3:19][O:18][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([S:3][CH3:4])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]
Reactant: CCCOc1c(Br)cc(C=O)cc1OC
Reactant: CSSC
Agent: [Cu]
Solvent: Cc1ccnc(C)c1
Product: CCCOc1c(OC)cc(C=O)cc1SC
Temperature: 25 °C
Yield: 26 %

Procedure:
50 (0.56 mole) of methyl disulfide in 400 ml of 2.4-lutidine was added 46 g (0.72 mole) of copper. The mixture was heated at 140 ° for 3 hours. The solution was cooled to room temperature and 74.90 g (0.56 mole) of 3-bromo-5-methoxy-4-propoxybenzaldehyde was then added. The mixture was refluxed for 16 hours at 175° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography first then recrystallized from hexane to give 17.01 g (26% yield) of 3-methoxy-5-methylthio-4-propoxybenzaldehyde as a white solid. m.p. 64°-66° C. NMR (CDCl3): δ 1.1 (t, 3H, term CH3), 1.79 (m, 2H, OCH2CH2CH3), 2.47 (s, 3H, SCH3), 3.87 (s, 3H, OCH3), 4.05 (t, 2H, OCH2CH2CH3), 7.20 (S, 2H, Ar-e,uns/H/ ), ##STR25##
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:12]([O-])=O.[Na+]>Cl.O>[F:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH:5][NH2:12]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
To a vigorously stirred suspension of 2-fluoro-4-methoxyaniline hydrochloride (665 mg, 3.7 mmol) in conc. HCl (5.5 mL) cooled to 0° C. was added a cold solution of NaNO2 (312 mg, 4.5 mmol) in H2O (1 mL). The mixture was stirred at 0° C. for 90 min. A cold solution of SnCl2-2H2O (3.4 g, 15.0 mmol) in conc. HCl (5.5 mL) was then added slowly to the solution of diazonium salt. The reaction was allowed to warm to room temperature, stirred for 30 min and the reaction was filtered. The collected precipitate was washed on the filter with several large portions of ether and dried under vacuum. The solid was dissolved in DCM and washed saturated NaHCO3, extracted and dried using a phase separator. Evaporation gave (2-fluoro-4-methoxyphenyl)hydrazine (220 mg 38%), which was used in the next step without further purification. The procedure was adapted from J. Med. Chem. 2000, 43, 4701.
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[CH:1]1([C:7]2[NH:33][C:31](=[O:32])[NH:30][CH:21]([C:20]3[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]([OH:26])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=3)[C:8]=2[C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(N)=O
Reactant: O=C(Cc1ccsc1)C1CCCCC1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(C3CCCCC3)=C2c2ccsc2)cc([N+](=O)[O-])c1O
Yield: 9.3 %

Procedure:
A mixture of 1-cyclohexyl-2-(thiophen-3-yl)ethanone (Intermediate 95) (176 mg, 0.56 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (140 mg, 0.67 mmol), urea (100 mg, 1.68 mmol) and concentrated HCl solution (0.1 mL) in absolute ethanol (5 mL) was reflux under N2 overnight. Solvent was removed, and residue was purified by column chromatography and prep-HPLC to give Compound 174 (23 mg, yield: 9%) as a yellow solid. 1H NMR (DMSO-d6400 MHz): δ 10.25 (brs, 1H), 8.26 (s, 1H), 7.45 (dd, J=4.8, 2.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 6.85 (d, J=4.0 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.10-3.90 (m, 2H), 1.90-1.40 (m, 7H), 1.35 (t, J=7.2 Hz, 3H), 1.20-1.00 (m, 3H). MS (ESI): m/z 444.2 [M+1]+.