Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Reactant: Nc1cccc(Br)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2c(OC)c1OC
Yield: 85.4 %

Procedure:
A mixture of 0.167 g of 4-chloro-6,7,8-trimethoxy-3-quinolinecarbonitrile, 0.12 g of m-bromoaniline, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.212 g of 4-(3-bromo-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 211-213° C.; mass spectrum (EI, m/e): M 413.0377.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[ClH:26]>C(O)C>[ClH:26].[ClH:26].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)CCC(Br)C(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Temperature: 110 °C
Yield: 35 %

Procedure:
A mixture of 2-bromo-5-methyl-1-phenylhexan-1-ol [prepared from 2-bromo-5-methyl-1-phenylhexan-1-one by usual NaBH4 -reduction] (1.0 g, 3.69 mmol) and 1-(3-aminopropyl)piperidine (1.05 g, 7.38 mmol) was heated at 110° C. for 4 hours in a nitrogen atmosphere. After being cooled, the reaction mixture was dissolved in lN-HCl (50 ml) and the solution was washed with ether. The aqueous layer was basified with lN-NaOH and then extracted twice with ether. The combined ethereal extract was washed three times with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC to give pale yellow oily matter. To a solution of the matter in ethanol was added in excess 18% HCl in EtOH and the resulting mixture was evaporated under reduced pressure. The residue was dissolved with heating in ethanol (15 ml) and to the mixture was then added 10 ml of acetone. The mixture was stirred at room temperature. Precipitated crystals were collected by filtration to obtain 0.52 g of the title compound (yield: 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][C:16]1[C:21]([C:22](O)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:15][C:16]1[C:21]([C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:23])=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: Cc1ccncc1C(=O)O
Product: Cc1ccncc1C(=O)Nc1ccc2c(c1)N(C)C(=O)C2(C)C

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 4-methylnicotinic acid. The title compound was obtained as red oil.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (52%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH3:25][NH:26][CH2:27][C@H:28]([OH:37])[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=1.CS(C)=O>CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([N:26]([CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=3)[OH:37])[CH3:25])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CN(CC(O)c1ccc(O)c(O)c1)C(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.3 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.167 g (0.9111 mmol) of (R)-(-)-epinephrine were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide (dried over barium oxide) and a magnetic stirring bar. The solution was stirred at room temperature (25°) and was initially heterogeneous. After about 45 minutes, as the epinephrine began to react with AIT-0081, the solution was a nearly homogeneous yellow orange color. The solution was stirred an additional two hours, drawn into a pasteur pipet, and added with stirring to a flask containing 50 ml acetone and a magnetic stirring bar. A copious white precipitate formed and the solution was stirred for ten minutes. The solution was filtered by vacuum and the white solid washed with acetone. The Buchner funnel was immediately placed under high vacuum to remove small traces of dimethylsulfoxide. 120 mg of a white solid, 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-N-methylpropanamide (AIT-0100), was obtained. Yield: 48%.
Reaction SMILES: C(O[C@@H:5]1[C@H:27](O)[C:26]([CH3:30])([CH3:29])[C@H:25]2[C@@:7]3([O:21][C:11]4[C:12]5[CH2:13][NH:14][C:15](=[O:20])[C:16]=5[CH:17]=[C:18]([OH:19])[C:10]=4[CH2:9][C@:8]3([CH3:32])[C@@H:22]([CH3:31])[CH2:23][CH2:24]2)[CH2:6]1)(=O)C.N1C=CC=CC=1.Cl.[NH2:40][OH:41].O>C(O)C>[OH:19][C:18]1[C:10]2[CH2:9][C@:8]3([CH3:32])[C@@H:22]([CH3:31])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:29])([CH3:30])[C:27](=[N:40][OH:41])[CH2:5][CH2:6][C@@:7]34[O:21][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:20])[C:16]=2[CH:17]=1
Reactant: NO
Reactant: CC(=O)O[C@H]1C[C@@]23Oc4c(c(O)cc5c4CNC5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C(C)(C)[C@H]1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NO)CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Compound (12) (Step-2 of Example 55) (30 mg, 0.078 mmol) in 3.0 ml of ethanol were added 0.3 ml (3.70 mmol) of pyridine and 9 mg (0.13 mmol) of hydroxylamine hydrochloride, and the mixture stirred for 3 hours at 80° C. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The crystalline residue was recrystallized from diethyl ether-pentane to give 26 mg (83%) of Compound (51a).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=1)[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2]>C1COCC1.CO.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCC1c1cc(C(=O)[O-])cc(C(C)C2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N1CCCCC1c1cc(C(=O)O)cc(C(C)C2CCCCC2)c1
Reaction time: 3 h

Procedure:
To a solution of 3-(1-acetylpiperidin-2-yl)-5-(1-cyclohexylethyl)benzoate (80 mg, 0.22 mmol) in THF:MeOH:water (1:1:1, 6 mL) was added NaOH (6 N, 10 drops) and the mixture was stirred for 3 h. The volatiles were removed in vacuo and the mixture was acidified with aqueous HCl (6 N) to a pH of about 2. The mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with water (1×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered and concentrated. The title compound was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH3:29])[CH:28]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CC(=O)OC(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccc(F)cc1

Procedure:
Following the procedure of example 1B, 13.8 g (0.0645 mol) of 2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethyl formamide dimethyl acetal to yield 13.6 g of 3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp 115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochloride to yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/Br)=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4].[CH3:25][S-:26].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:11]=[CH:12]/[S:26][CH3:25])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/Br
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1/C=C/SC
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (0.915 g, 2.196 mmol) was dissolved in DMSO (10 mL) and sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 min at ambient temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was diluted with petroleum ether to decrease the solubility of residual DMSO, washed with water thrice, filtered and concentrated. The product was purified by flash chromatography (hexane/ethyl acetate gradient) to provide the title compound (0.510 g, 60.5% yield) as a yellow solid: 1H NMR (CDCl3) δ 7.63 (dd, 1H), 7.19 (dd, 1H), 6.74 (d, 1H), 6.32 (d, 1H), 5.34 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[NH:6][C:5]1=O)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]n(-c2ccc(Cl)cc2F)c1=O
Product: CC(C)n1c(Cl)nn(-c2ccc(Cl)cc2F)c1=O
Reaction time: 30 h

Procedure:
4-Isopropyl-1-(4-chloro-2-fluorophenyl)-1,2,4-triazolidine-3,5-dione (6.32 g; 0.023 mol) and phosphorus oxychloride (50 ml) were boiled with stirring for 30 hours. After completion of the reaction, excessive phosphorus oxychloride was removed by distillation under reduced pressure. The separated oily substance was poured into icewater and extracted with chloroform (50 ml) three times. The chloroform layer was washed with a saturated sodium chloride solution until the washings became neutral, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oily substance was chromatographed on silica gel to give 2.5 g of 3-chloro-4-isopropyl-1-(4-chloro-2-fluorophenyl)-1,2,4-triazolin-5-one.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](OC(C)(C)C)=[O:23])[C:14]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56]C(Cl)=O.C(N(CC)CC)C>C(#N)C.O1CCCC1>[NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:29])[CH:17]3[NH:21][C:22](=[O:23])[CH2:56][C:52]3[S:51][CH:55]=[CH:54][CH:53]=3)[C:14]=2[C:30]([O:32][CH:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:31])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12

Procedure:
3-(2-Anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.3 g) is treated with methanesulphonic acid (2.3 cc) in acetonitrile (23 cc) by following the procedure described in Reference Example 1. This gives crude 7-amino-3-(2-anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.85 g), which is acylated with (thien-2-yl)-acetyl chloride (0.445 cc) in tetrahydrofuran (25 cc), in the presence of triethylamine (0.505 cc), by following the procedure described in Reference Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1.2 bars (120 kPa) with a 70/30 (by volume) mixture of cyclohexane and ethyl acetate (3 liters), and 50 cc fractions being collected. Fractions 20 to 50 are combined and concentrated to dryness. After trituration in isopropyl ether, 3-(2-anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) is obtained in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][CH2:17][CH2:18][OH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][CH2:17][CH2:18][O:19][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCOCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCCOCc2ccccc2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and benzyloxy-2-ethanol by the method of Example 10 (b).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-:3])=[O:2].[NH2:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21]>CO>[OH:21][CH2:20][CH:19]([NH:18][C:9](=[O:11])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:14]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:16])[CH:7]=1)[CH2:22][OH:23]
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Reactant: NC(CO)CO
Solvent: CO
Product: O=C(NC(CO)CO)c1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 99.7 %

Procedure:
Dimethyl 5-nitroisophthalate (120 g, 0.5 mol) and serinol (113.6 g, 1.25 mol) are dissolved in methanol (960 mL), and then heated to reflux for 48 h. Cooled to 20° C., the solid is collected filtration using vacuum and the filter cake washed with methanol (50 mL×3). The filter cake is then dried to constant weight to obtain 178.2 g product as a white powder in 99% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1.[CH:21](O)=[O:22]>>[Cl:13][C:12]1[C:3]([CH2:2][NH:1][CH:21]=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=CO
Reactant: COC(=O)c1cc(Cl)c(CN)nc1-c1cccc(F)c1
Product: COC(=O)c1cc(Cl)c(CNC=O)nc1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate (1.1 g, 3.7 mmol) was stirred in formic acid (10 mL) and heated to 90° C. for 10 hours. Evaporation gave the crude material which was contaminated with the corresponding dechlorinated byproduct (1.1 g, quantitative). LCMS calculated for C15H13ClFN2O3 (M+H)+: m/z=323.1. found: 322.9.
Reaction SMILES: C(S[C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N+:8]=1[CH2:9][CH3:10])C.[CH2:15]([N:22]1[C:26](=[O:27])[CH2:25][S:24][C:23]1=[S:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[CH2:15]([N:22]1[C:26](=[O:27])[C:25](=[S:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([CH2:9][CH3:10])[CH2:4]2)[S:24][C:23]1=[S:28])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCSc1sc2ccccc2[n+]1CC
Reactant: O=C1CSC(=S)N1Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1CS(=C2SC(=S)N(Cc3ccccc3)C2=O)c2ccccc21

Procedure:
To 30 ml of an ethanol solution of 13.0 g of the intermediate product obtained in Preparative Example 2, viz., 2-ethylmercapto-3-ethylbenzothiazolium p-toluenesulfoante, was added 4.5 g of 3-benzylrhodanine, while stirring the mixture at room temperature (about 20° C.), 6.1 g of triethylamine was added dropwise to the mixture over a 3 minute period, and thereafter, the resultant mixture was refluxed for 10 minutes. After cooling the reaction mixture, precipitate formed was recovered by filtration and recrystallized from a mixture of chloroform and ethanol to provide 4.6 g of 3-benzyl-5-(3-ethylbenzothiazolylidene)rhodanine (melting point 209° to 211° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:77]=[CH:76][C:69]([C:70]([NH:72][CH:73]3[CH2:75][CH2:74]3)=[O:71])=[CH:68][CH:67]=2)[N:65]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[C@H:12]1[C:17](=[O:19])[NH:60][C:61]1[S:62][CH:63]=[C:64]([C:66]2[CH:67]=[CH:68][C:69]([C:70](=[O:71])[NH:72][CH:73]3[CH2:75][CH2:74]3)=[CH:76][CH:77]=2)[N:65]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3[C@@H](O)CCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,3S)-3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (41.9 mg, 1.6 mmol) and HATU (66.3 mg, 1.7 mmol) were dissolved in DMF (2 mL). DIEA (55 μL, 0.32 mmol) was then added, and the reaction was stirred at ambient temperature for 15 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide trifluoroacetic acid salt (62.9 mg, 0.17 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 11.8 mg. MS: 507.2 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.50-77 (m, 4H), 1.70-2.10 (m, 2H), 4.20-4.40 (m, 1H), 4.86-5.17 (m, 2H), 7.00-7.42 (m, 4H), 7.74-8.01 (m, 5H), 8.40-8.48 (m, 1H), 12.58-12.67 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Li+].O>>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCCn1cc(C(=O)OCC)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1cc(C(=O)O)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 40 h
Yield: 99.3 %

Procedure:
1-Propyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of lithium hydroxide monohydrate (127 mg, 3.0 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at 40° C. for ˜40 hours to yield the title compound (380 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:22])[N:12]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.O>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][OH:22])[N:12]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2ccccc2C=O)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2ccccc2CO)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
tert-Butyl{[5-(2-formylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (218 mg) was dissolved in tetrahydrofuran (2 mL), and sodium borohydride (24 mg) and methanol (1 mL) were added at 0° C. After stirring at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:3) to give the title compound as a colorless oil (yield 132 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(F)cc2)cc1N1CCN(C)CC1
Yield: 88.9 %

Procedure:
4-Fluorobenzoyl chloride (0.23 ml, 1.95 mmol) with 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (400 mg, 1.95 mmol) in dry dichloromethane (40 ml) and triethylamine (1 ml) was stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by column chromatography (silica, chloroform,/methanol 5%) to afford the tide compound (595 mg, 89%) which was crystallised from methanol/diethyl ether as the oxalate salt.