Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[ClH:45].[C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Sc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(Sc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Tert-butyl 4-(5-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol (4 mL) and 4N HCl in dioxane added (2 mL) and stirred at ambient temperature for 1 hour. The solvent was removed and placed on high vacuum to afford the title compound (100 mg, 89.6% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 8.70 (m, 2H), 8.20 (m, 3H), 7.95 (m, 1H), 7.40 (m, 5H), 3.80-3.05 (m, 9H). Mass spectrum (apci) m/z=535.2 (M+H-3HCl).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]CCCC.[C:15](Cl)(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C>C1COCC1>[O:5]=[C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A stirred solution of monoethyl malonate (5.3 g, 40 mmol) in anhydrous THF (150 mL) was cooled to −78° C. under an argon atmosphere, and n-BuLi (2.5 M, 32 mL, 80 mmol) was added drop-wise via an air-tight syringe. After the addition, the temperature was raised to 0° C., and the stirring was continued for 1 hour. The reaction mixture was then re-cooled to −78° C., and 10-undecenoyl chloride (25 mmol) was added drop-wise via an air-tight syringe. The mixture was stirred for one hour at −78° C., 30 minutes at 0° C., and 30 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was re-dissolved in 50 mL ethyl acetate. The solution was washed with 1 M HCl (100 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to give (1) (6.270 g). The crude product was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 1.28-1.40 (m, 13H), 1.58 (m, 2H), 2.03 (m, 2H), 2.53 (t, J=7 Hz, 2H), 3.43 (s, 2H), 4.21 (q, J=7 Hz, 2H), 4.97 (m, 2H), 5.80 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[S:57]1[CH:61]=[CH:60][N:59]=[C:58]1[NH2:62]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([NH:62][C:58]2[S:57][CH:61]=[CH:60][N:59]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)nc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)nc1

Procedure:
A solution of 2-(6-chloropyridin-3-yl)-3-cyclopentylpropionic acid (Preparation 1, 0.56 g, 2.2 mmol), TBTU (1.41 g, 4.4 mmol), HOBt (0.45 g, 3.3 mmol), NEt3 (0.31 mL, 2.2 mmol), and thiazol-2-ylamine (0.44 g, 4.4 mmol) in anhydrous DMF (23 mL) was stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc, before being washed with 2 M Na2CO3, H2O, and brine. After drying (Na2SO4), the organic phase was filtered and concentrated to give the title compound: RTA=3.82 min; m/z (ES+)=336.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+:18].[Na+].[Na+].[Na+].[Na+].Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])[N:27]=[C:26]([NH:43][C:44]2[CH:45]=[C:46]([C:53]([O-:55])=[O:54])[CH:47]=[C:48]([CH:52]=2)[C:49]([O-:51])=[O:50])[N:25]=1>O.[OH-].[Na+]>[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[N:25]1[C:24]([NH:1][C:2]2[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=2)[C:7]([O-:9])=[O:8])=[N:29][C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])=[N:27][C:26]=1[NH:43][C:44]1[CH:52]=[C:48]([C:49]([O-:51])=[O:50])[CH:47]=[C:46]([CH:45]=1)[C:53]([O-:55])=[O:54]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: O=C([O-])c1cc(Nc2nc(Cl)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(Nc2nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1

Procedure:
To a stirred solution of 3.62 g of 5-aminoisophthalic acid and 1.85 g of sodium bicarbonate in 80 ml of water plus 7.8 ml of 5N sodium hydroxide is added 11.24 g of crude 5,5'-[6-chloro-s-triazine-2,4-diyl)diimino]diisophthalic acid tetrasodium salt (prepared as described in Example 2). The reaction mixture is refluxed for 15 hours, then is filtered. The filtrate is diluted with 100 ml of absolute ethanol to give a precipitate. The precipitate is collected by filtration and is washed with (8:10) aqueous ethanol, 75% aqueous ethanol, ethanol and ether to give 14.2 g of crude product. The product is warmed with 80 ml of water and 0.1 ml of 5N sodium hydroxide is added to achieve pH 9. The mixture is filtered through diatomaceous earth and the filtrate is diluted with 100 ml of absolute ethanol with formation of a thick paste on stirring. The paste is filtered, stirred in absolute ethanol and filtered again, then is washed with ether and dried by conventional means to give a 9.9 g of a colorless powder as the product of the example.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[Cl:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(O[C@H]3CCNC3)n2)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Temperature: -20 °C
Yield: 49.2 %

Procedure:
To (S)-3-(8-chloro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (42.6 mg, 0.116 mmol) in DCM (25 mL) was added 2,6-dimethylpyridine (37.24 mg, 0.35 mmol). The resulting mixture was cooled to −20° C. Acryloyl chloride (26.1 mg, 0.29 mmol, 10 mg/mL in dry DCM) was added dropwise and the reaction mixture was warmed to 0° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (22.02 mg, 49.25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 11.87 (s, 1H), 8.01-7.98 (m, 2H), 7.71-7.70 (d, J=4.0 Hz, 2H), 6.67-6.57 (m, 1H), 6.26-6.14 (m, 2H), 5.72-5.63 (m, 1H), 4.01-3.71 (m, 4H), 2.33-2.24 (m, 2H); ESI-MS m/z [M+H]+ 386.1.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[CH:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1)=[O:9].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:7][C:5]1[N:6]=[C:2]([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:8]=[O:9])[S:3][CH:4]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1csc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2nc(Cl)cs2)c1
Temperature: 60 °C

Procedure:
A mixture of commercially available 2,4-dichlorothiazole (800 mg; 5.19 mmol), (3-formylphenyl)boronic acid (833 mg; 5.56 mmol), potassium phosphate tribasic K3PO4 (3.308 g; 15.60 mmol), Xantphos (75 mg; 0.13 mmol), and Pd(OAc)2 (29 mg; 0.13 mmol) in anh. THF (26 ml) was heated to 60° C., under nitrogen, for 3 h. After cooling to rt, the mixture was filtered over celite, and the separated solids were washed with DCM. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 3-(4-chlorothiazol-2-yl)benzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 224.03 g/mol.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([O:33][CH3:34])=[N:16][N:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([O:33][CH3:34])=[N:16][N:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:13][CH:12]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(Cn2nc(OC)c3ccc(N)cc32)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Cyclopentyl chloroformate (0.17 ml.) was added to a cooled (-20° C.) solution of methyl 4-[6-amino-3-methoxyindazol -1-ylmethyl]-3-methoxybenzoate (S) (0.381 g.) and pyridine (0.11 ml.) in dichloromethane (3.0 ml.). After warming to ambient temperature, the mixture was diluted with ethyl acetate, and washed with hydrochloric acid (1N), water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (56 g.), eluting with 5:95 v/v ethyl acetate: dichloromethane, to give the title compound (0.365 g., 75%) as an oil, with satisfactory NMR spectral data.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[C:21]#[N:22].[CH:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:29][CH2:30][NH:31][C:2]2[C:10]3[NH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:7][C:6]=3[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][C:3]=2[C:21]#[N:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCC1CCCCC1
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1Cl
Product: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)F)[nH]c2c1NCCC1CCCCC1

Procedure:
4-Chloro-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole is reacted with 2-cyclohexylethylamine to obtain 4-(2-cyclohexylethylamino)-7-nitro-5-cyano-2-pentafluoroethylbenzimidazole, m.w., 329.3.
Reaction SMILES: COC(=O)[C:4]([C:20]#[N:21])([CH:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Na+].[Cl-].O>CS(C)=O.[Cl-].[Na+].O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([C:20]#[N:21])[CH:13]([CH:17]([CH3:18])[CH3:19])[CH2:14][CH2:15][CH3:16])([CH3:10])([CH3:12])[CH3:11]
Reactant: CCCC(C(C)C)C(C#N)(CC(=O)OC(C)(C)C)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(C(C)C)C(C#N)CC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 75.2 %

Procedure:
A mixture of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester (1.3 g, 4.2 mmol), NaCl (0.25 g, 4.2 mmol), and H2O (0.15 g, 8.3 mmol) in 25 mL of DMSO is warmed to 130° C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of brine. The organic products are extracted into Et2O (3×50 mL). The organic layers are combined and washed with 50 mL of H2O and 50 mL of brine. Drying over Na2SO4 and evaporation of the solvent gives 0.8 g (75% yield) of 3-cyano-4-isopropyl-heptanoic acid t-butyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](I)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1ccc(-c2cc(C)c(Br)c(C)c2)cn1

Procedure:
The title compound is prepared from 2-methyl-pyridine-5-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.93 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH:11]([CH3:13])[CH3:12].N1CCCCC1.CC(O)=O>C1C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Yield: 83.9 %

Procedure:
A mixture of 4-fluorobenzaldehyde (3.00 gm, 24 mmol), ethyl isobutyrylacetate (3.82 gm, 24 mmol), piperdine (240 ul), and HOAc (42 ul) was refluxed in benzene (15 ml) with removal of water (Dean-Stark trap) for 22 hours. The cooled mixture was diluted with Et20 and washed successively with 2% HCl, saturated NaHCO3, H2O, and brine, then dried (Na2SO4), filtered, and stripped to yield an oil. Distillation of the oil (bp 110°-113° C. at 0.25 mm) afforded the title compound (5.32 gm, 83%) as a pale yellow liquid. This reaction has been successfully scaled up to 300 mmol.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH3:13])[C:4]=2[S:5][CH:6]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:13])[C:4]=2[S:5][CH:6]=1
Reactant: CNCc1cccc2c(Cl)csc12
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 50 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
To a solution of 0.22 g (1.0 mmol) of 3-chloro-N-methylbenzo[b]thiophene-7-methanamine in 3 ml of dimethyl sulfoxide were added 0.12 ml. (1.2 mmol) of 1,3-dichloropropene (E/Z=9/1) and 0.21 g (1.5 mmol) of ground potassium carbonate. The mixture was stirred for 17 hours at 50° C., and poured into 50 ml of ethyl acetate. The organic layer was washed with 25 ml x 2 of water and 10 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-heptane→n-heptane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 0.21 g (yield: 73%) of the above identified compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH3:19])[CH:9]([C:14](=O)[CH3:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:25]>C(O)(=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:15][C:14]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:18]([CH3:19])[N:25]=1
Reactant: COC(=O)C(C(C)=O)C(CC(C)=O)c1ccc(F)cc1
Reactant: [NH4+]
Agent: Cl[Fe](Cl)Cl
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)cc(C)nc1C

Procedure:
A suspension of 28.0 g (100 mmol) of methyl 3-(4-fluorophenyl)-2-(1-oxoethyl)-5-oxohexanoate (=Xa from Example 1), 120 g of ammonium acetate and 120 g of iron(III) chloride hexahydrate in 1000 ml of glacial acetic acid was refluxed, with stirring, until the precursor could no longer be detected by thin-layer chromatography (4 h). The mixture was cooled and then filtered, and the solid residue was washed with ethanol and toluene. The filtrate was evaporated and then the residue was suspended in water, the pH was adjusted to 8-9 by addition of solid sodium bicarbonate, and the mixture was extracted several times with ether. The combined extracts were washed with saturated NaCl, dried over MgSO4 and evaporated. Purification of the crude product by column chromatography (silica gel, cyclohexane/ethyl acetate 2:1) provided 23.6 g (91%) of XVa in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:20](=[O:23])[CH2:21][CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Yield: 98.1 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: [CH:1]12[C:10](=[O:11])[O:9][C:7](=O)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>>[O:9]=[C:7]1[CH:2]2[CH:1]([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:10](=[O:11])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(N2C(=O)C3CCCCC3C2=O)cc1

Procedure:
Equimolar amounts of cyclohexane-1,2-dicarboxylic acid anhydride and p-aminophenylacetic acid were reacted as described in step (a) of Example 1, yielding quantitatively 4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenylacetic acid (melting point 219°-221° C.).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[Cl:17][C:18]1[S:22][N:21]=[N:20][C:19]=1[CH2:23]Cl>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:23][C:19]3[N:20]=[N:21][S:22][C:18]=3[Cl:17])=[N:6][C:5]=2[N:16]=1
Reactant: ClCc1nnsc1Cl
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: C[C@H](CO)Nc1nc(SCc2nnsc2Cl)nc2nc(N)sc12

Procedure:
The titled compound was prepared from the product of example 4, step (b), and 5-chloro-4-(chloromethyl)-1,2,3-thiadiazole, using the method of example 4, step (c).
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([NH:16][C@H:17]([CH:22]=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:6]([NH:16][CH:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH:22]([OH:23])[C:24]#[N:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: [C-]#N
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C#N
Reaction time: 14 h
Yield: 81.6 %

Procedure:
A solution containing 3.43 g of sodium hydrogen sulfite in 20 ml of water was added to 2.81 g of N-carbobenzoxy-L-leucinal, and the mixture was stirred for 14 hours under ice-cooling. A solution of 1.41 g of potassium cyanide in 50 ml of water and 200 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 4 hours at room temperature. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2.54 g of 3-carbobenzoxyamino-2-hydroxy-5-methylhexanenitrile as a colorless oil. A mixture of 20 ml of dioxane and 20 ml of concentrated hydrochloric acid was added to 500 mg of the nitrile, and the mixture was heated under reflux for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residual crystals were purified by cation exchange column chromatography (eluent: a 2N aqueous NH4OH solution) to obtain 254 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid as colorless crystals (a mixture in ratio of 2R and 2S being about 7:3).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](C2NC=CC=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].CCO.S(Cl)([Cl:31])(=O)=O>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13]([Cl:31])(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2sccc2S(=O)(=O)c2ccc[nH]2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(OCc2sccc2S(=O)(=O)Cl)cc1
Yield: 46 %

Procedure:
2-[(4-Methylphenoxy)methyl]thiophene-3-sulfonyl chloride was prepared, as described in Example 15E, using N-{2-[(4-methylphenoxymethyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (NaOH/EtOH) followed by conversion to the corresponding sulfonyl chloride, in 46% yield.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][CH3:17])[N:15]=2)=[CH:7][C:6]=1[CH2:18][CH2:19][CH3:20].[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]2.O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([C:14]1[N:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]4)=[C:6]([CH2:18][CH2:19][CH3:20])[CH:7]=2)[S:12][CH:13]=1)[CH3:17]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCBr
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of 2-[4-(2-bromoethoxy)-3-propylphenyl]-4-ethyl-1,3-thiazole (105 mg, 0.30 mmol) (Example 34) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (65 mg, 0.30 mmol) (Example 6) in DMF (4 mL, containing 1% v/v of water), was added Cs2CO3 (145 mg, 0.44 mmol), and the mixture was stirred for 24 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (gradient:100% hexane to 1:9 (v/v) EtOAc/hexane) to give 66 mg (41%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 7.72-7.58 (m, 3H), 6.98 (d, 1H), 6.86-6.60 (m, 3H), 4.33-4.28 (br, 2H), 4.28-4.20 (br, 1H), 4.10 (q, 2H), 3.52-3.40 (m, 1H), 2.84 (m, 4H), 2.64 (dd, 1H), 2.58-2.50 (m, 3H), 2.40-2.24 (m, 2H), 1.72-1.50 (m, 3H), 1.26 (t, 3H), 1.20 (t, 3H), 0.84 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([NH:19][NH2:20])=[O:18])=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[N:20][NH:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[O:14][CH2:13][C:10]1[N:11]=[CH:12][N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)[N:9]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1ccccc1OCc1ncn(-c2cccc(Cl)n2)n1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccccc1OCc1ncn(-c2cccc(Cl)n2)n1

Procedure:
The title compound was prepared from 2-[1-(6-chloro-pyridin-2-yl)-1H-[1,2,4]triazol-3-ylmethoxy]-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 11.92 (s, 1H), 8.43 (s, 1H), 8.0 (m, 3H), 7.80 (m, 3H), 7.70 (t, J=7.5 Hz, 1H), 7.60 (m, J=7.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 5.50 (s, 1H).