Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[C:17]([C:20]1[CH:46]=[CH:45][C:23]([CH2:24][CH2:25][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:22][CH:21]=1)([OH:19])=[O:18]>>[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH:25]=[CH:24][C:23]1[CH:45]=[CH:46][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([OH:18])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=Cc1ccccc1Cc1ccccc1
Agent: [Br-]
Product: O=C(O)c1ccc(C=CCc2ccccc2Cc2ccccc2)cc1
Product: O=C(O)c1ccccc1Cc1ccccc1

Procedure:
4-[3-(2-Benzylphenyl)prop-1-enyl]benzoic acid was prepared by reaction of 2-benzylbenzaldehyde with 4-carboxyphenethyltriphenylphosphonium bromide using a similar method to that of example 33(B) to give a gum. [2-Benzylbenzaldehyde (an oil) was obtained from 2-benzylbenzoic acid using a similar method to that of example 33(A)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([CH3:12])=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[S:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[C:4]([F:13])[C:5]=3[CH3:12])[NH:9][C:8]=2[CH3:11])=[N:16]1
Reactant: Cc1cc2c(C)c(F)cc(Cl)c2[nH]1
Reactant: Clc1nsc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1[nH]c2c(Cl)cc(F)c(C)c2c1-c1nsc2ccccc12
Reaction time: 1 h

Procedure:
A solution of the product from step b) (200 mg) and 3-chloro-1,2-benzisothiazole (171 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 hour, and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated. The residue was purified by silica chromatography using 20% acetone in isohexane as eluent to give the title compound (219 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:37]1[S:36][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A mixture of methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.26 g, 20 mmol), 2-thiopheneboronic acid (3.07 g, 24 mmol), sodium carbonate (5.30 g, 50 mmol), toluene (50 ml), methanol (10 ml) and water (10 ml) was stirred at room temperature for 30 min under an argon atmosphere. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol), the mixture was refluxed under heating for 10 h under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate (2.11 g, 23.6%) as crystals.
Reaction SMILES: [OH:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Na]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2COCCCN(O)C(N)=O)c1
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON(CCCOCn1c(Cc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O)C(N)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 1-(3-N1-hydroxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil obtained in the above Example 1-C (85 mg, 0.2 mmol) in dichloromethane (3.5 ml), was added DMAP (4-dimethylaminopyridine) (5 mg, 0.04 mmol), triethylamine (45 μl, 0.3 mmol) and acetic anhydride (25 μl, 0.24 mmol) and the mixture was stirred for 3 hours at 20° C. Then, it was added thereto dichloromethane (5 ml) and an aqueous saturated sodium hydrogenocarbonate solution (5 ml). The reaction medium was then extracted with dichloromethane (50 ml) and the organic phase was washed with water (10 ml) and then with a saturated sodium chloride solution (10 ml) and dried (sodium sulfate). The organic phase was then concentrated and subjected to a flash column chromatography on silica gel (dichloromethane/methanol 9:1) to give 70 mg (75%) of the desired 1-(3-N1-acetoxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil in the form of a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[C:17]([CH2:21][N:22]2[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23]2)[CH:18]=[CH:19][CH:20]=1.Cl.CN(C)CCCN=C=NCC>CO>[NH2:8][C:7]1[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3](=[O:12])[C:2]=1[NH:1][C:27]([C:25]1[CH:24]=[N:23][N:22]([CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:31])([F:13])[F:30])[CH:16]=2)[CH:26]=1)=[O:28]
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Reactant: CCn1c(N)c(N)c(=O)[nH]c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCn1c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5,6-diamino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (2 g, 11.76 mmol) and 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylic acid (3.5 g, 12.94 mmol) in methanol (50 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.47 g, 12.94 mmol), and the reaction mixture was stirred for 16 hours at room temperature. Solvent was removed under reduced pressure, and the residue was washed with water and methanol. The product was dried under vacuum to provide N-(6-amino-1-ethyl-2,4-dioxo(1,3-dihydropyrimidin-5-yl))(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)carboxamide, a compound of formula (16).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:40])=[N:26]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:28]2[C:27]([CH3:40])=[N:26][N:25]([CH3:24])[C:29]=2[CH3:30])[CH2:12]1)([CH3:21])[CH3:20]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)N(C)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)C(C)C)C2
Reaction time: 4 h
Yield: 55.8 %

Procedure:
(S)-6-(Isopropyl(methyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (184 mg, 0.524 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (142 mg, 0.602 mmol) and Pd(PPh3)4 (60 g, 0.0524 mmol) were added to a solution of K2CO3 (145 mg, 1.047 mmol) in a mixture of 1,2-dimethoxyethane (7 mL) and H2O (1 mL). The reaction mixture was purged with Ar (g) for 10 min, and warmed up to reflux. The reaction was completed in 4 h. It was allowed to reach room temperature, diluted with CH2Cl2 (20 mL) and acidified with HCl aqueous solution (10%, 30 mL). The organic layer was discarded, and the aqueous layer was taken to pH=9-10 with NaOH aqueous solution (10%). It was extracted with CH2Cl2 (3×20 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude was purified by flash chromatography on silica gel (5% Et3N/AcOEt), to afford 91 mg of the desired product (yellow oil, 56% yield).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1

Procedure:
79 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(2-fluorophenyl)piperazine (40 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[O:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1ccccc1F
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1F)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 1-fluoro-2-isocyanato-benzene ([16744-98-2]) in toluene for 48 h under reflux conditions to give the title compound as colorless oil. MS: m/e=429.5 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1.Br[C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[N:29][CH:30]=1>O>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:22][CH:21]=2)=[CH:30][N:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccc(-n2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-n3cncn3)cc2)cn1
Temperature: 70 °C
Yield: 31.9 %

Procedure:
Cesium carbonate (1.3 g, 4.03 mmol) was mixed with 3 ml of dry dimethylformamide, 4-(1H-1,2,4-triazol-1-yl)phenol (0.5 g, 3.1 mmol) and 5-bromo-2-nitropyridine (0.63 g, 3.1 mmol) and the reaction mixture was heated at stirring at 70° C. in a closed vial. The reaction mixture was then mixed with 40 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting greenish-brown solid was washed thoroughfully with methylene chloride to give 280 mg of desired compound (32% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]=2[N:4]=[C:3]1[SH:13].[OH-].[Na+].O.CN(C=O)C.[C:22]([O:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>C(O)C.O>[C:22]([O:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([C:32]2[CH:33]=[CH:34][C:35]([CH2:36][S:13][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[C:6]4[C:9]([CH3:12])=[CH:10][S:11][C:5]=4[N:4]=3)=[CH:38][CH:39]=2)=[O:31])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cc1csc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4scc(C)c4c(=O)n3C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethyl-2-mercaptothieno[2,3-d]pyrimidin-4(3H)-one (1.40 g) and 1N-sodium hydroxide/water (6.7 ml) in ethanol (13 ml)-DMF (25 ml) was added 4-(4-acetoxybenzoyl)benzyl bromide (2.68 g) and the mixture was stirred at room temperature at 60° C. for 1 hour. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated, and the residue was recrystallized from methanol to provide the title compound as colorless solid (887 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:10]([O-:13])(O)=[O:11].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C2C(=O)N(C([O-])=O)C=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C1COCC1>[OH:9][C@H:6]([CH2:7][CH3:8])[C@H:2]([NH:1][C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: O=C([O-])O
Reactant: CC[C@@H](O)[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 46.1 %

Procedure:
To a stirred mixture of (2S*,3R*)-2-amino-3-hydroxy-pentanoic acid (0.068 g, 0.51 mmol) and NaHCO3 (0.128 g, 1.53 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (0.218 g, 0.77 mmol) [prepared as for example 32, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.076 g, 46% over 3 steps), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 324 [M−NH4]+; (ESI) m/z: 322 [M−H]−. 1H NMR (DMSO-d6) δ 0.85 (t, J=7.38 Hz, 3H), 1.28-1.49 (m, 4H), 1.50-1.68 (m, 4H), 2.58 (t, J=7.67 Hz, 2H), 3.79 (td, J=2.93, 6.83 Hz, 1H), 3.97 (t, J=6.60 Hz, 2H), 3.99-4.11 (m, 1H), 6.63 (d, J=9.23 Hz, 1H), 7.12-7.32 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.Br>O1CCOCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(C=C2CCCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(C=C2CCCC2=O)cc1
Yield: 23.9 %

Procedure:
A solution of 1.4 g of ethyl 2-[4-(2-oxo-1-cyclopentylidenemethyl)phenyl]propionate in 15 ml of dioxane and 100 ml of a 10% aqueous solution of hydrogen bromide was heated under reflux for 1 hour. After cooling, the reaction mixture was extracted with ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was distilled off to leave an oily substance, which was then vacuum distilled to afford 0.3 g of the desired product having a boiling point of 210°-215° C./0.2 mmHg (bath temp.). This product solidified and crystallized after cooling. m.p. 106°-107° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:33][NH:34][CH:35]([CH2:37][CH3:38])[CH3:36]>C(Cl)(Cl)Cl>[CH3:33][N:34]([CH:35]([CH3:36])[CH2:37][CH3:38])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18]
Reactant: CCC(C)NC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 63.5 %

Procedure:
Operations are carried out as for Example 7, starting with 2.96 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.33 g of triethylamine, 1.49 g of ethyl chloroformate and 1.34 g of N-methyl 2-butanamine in 120 ml of chloroform. 2.4 g of N-methyl N(1-methyl propyl) 1-phenyl isoquinoline 3-carboxamide melting at 95°-96° C., are obtained.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]#[N:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C.[N-:27]=[N+:28]=[N-:29].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH2:16][C:17]2[NH:29][N:28]=[N:27][N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1nnn[nH]1)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To an N,N-dimethylformamide (100 ml) solution of 4-chlorophenylsulfonylacetonitrile (2.81 g, 13.0 mmol) and triethylamine hydrochloride (4.24 g, 65.2 mmol) was added sodium azide (10.8 g, 78.2 mmol) and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was then cooled to room temperature. Ethyl acetate was added and the mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was washed with diethyl ether and then, collected by filtration, whereby the title compound (2.53 g, 9.78 mmol, 75%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([N-]C(C)C)(C)C.[Li+].Cl>O1CCCC1>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:4]1[C:3]([F:8])=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccccc1Br
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Br)c1F
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.42 mmol) and trimethylsilyl chloride (5.79 ml, 45.69 mmol) in dry tetrahydrofurane (30 ml) at −78° C., under nitrogen, lithium diisopropylamide (2 M in hexane, 28 ml, 12.56 mmol) was added dropwise. The mixture was stirred for 1 h and then brought to ambient temperature. 10% Hydrochloric acid (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate/isooctane, 1:1) to give the title compound (2.3 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 22), 246 (20), 151 (96), 105 (bp), 75 (64).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=CC=2)CCC(OC)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:32].[Na+].[O:34]1[CH2:39]COCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:13][CH:14]([CH2:15][CH2:16][CH2:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:2][CH2:3][CH3:4])[C:39]([OH:34])=[O:32])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CC[C@@H](CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCC(CCCc1cccnc1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 62 h

Procedure:
A mixture of methyl (R)-8(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]octanoate (1.5 g, 3.2 mmol), dioxane (15 ml) and 1N sodium hydroxide (6.6 ml, 6.6 mmol) is stirred at room temperature for 62 hours. The solvent is evaporated and the residue taken up in water and the mixture is adjusted to pH=5.0. The product separates an an oil which solidifies rapidly. It is filtered off and washed with water (4×5 ml) and ether (4×5 ml). Upon drying under vacuum at 60° C. for 18 hours, (R)-8-(p-chlorophenylsulfonamido-4-[3-(3-pyridyl)propyl]octanoic acid is obtained as a white solid, m.p. 113°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH2:20]Cl)[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[CH2:27][O:26][CH2:25]C1.CO.C([O-])([O-])=[O:31].[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:26][C:27](=[O:31])[CH2:20][C:11]1[C:10]([CH3:22])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CCl)cc2ccc(F)cc2c1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a stirred solution of 1-benzyloxy-3-chloromethyl-7-fluoro-2-methyl-naphthalene (18.5 g, 58.9 mmol) in a THF-methanol mixture (2:3; 500 mL) was added K2CO3 (8.94 g, 64.7 mmol) and PdCl2(PPh3)2 (2.06 g, 2.96 mmol) at room temperature. The solution was degassed by purging with argon for 5 minutes. The reaction mixture was stirred under a balloon of carbon monoxide overnight at room temperature. After this time, the reaction progress was monitored by TLC (5% ethyl acetate in hexanes). The reaction mixture was concentrated, and the obtained crude residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Silica gel chromatography (100-200 mesh, 5% ethyl acetate-hexanes) yielded (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (5.5 g, 28%) as a pale yellow solid. MS calcd. for C21H20FO3 [(M+H)+] 339, obsd. 339.0.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:9](=[O:10])[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)(=O)[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[CH3:2][C:1]1[O:10][C:9]2[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:5]=2[N:4]=1
Reactant: CC(=O)NC1CN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2c(o1)CN(C(=O)OC(C)(C)C)C2

Procedure:
A solution of tert-butyl 3-(acetylamino)-4-oxopyrrolidine-1-carboxylate obtained in Step B (310 mg) in tetrahydrofuran (4 mL) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide (762 mg) was heated in a sealed tube at 75° C. for 3 h and evaporated under reduced pressure. The residue was then purified on a Biotage Horizon® system (silica, gradient 30-55% ethyl acetate in hexane) to yield the title compound.