Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:33])([CH3:32])[CH3:31].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>C(Cl)Cl>[C:30]([Si:34]([CH3:45])([CH3:44])[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:29])=[N:39]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (72.42 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide (77.3 mg, 59%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H45Cl2N5O2S+H [(M+H)+]: 654.2793. found: 654.2790.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1])([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5 g of 2-amino-3-nitrophenol in 10 mL DMF were added 4.9 g of K2CO3 and 3.6 mL of 2-iodopropane. The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was taken up in sat. aq. NH4Cl and extracted with EtOAc (3 times). The organic phases were combined, washed with water, brine, dried over MgSO4 and concentrated in vacuo. Purification by CC with EtOAc-Hept (2:8) afforded 5.2 g of 2-isopropoxy-6-nitro-phenylamine as orange oil.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:31].[CH2:32](O)[CH3:33]>>[N:1]#[N:2].[ClH:31].[ClH:31].[CH2:32]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: CCO
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Agent: Cl
Agent: N#N
Product: CCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -dansyl-L-arginine in 15 ml of anhydrous ethanol was saturated with dry hydrogen chloride for 1 hour. The reaction mixture was reflexed for an additional 1 hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a crystalline product. After crystallization from ethanol-ethyl ether, N2 -dansyl-L-arginine ethyl ester dihydrochloride was obtained in 95% yield; mp. 140°-144°C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.C1C=CC=CC=1>[Cl:18][C:17]1[C:12]([S:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: CSc1nnc(S)s1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CSc1nnc(Sc2nccnc2Cl)s1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according the procedure described in Example 1 by using 5-(methylthio)-1,3,4-thiadiazole-2-thiol (1.64 g, 10.00 mmol), NaH (60% dispersion in mineral oil, 445 mg, 11.00 mmol), and 2,3-dichloropyrazine (1.04 ml, 10.00 mmol) in DMF and benzene (12 ml, 1/1) by stirring at 50° C. for 20 hr and then at 110° C. for 4 hr under nitrogen atmosphere.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:4]=1.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:11][C:5]2[CH:4]=[C:3]([CH2:2][C:16]#[N:17])[CH:8]=[CH:7][C:6]=2[O:9][CH3:10])[CH2:15][CH2:14]1
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cc1OCC1CC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)cc1OCC1CC1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
A mixture of 4-(chloromethyl)-2-(cyclopropylmethoxy)-1-methoxybenzene (7.4 g) in DMF (68 ml) was stirred at 60° C. A mixture of potassium cyanide (4.26 g) in water (3.4 ml), previously heated to 80° C., was added dropwise. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, treated with water (47 ml), and extracted with DIPE. The separated organic layer was dried (Na2SO4), filtered, and the solvent was evaporated, yielding 6.2 g (85%) of 3-(cyclopropylmethoxy)-4-methoxybenzeneacetonitrile (interm. 16).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:33][C:34]#[N:35].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:34](=[O:33])[N:35]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccc([N+](=O)[O-])c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A red solution of 34 g (79.4 mmol) of the benzophenone prepared in step A in 200 ml acetic acid is treated with 6.2 g (95 mmol) sodium cyanate under vigorous stirring which is continued overnight. The mixture is diluted with water and extracted with ethyl acetate. Concentration after washing with bicarbonate solution yields several crops of product. While the initial batches are yellow and pure, the subsequent ones are orange and have to be purified by flash chromatography. Combined yield: 25.9 g (72%). m.p. 167-168° C.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1)NCCCCCC(=O)NO
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
(Method J1B) A solution of sodium methylate (6 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4 mmol) in methanol (8 ml). A mixture was stirred for 10 min. and the precipitate was filtered off. (2E)(4E)-6-(5-Phenylpenta-2,4-dienoylamino)hexanoic acid methyl ester (3/1) (0.30 g, 1 mmol) was added to the filtrate and the mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and acidified with 3% HCl. Precipitate was filtered off and crystallized from methanol. The title compound (0.23 g, 66%) was obtained as a white solid. M.p 160-161° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.05-1.69 (6H, m, CH2); 1.81-2.07 (2H, m, CH2); 3.12 (2H, q, J=5.8 Hz, CH2H); 6.14 (1H, d, J=14.8 Hz, CH); 6.89-7.14 (2H, m, CH—CH); 7.23-7.65 (6H, m, C6H5, CH); 8.05 (1H, t, J=6.0 Hz, NH); 8.63 (1H, s, NH), 10.34 (1H, s, OH). HPLC analysis on Symmetry C18: impurities 1.0% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 30:70; detector UV 230 nm; sample concentration 0.1 mg/ml). Anal. Calcd for C17H22N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.63; H, 6.60; N, 10.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[K+].[CH2:31](I)[CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH2:31][CH3:32])[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCI
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)[nH]2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=Nc2c(C)cc(C)cc2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.63 g) in N,N-dimethylformamide (15 ml) were added potassium hydroxide (0.16 g) and ethyl iodide (0.66 ml) and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 ml), and was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.39 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]4)[O:25][C:24]3=[O:38])=[C:19]([F:39])[C:18]=2[F:40])=[C:13]([F:41])[C:12]=1[F:42])[CH3:9].[H-].C([Al+]CC(C)C)C(C)C>C(O)=O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][CH3:37])[CH2:33][CH2:34]4)[O:25][CH:24]3[OH:38])=[C:19]([F:39])[C:18]=2[F:40])=[C:13]([F:41])[C:12]=1[F:42])[CH3:9]
Reactant: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(=O)O2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(O)O2)CC1
Reaction time: 3 h
Yield: 97 %

Procedure:
Toluene (20 ml) was added to 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) prepared in the ninth step. A toluene solution of diisobutylaluminum hydride (0.99 M; 9.6 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (50 ml) to give two layers. The water layer was extracted with toluene (20 ml) twice and the combined organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-ol (12) (2.29 g) in 99% yield.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-:46].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[OH:46][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(O)c2)s1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a solution of tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (630 mg, 982 μmol) (prepared as described in Example 1) in 15 mL DMF were added cesium carbonate (3199 mg, 9819 μmol) and acetic acid (590 mg, 9819 μmol). The mixture was heated at 70° C. for 45 minutes. The reaction mixture was concentrated, and the resulting residue was diluted with 100 mL EtOAc. The organic phase was washed with water and saturated aqueous ammonium chloride twice and then dried over sodium sulfate. Removal of the solvent gave the compound as a tan solid (500 mg, 79%). LCMS (API-ES) m/z (%): 640.0 (100%, M++H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 9H) 1.54 (s, 9H) 2.84-2.94 (m, 2H) 4.23-4.31 (m, 3H) 7.47 (t, J=8.78 Hz, 3H) 7.62-7.69 (m, 3H) 8.01 (d, J=8.53 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O.[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[CH2:20][C:21](=O)[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[F:17][C:18]([F:26])([F:25])[C:19]([C:20]1[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:24]
Reactant: Nc1sc2c(c1C(=O)c1ccco1)CCC2
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccco2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To a stirred solution of 50 mg (0.21 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-furan-2-yl-methanone (the preparation of which is described in example 18) in 2 ml acetic acid was added 0.027 ml (0.21 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 19 mg (25%) 2,2,2-trifluoro-1-(4-furan-2-yl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 352 (M+H+, 72).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.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>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([NH:22][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[C:15]([CH:20]=1)[C:14]([NH:13][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Temperature: 80 °C
Yield: 52.3 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (150 mg, 0.36 mmol), Pd (PPh3)4 (84 mg, 0.072 mmol), and 4-phenoxyphenylboronic acid (233 mg, 1.09 mmol) were dissolved in 5 mL of toluene, a 1M Na2CO3 solution (0.9 mL, 0.91 mmol) added and the mixture heated at 80° C. for 12 h. The reaction mixture was diluted with 5 mL of CH2Cl2 and filtered, all volatiles are removed under vaccum and the ester product was hydrolyzed according to Procedure C, and purified over silica gel (ethyl acetate:hexanes) to give the title compound(118 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])[CH3:13].[H-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]([C:2]([O:24][C:17]2[CH:18]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=[C:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)c1cc(O)cc(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccc(Cl)cc2C(=O)O)cc(C(C)C)c1
Yield: 49.4 %

Procedure:
2,5-dichlorobenzoic acid (5 g) and 3,5-diisopropylphenol (4.66 g) were dissolved in dry xylene and the solution placed under dry oxygen-free nitrogen. Sodium hydride (1.25 g) was added as a suspension in petroleum ether. Cuprous bromide was added and the solution refluxed for 5 hours and cooled. The xylene was removed by low pressure distillation. The remaining solid was acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal layer was separated, dried and distilled under low pressure to give an oil. The oil was dissolved in petroleum ether (30°-40° ). Standing gave a crystalline solid, which was recrystallised from hexane to give the title compound (4.3 g), mp 129°-130° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>>[C:1]([NH:4][C:5]1[C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][C:8]([S:11]([Cl:14])(=[O:12])=[O:13])=[CH:9][C:10]=1[N+:24]([O-:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(S(=O)(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 G. of 4-acetylamino-3-trifluoromethylbenzenesulfonylchloride is dissolved in 15 ml. of concentrated sulfuric acid. 0.9 Moles of nitric acid is added dropwise over a period of 15 minutes, while the temperature is kept below 35° C. When the addition is complete the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto 150 ml. of ice water and the precipitate is filtered, washed with water and dried affording 4-acetylamino-3-nitro-5-trifluoromethylbenzenesulfonylchloride, used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]#[N:24])=[CH:11][N:10]=1)=[O:8])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:9]([C:7]([C:6]1[CH:25]=[CH:26][CH:27]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:8])=[N:10][CH:11]=[C:12]2[C:23]1[NH:30][N:29]=[N:28][N:24]=1
Reactant: CCOc1cccc(C(=O)c2ncc(C#N)c3cc(OC)c(OC)cc23)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(C(=O)c2ncc(-c3nnn[nH]3)c3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
The mixture of 1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (50 mg, 140 mmol), sodium azide (20 mg, 310 mmol) and ammonium chloride (16.2 mg, 310 mmol) in DMF (2 mL) was stirred at 120° C. for 24 h. After removal of solvent, the crude product was purified directly by HPLC (Reverse C18, 10%-90% acetonitrile in water in 10 min) afforded our desired product [6,7-Dimethoxy-4-(1H-tetrazol-5-yl)-isoquinolin-1-yl]-(3-ethoxy-phenyl)-methanone with trifluoro-acetic (31 mg, 55%) as a light yellow solid. LC/MS m/e calcd for C21H19N5O4 (MH+) 406, found 406.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[C:21]([C:31]#[N:32])=[CH:20][C:19]=3[F:33])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].OO.CC(O)=[O:40]>CCO.CS(C)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[C:19]([F:33])=[CH:20][C:21]([C:31]([NH2:32])=[O:40])=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:23]=3)[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (9 mg, 0.019 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (5 mg). MS 480.3 (M+H); UV 204.7, 292.8 nm.