Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH:22](Br)([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].N>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Reactant: CC(C)Br
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC(C)C)cc12
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 2-(4-fluorophenyl)-5-hydroxy-1-benzofuran-3-carboxylate (18.86 g, 65.9 mmol), isopropyl bromide (24.74 mL, 264 mmol) and cesium carbonate (42.9 g, 132 mmol) in dry N-Methyl-2-pyrrolidone (191 mL) was stirred at 60° C. under nitrogen for 20 hours. The resultant thick suspension was allowed to cool to room temperature and then 7% aqueous ammonia solution (200 mL) was added with rapid stirring. This mixture was extracted with heptane (700 mL) and then the aqueous phase was separated off. Ethyl acetate (˜100 mL) was added to the organic phase and the resultant mixture was shaken and then dried over Na2SO4 and evaporated to give a brown oil which crystallized on standing overnight. This material was recrystallized from hot methanol and the solid was collected by filtration, washed with methanol and finally dried under vacuum to give methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate. LCMS (m/z, ES+)=329 (M+1). The mother liquors from the first recrystallization were crystallized a second time to give an additional batch of methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-1-benzofuran-3-carboxylate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25]Cl)[CH2:2][CH2:3][CH3:4].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][N:31]1[C:27](=[O:37])[C:28]2[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Yield: 97.8 %

Procedure:
A solution of 4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.38 g, 1 mmol) and potassium phthalimide (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.48 g, 98.0%) as an amorphous.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:46]=[CH:45][C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=2)=[O:16])=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:16])([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:23]=2)=[CH:45][CH:46]=1
Reactant: CN1CCC(Cl)CC1
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 45 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A 25 mL round bottom flask charged with magnesium turnings (23.0 mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran (1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45° C. for 10 min and cooled to rt. To the mixture was added 4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction was stirred at 35° C. under an atmosphere of nitrogen for 12 hrs. The mixture turned cloudy, and magnesium turnings eventually disappeared, as the reaction progressed. To a solution of N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added the pre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, the reaction was warmed to rt. In another 3 hrs, the reaction was quenched with water and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 1-20% MeOH) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; 1H NMR (400 MHz, CDCl3) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23 (d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m, 3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H), 3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2 Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H), 1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d, J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-−0.04 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:23]([CH3:26])([OH:25])[CH3:24]>>[CH:28]1([CH2:27][C@H:22]([NH:21][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:23]([OH:25])([CH3:26])[CH3:24])[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(O)[C@@H](N)CC1CC1
Product: CC(C)(O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol as starting materials, MS (EI): m/e=410.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (0.150 mmol), 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL), and acetic acid (0.048 mL) was added NaBH3CN (0.75 mmol) in methanol (1.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to afford (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].ClCCl>O>[C:10]1([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCNC1
Reactant: ClCc1cc(-c2ccccc2)ccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: c1ccc(-c2ccnc(CN3CCCC3)c2)cc1
Reaction time: 1 h

Procedure:
The product from stage (i) (14.0 g) was added to a solution of pyrrolidine (17.0 ml) in water (80 ml) at 22°. The solution was stirred for 1 h at 22° and then potassium hydroxide (40 g), dichloromethane (200 ml) and water (200 ml) were added. The mixture was stirred for 0.25 h and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts were washed with water (2×100 ml), saturated brine, dried and evaporated to leave an oil (15.2 g), a portion of which (0.5 g) was purified by flash chromatography eluting with dichloromethane, ethanol and ammonia (200:8:1) to give the title compound as an oil (0.4 g). T.l.c. Silica (Dichloromethane, ethanol and ammonia 200:8:1) Rf 0.4.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@:9]([C@H:18]1[CH2:22][O:21][CH2:20][C@H:19]1[OH:23])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[C:24]([Si:28]([CH3:31])([CH3:30])[O:23][C@@H:19]1[CH2:20][O:21][CH2:22][C@@H:18]1[C@:9]([NH2:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1[C@](C)(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Triethylamine (8.05 g, 79.6 mmol) was added to a solution of rel-(3S,4S)-4-((S)-1-amino-1-(2-fluorophenyl)ethyl)tetrahydrofuran-3-ol (5.6 g, 24.9 mmol) in dichloromethane (100 ml) at 0° C., then 4-dimethylaminopyridine (1.52 g, 12.4 mmol) followed by tert-butyldimethylchlorosilane (7.49 g, 49.7 mmol). The reaction mixture was stirred at room temperature overnight. For the workup, the reaction mixture was extracted with a saturated solution of sodium hydrogencarbonate and brine. The organic layer was dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. The rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine (8.13 g, 96% yield) was obtained as a colorless oil. MS (ISP): m/z=340.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:14](O)=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.Cl>C1COCC1>[Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:14]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: CC(C)Oc1c(Br)c(Br)n(-c2ccccc2)c1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)c(Br)n(-c2ccccc2)c1C(=O)Nc1nnn[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 4,5-dibromo-3-(1-methylethoxy)-1-phenyl-1H-pyrrole-2-carboxylic acid (2.0 g, 0.005 moles) and 1,1'-carbonyldiimidazole (0.8 g, 0.005 moles) in THF (25 mL) is heated under argon to reflux. After 1 hour, 5-aminotetrazole (0.4 g, 0.005 moles) is added. After 2.5 hours, the mixture is stirred into ice water (250 mL) and acidified with dilute HCl. The precipitate is filtered off, rinsed with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (0.8 g); mp 184° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16]Br)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[S:21](C#N)[C:22]#[N:23].[K]>O.C(O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:21][C:22]#[N:23])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CSC#N
Reactant: CC(CBr)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(CSC#N)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1

Procedure:
A mixture of 2 g of N(3-bromo-2-methyl-propanoyl)-N-cyclopentyl glycine-t-butyl ester, 0.7 g potassium thiocyanide in 5 ml water and 40 ml ethanol was stirred and refluxed for 16 hours. After removal of the solvent, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness. The oily residue was purified by HPLC using 20% EtOAc-hexane as eluent giving pure N(3-thiocyano-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:12]
Reactant: BrCCCCCBr
Reactant: COc1cccc2c1CCC2=O
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc2c1CC1(CCCCC1)C2=O

Procedure:
A solution of 20 g 4-methoxyindan-1-one and 24 g 1,5-dibromopentane in 150 ml benzene is added quickly dropwise to a solution of potassium tert.-butylate (produced from 9.7 g potassium and excess tert.-butanol) in 200 ml benzene at 80°. The mixture is refluxed for 4 hours, treated with 50 ml water and 200 ml 2 N hydrochloric acid, and extracted with benzene. Chromatography on silicagel of the benzene phase gives 4'-methoxy-spiro(cyclohexane-1,2'-indan)-1'-one. M.Pt. 94°-96°.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(CC2CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)cc3)CC2)cc1
Yield: 70.3 %

Procedure:
A mixture of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine hydrochloride (250 mg, 0.55 mmol) in 25 mL of ethanol with 60 mg of 20% Pd(OH)2 was hydrogenated at 30 psi of hydrogen to give 140 mg (88%) of the title compound, mp 198-200° C. 1H NMR (CD3OD) 1.6 (m, 2 H), 1.881-1.923 (m, 3 H), 2.288 (s, 3 H), 2.572 (d, J=6.6 Hz, 2 H), 3.06 (m, 2 H), 3.473 (m, 2 H), 3.61 (m, 2 H), 4.243 (t, J=5.1 Hz, 2 H), 6.709 (dd, J1 =2.4 Hz, J2 =6.6 Hz, 2 H), 6.830 (dd, J1 =2.4 Hz, J2 =6.6 Hz, 2 H), 7.703 (m, 4 H). Anal. Calcd for C21H28ClNO2.0.5H2O: C, 68.00; H, 7.88; N, 3.78. Found: C, 68.14; H, 7.65; N. 3.72.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1Br)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][C:15]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(COC(C)=O)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: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of methyl 3-[(acetyloxy)methyl]-4-bromobenzoate obtained in step 2 (4.7 g; 16.4 mmol), o-tolylboronic acid (2.45 g; 18 mmol), potassium carbonate (11.3 g; 82 mmol) and Pd(PPh3)4 (1.89 g; 1.64 mmol) in toluene (23.5 mL) and water (23.5 mL) was refluxed for 2 hours. After cooling to RT, the reaction mixture was filtered through a pad of Celite® which was further washed with toluene (50 mL). The filtrate was concentrated in vacuo, the residue taken up in EtOAc (250 mL) and washed with sat. aq. NaHCO3, water and brine, dried over magnesium sulphate and concentrated in vacuo to afford the title compound (4.9 g, quantitative) as a brown oil. HPLC (Method A) Rt 5.23 min (Purity 62.3%).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[O:3][C:2]2=[O:10].C(N(CC)CC)C.Cl.[CH2:19]([NH:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:29]1([CH2:28][O:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([C@@H:5]2[CH2:6][CH2:7][C@H:1]([C:2]([OH:3])=[O:10])[CH2:8]2)=[O:9])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1OC(=O)C2CCC1C2
Reactant: c1ccc(CNOCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@@H](C(=O)N(Cc2ccccc2)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
552 mg of 3-Oxabicyclo[3.2.1]octane-2,4-dione (3.94 mmol, prepared according to the procedure described in Chem. Lett., p 93, (1994)) is added to a rapidly stirring solution of triethylamine (0.55 mL, 3.94 mmol) and N-benzyl-O-benzylhydroxylamine hydrochloride (983 mg, 3.94 mmol) in CH2Cl2 in a flame dried flask under nitrogen. After stirring at ambient temperature for 3 days, the reaction is quenched with aqueous citric acid (1M). Extraction into CH2Cl2 (3×50 mL), followed by drying over MgSO4, yielded a pale yellow oil, 1.51 g. Recrystallization in ethyl acetate/hexane provided the product as a white crystalline solid, 1.32 g (95%). mp. 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](COC)[C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[N:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc2[nH]ncc12)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2ccnc3[nH]ncc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 4-chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (50 mg, 0.092 mmol) in 4M HCl in dioxane (4 mL) and water (1 mL) was stirred at 70° C. for overnight. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (28.9 mg) as yellow solid (after lyophilization) in 63% yield. 1H NMR (400 MHz, CDCl3) δ10.75 (s, 1H), 8.65 (d, 1H), 8.24 (m, 1H), 8.14 (d, 1H), 8.08 (s, 1H), 7.94-7.99 (m, 2H), 7.59 (d, 1H), 7.58 (d, 1H), 2.48 (s, 3H); ESMS m/z (relative intensity): 496 (M+H)+ (100).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CC(N(C)C)=O>[CH:12]1([NH:17][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: NC1CCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc2cccc(NC3CCCC3)n2n1
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.5 g, 2.35 mmol) in dimethylacetamide (2 mL), cyclopentylamine (2.3 mL, 23.5 mmol) was added and the solution was heated under microwave irradiation (180° C., 180 min). The resulting mixture was dilluted with water and extracted into ethyl acetate. The organics were washed with water then brine, and dried over magnesium sulfate. The solid (0.5 g) was used without further purification. LCMS1: 2.84 min, 218 [M+1].
Reaction SMILES: ClC1N=C(Cl)C2SCCC=2N=1.[NH2:12][C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1.[Cl:18][C:19]1[N:20]=[C:21](NC2(CO)CC2)[C:22]2[S:27](=[O:28])[CH2:26][CH2:25][C:23]=2[N:24]=1>>[Cl:18][CH:19]1[N:24]([NH:12][C:13]2([CH2:16][OH:17])[CH2:15][CH2:14]2)[C:23]2[CH2:25][CH2:26][S:27](=[O:28])[C:22]=2[CH:21]=[N:20]1
Reactant: NC1(CO)CC1
Reactant: O=S1CCc2nc(Cl)nc(NC3(CO)CC3)c21
Agent: Clc1nc(Cl)c2c(n1)CCS2
Product: O=S1CCC2=C1C=NC(Cl)N2NC1(CO)CC1

Procedure:
Starting from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 1-amino-cyclopropanmethanol the two enantiomers of [1-(2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol may be prepared as described in Example 28 (cf 2.1.2). The enantiomers may be separated by chiral HPLC (column Diacel IA, 250×4.6 mm, 5 m, eluant: (hexane+cyclohexylamine (0.2%))/ethanol (80/20), flow rate: 1 ml/min): enantiomer 1: RT=11.1 min; enantiomer 2: RT=16.5 min.
Reaction SMILES: C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:10])=CC=C([N+]([O-])=O)C=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[NH:21]1[CH2:28][C@H:27]([OH:10])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pHuCol(α1)Ec, FIG. 65) containing the gene for Type I (α1) collagen with optimized E. coli codon usage (FIG. 39A-39E) (SEQ. ID. NO. 19) under control of the tac promoter and containing the gene for chloramphenicol resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 20 μg/ml chloramphenicol. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 20 μg/ml chloramphenicol. This culture was grown to an OD600nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 20 μg/ml chloramphenicol. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 20 μg/ml chloramphenicol, and the washed cells used to inoculate 1 L of 2×YT medium containing 20 μg/ml chloramphenicol. This culture was grown at 37° C. to an OD600nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol). The cells were resuspended in 910 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chlorarnphenicol) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at −20° C.