Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H]2OC(OCC)[O:18][C@@H:14]2[C@@H:13](CO)[CH2:12]1.[CH3:24][O:25][C:26]([O:29][CH3:30])([CH3:28])[CH3:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:24]2[O:25][C:26]([CH3:28])([CH3:27])[O:29][C@@H:30]2[C@@H:13]([CH2:14][OH:18])[CH2:12]1
Reactant: CCOC1O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above crude ((3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2-ethoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol was taken up in 2,2-dimethoxypropane (214 mL, 1740 mmol) and treated with p-toluenesulfonic acid monohydrate (13.2 g, 69.5 mmol) to afford a brown oil partially suspended in a cloudy solution, which was stirred at rt for 1 h 20 min; HPLC/LC MS indicated complete conversion to the desired product. The reaction was quenched by the careful addition of sodium bicarbonate (8.76 g, 104 mmol) and a minimal amount of water. The volatiles were removed in vacuo and the remaining aqueous layer was diluted with water (100 mL) and extracted with CH2Cl2 (3×400 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown oil. Purification by column chromatography (7×16 cm silica; 0-5% MeOH/CH2Cl2) afforded the title compound (8.30 g, 74% over 3 steps) as a yellow foam: MS (ESI+) for C14H17ClN4O3 m/z 325.1 (M+H)+; MS (ESI−) for C14H17ClN4O3 m/z 369.0 (M+HCO2)−; HPLC purity >95 area %.
Reaction SMILES: C([O:3][C:4](=[O:30])[C@H:5]([CH2:20][C:21]1[N:25]=[C:24]([S:26][CH2:27][CH2:28][CH3:29])[NH:23][CH:22]=1)[N:6](CC1C=CC=CC=1Cl)[C:7](=[O:11])[CH2:8][CH2:9][CH3:10])C.[CH2:31](O)[CH3:32].[OH-].[K+].[ClH:36]>O>[Cl:36][C:22]1[CH:21]=[CH:20][CH:5]=[CH:4][C:31]=1[CH2:32][N:25]1[C:21]([CH2:20][C@@H:5]([C:4]([OH:3])=[O:30])[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])=[CH:22][N:23]=[C:24]1[S:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCSc1nc(C[C@@H](C(=O)OCC)N(Cc2ccccc2Cl)C(=O)CCC)c[nH]1
Reactant: Cl
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCSc1ncc(C[C@H](NC(=O)CCC)C(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[(2-chlorophenyl)methyl-2-propylthio-N-butyrylhistidine ethyl ester (0.37 g, 0.819 mmole), ethanol (4 mL), water (4 mL) and potassium hydroxide pellets (0.098 g, 1.75 mmole) was stirred at 25° C. for 1 hours. The reaction was then diluted with water and the pH was adjusted to 4 with 1N aqueous hydrochloric acid solution. The product was extracted into methylene chloride, washed with water, dried and concentrated to an orange solid. Two crystallizations from chloroform provided 0.22 g of 3-[(2-chlorophenyl)methyl]-2-propylthio-N-butyrylhistidine; m.p. 178°-181° C.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([Br:46])[CH:42]=3)[N:37]=2)(=O)=O)=CC=1>C(#N)C>[Br:46][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([CH2:35][CH2:34][N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH3:11])[CH:45]=[CH:44]2
Reactant: C[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3cc(Br)ccc3n2)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled), potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile (190 mL) were combined and heated at 60° C. with agitation for 48 hours. The mixture was allowed to cool to 30° C., and treated with the product from Example 42C (8.00 g, 0.0197 mole). The reaction mixture was heated at −60° C. for 36 hours and then distilled down to ˜1/4 volume, and isopropyl acetate (200 mL) was added. The mixture was washed with 5% NaHCO3 aq. solution (200 mL×2), and 25% brine (200 mL). The upper organic was dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated to dryness. The crude product was purified with a short-path silica gel column eluted with heptane:ethyl acetate:TEA (60:40:1) to give 5.8 g (92% yield) of product as an oil, which solidified on standing; mp 49-50° C. (uncorrected); MS (ESI): 319, 311 (M+H)+; 1H-NMR (CDCl3) δ 7.95 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz), 7.35 (1H, d, J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m), 2.38 (1H, m), 2.25 (1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m), 1.71 (1H, m), 1.42 (1H, m), 1.11 (3H, d, J=6.0 Hz); 13C-NMR (CDCl3) δ 161.3, 146.1, 134.7, 132.3, 130.3, 129.2, 127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0, 22.0, 19.4.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](SC)[N:3]=1.[CH:18]1([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CC(C)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:24])[CH2:26][CH2:27]2)[N:3]=1
Reactant: COc1cc2nc(SC)nc(N)c2cc1OC
Reactant: O=C(C1CCCC1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 4-amino-2-methylmercapto-6,7-dimethoxyquinazoline (0.1 mole) and from 0.1 to 0.15 mole of N-(cyclopentylcarbonyl)piperazine in 150 ml. of isoamyl alcohol is refluxed for a period of 8 to 24 hours. The solvent is evaporated and residual material, treated according to procedure of Example 1(a), provides 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:12]=1[C:13]([N:66]1[CH2:65][CH2:64][N:63]([C:46](=[O:45])[CH2:47][NH:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:53][CH:52]=2)=[O:50])[CH2:68][CH2:67]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2c(F)cccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.8 %

Procedure:
DIPEA (118 mg, 0.16 mL, 0.92 mmol) was added to a stirred solution of 2-fluoro-6-trifluoromethyl-benzoic acid (48 mg, 0.23 mmol) in DMF (2 mL). HOBT (46 mg, 0.35 mmol) and EDCI (100 mg, 0.57 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (75 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 60 mg (50.8% yield) of biphenyl-4-carboxylic acid {2-[4-(2-fluoro-6-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.5%. 1H NMR (CDCl3): δ 7.9 (m, 2H), 7.6 (m, 6H), 7.4 (m, 4H), 4.3 (m, 2H), 3.8 (m, 3H), 3.8 (m, 3H), 3.6-(m, 2H), 3.5 (m, 1H) 3.3 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5](Cl)=[O:6].[CH2:10]([OH:12])[CH3:11]>S(=O)(=O)(O)O>[F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:12][CH2:10][CH3:11])=[O:6]
Reactant: CCO
Reactant: CC1(C(=O)Cl)CC1(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)F
Yield: 87 %

Procedure:
35 ml of ethanol are added dr.COPYRGT.pwise at 20° C. to 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropanecarbonyl chloride, with stirring. After the addition of 2 drops of concentrated sulphuric acid, the reaction mixture is refluxed for another hour. Excess ethanol is subsequently distilled off, and the residue is dried and distilled under atmospheric pressure. In this manner, 14.2 g (87% of theory) of ethyl 2,2-difluoro-1-methyl-cyclopropane-carboxylate are obtained in form of a liquid of boiling point 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:31]([O-:34])([O-])=O.[K+].[K+].O.[NH2:38][C@H:39]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42]>C1COCC1.CCOC(C)=O>[CH2:48]([O:47][CH2:46][C@@H:39]([NH:38][C:31]([NH:16][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:34])[C@@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: N[C@H](COCc1ccccc1)[C@@H](O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(N[C@H](COCc1ccccc1)[C@@H](O)C(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (61.2 mg, 0.14 mmol), prepared as described in Procedures 3, 5, 6 and 7, in THF (1 mL), K2CO3 in H2O (28 mg, 2 M in H2O, 0.21 mmol) was added, followed by the addition of isopropenyl chlororoformate (16 μL, 0.15 mmol). The reaction mixture was stirred at room temperature for 2 hr, diluted with EtOAc (25 mL), and the organic portion washed with saturated NaCl (25 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was combined with (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol (22 mg, 0.09 mmol), TEA (38 uL, 0.27 mmol) in THF (1.0 mL) and the reaction mixture was heated at 50° C. for 18 h. The solvent was removed and the residue purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 30 min) to give 1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea as a clear oil at a retention time of 23-25 min (36.8 mg, 57% yield) LCMS: RT=2.13 min [M+H] 718.32 (LCMS Method 2); HPLC: RT=4.33 min, Purity 92% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 8.25 ppm, 1 H, d, J=2.20 Hz; 7.66 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.35 ppm, 6 H, m; 7.13 ppm, 5 H, m; 7.06 ppm, 2 H, t, J=7.47 Hz; 6.88 ppm, 1 H, d, J=8.79 Hz; 6.58 ppm, 2 H, t, J=7.03 Hz; 5.87 ppm, 1 H, tt, J=52.95, 2.64 Hz; 5.23 ppm, 1 H, d, J=8.35 Hz; 4.52 ppm, 3 H, m; 4.36 ppm, 1 H, d, J=12.74 Hz; 4.24 ppm, 1 H, dd, J=8.13, 3.30 Hz; 4.04 ppm, 1 H, m; 3.93 ppm, 1 H, dd, J=9.89, 3.74 Hz; 3.75 ppm, 1 H, dd, J=10.11, 2.20 Hz; 3.53 ppm, 1 H, d, J=12.74 Hz.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH:30]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:5]3[CH2:4][C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[C:6]3=[O:11])=[CH:17][CH:18]=2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1NCc2c(F)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
At 0° C., 280 mg (1.85 mmol) of 4-fluoro-2,3-dihydro-1H-isoindol-1-one were added to a suspension of 96.3 mg (2.41 mmol, 60% pure) of sodium hydride in 1 ml of DMF. The mixture was stirred for 30 min, and 654.5 mg (1.85 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were then added at 0° C. Stirring was continued for a further 2 h, and water and ethyl acetate were then added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 5:1). This gave 394 mg (50.2% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][C:5]([NH2:6])=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1.Cl.[C:26](=N)(OC)[CH3:27].O>CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:8]1[C:2]([Cl:1])=[CH:3][C:4]2[N:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:26]([CH3:27])=[N:6][C:5]=2[CH:7]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Reactant: COC(C)=N
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)c(Cl)cc2n1C1CCOCC1
Yield: 40.8 %

Procedure:
To a solution of 2-(4-chloro-2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 112-3) (0.04 g, 0.2 mmol) in methanol (1.2 mL) was added methyl acetimidate hydrochloride (0.06 g, 0.6 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.03 g, 79% yield) as a yellowish-brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]#[N:9].[S:10](Cl)(=[O:13])(=O)[NH2:11].[OH-:15].[Na+].Cl>CC(N(C)C)=O.O>[CH3:7][C:5]1[S:4][C:3]2[C:8]([NH2:9])=[N:11][S:10](=[O:13])(=[O:15])[NH:1][C:2]=2[CH:6]=1
Reactant: [OH-]
Reactant: Cc1cc(N)c(C#N)s1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc2c(s1)C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A solution of 3-amino-5-methylthiophene-2-carbonitrile (250 mg, 1.0 eq., 1.81 mmol) and sulfamoyl chloride (2.71 mmol, 1.5 eq., 314 mg) in DMA (5 mL) was stirred at room temperature overnight. Water (30 mL) and NaOH (1.5 eq., 10 N, 2.71 mmol, 271 μL) were added and the mixture was frozen in a dry ice/acetone bath and the volatiles were removed on the lyophilizer. The resulting solid was washed with water and then suspended in EtOH (25 mL, 200 proof). To this suspension was added NaOH (1 N, 2.5 eq., 4.52 mmol, 4.52 mL) and the mixture heated to reflux for 45 minutes. The reaction mixture was cooled to room temperature and quenched with HCl (1 N, 2.5 eq., 4.52 mmol, 4.52 mL). The pH was adjusted to ˜1-2 with 1 N HCl and the volatiles removed on a rotary evaporator. The resulting solid was suspended in water (10 mL), stirred, filtered off, and washed with water. The crude product was dried in a vacuum oven to give 6-methyl-1H-thieno[3,2-c][1,2,6]thiadiazin-4-amine-2,2-dioxide (257 mg) as an off-white powder 1H NMR (400 MHz, DMSO-d6) δ 2.46 (d, J=0.8 Hz, 3H), 6.53 (q, J=0.8 Hz, 1H), 7.75 (br. s, 2H), 11.34 (s, 1H). 1H NMR (400 MHz, CD3OD) δ 2.52 (d, J=0.8 Hz, 3H), 6.55 (q, J=0.8 Hz, 1H). MS 218 (MH+).
Reaction SMILES: CC([N:5]([C:9]([CH3:33])([CH3:32])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:21]3[CH:22]4[CH2:30][C:23]4([CH3:31])[CH2:24][O:25][C:26]=3[CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:33][C:9]([C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:21]3[CH:22]4[CH2:30][C:23]4([CH3:31])[CH2:24][O:25][C:26]=3[CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)=[O:11])([CH3:32])[NH2:5]
Reactant: CC12COc3cccc(Oc4ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn4)c3C1C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2CC2(C)CO3)nc1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl[1,1-dimethyl-2-({6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}amino)-2-oxoethyl]carbamate (Intermediate 128, 135 mg, 0.298 mmol) in dry dichloromethane (10 ml) at 0° C. TFA (5 ml, 64.9 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The solvent and the excess of TFA were evaporated and the residue was dissolved in dichloromethane and a saturated solution of NaHCO3 was slowly added while the pH was allowed to reach 8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated affording the title compound as a colourless oil used as it was without any further purification (105 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:14][C:13]2[C:8]1=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)(=O)=O.[CH3:19][O:20][C:21]1[C:37]([O:38][CH3:39])=[CH:36][C:24]2[CH2:25][C:26](=[O:35])[N:27]([CH2:30][CH2:31][CH2:32][NH:33][CH3:34])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[CH3:34][N:33]([CH2:6][C@@H:7]1[C:8]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH2:14]1)[CH2:32][CH2:31][CH2:30][N:27]1[C:26](=[O:35])[CH2:25][C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[C:37]([O:38][CH3:39])[CH:36]=2)[CH2:29][CH2:28]1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: COc1cc2c(cc1OC)[C@@H](COS(C)(=O)=O)C2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Procedure:
By proceeding as in Example 5, starting from (7S)-(iodomethyl)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene (or from (7S)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl methanesulphonate) and from 7,8-dimethoxy-3-[3-(methylamino)-propyl]-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, there is obtained ivabradine base, which is then converted into its hydrochloride by following the procedure described in patent specification EP 0 534 859 (Example 2, Step E).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(O)(=O)C>CO.O>[C:11]1([C:10]2[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[NH:1][CH2:22][CH2:21][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Reactant: C=Cc1ccncc1
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCCc2ccncc2)c1-c1ccccc1

Procedure:
A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g), 4-vinylpyridine (1.0 ml) and acetic acid (0.5 ml) in methanol (7.5 ml) is refluxed for 5-6 hours. After cooling, the resulting solution is diluted with water (16 ml) to precipitate crude 4-phenyl-3-(4-pyridylethylamino)-5-sulfamylbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, the acid is obtained with a melting point of 216.5°-217.5° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[C:12]([OH:21])[C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]>>[C:12]([OH:21])(=[O:11])[C:13]([CH2:15][C@@H:17]([CH2:19][OH:20])[OH:18])=[O:14].[O:11]=[C:12]([O-:21])[C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14].[O:1]=[C:2]([OH:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(O)C(=O)C[C@H](O)CO
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Exemplary metabolites include D-xylose, D-xylonic acid, 3-deoxy-D-glycero-pentulosonic acid, 3,4-dihydroxy-D-butanal, 1,2,4-D-butanetriol, 4-hydroxy-D-butanal, and 1,4-butanediol. For example, as shown in FIG. 1, a recombinant microorganism can be metabolically engineered to provide elevated expression or heterologous expression of enzymes useful in the production of 1,4-butanediol. For example, xylose is converted to xylonic acid by a xylose dehydrogenase. 3-Deoxy-D-glycero-pentulosonic acid is produced by xylonate dehydratase from xylonic acid. 3-Deoxy-D-glycero-pentulosonoic acid is further converted by a decarboxylase to 3,4-dihydroxy-D-butanal. 3,4-Dihydroxy-D-butanal is then reduced to 1,2,4-D-butanetriol by a dehydrogenase. 1,2,4-D-butanetriol is further dehydrated into 4-hydroxy-D-butanal by a dehydratase. 4-hydroxy-D-butanal was then reduced to 1,4-butanediol by a dehydrogenase.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Product: N#Cc1ccc2[nH]cc(CCCCCl)c2c1

Procedure:
According to U.S. Pat. No. 5,418,237 (hereinafter referred to as the '237 patent) & the Research Article ‘Drugs of the Future 2001, 26(3), 247’, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting 5-cyanoindole with 4-chlorobutyryl chloride to give 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which then reduced with diborane to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.