Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:58]([O:60][P:61]([O:64][CH2:65][CH2:66]C1C=CC(C(O)=O)=CC=1)([CH3:63])=[O:62])[CH3:59].CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:63][P:61](=[O:62])([O:64][CH2:65][CH3:66])[O:60][CH2:58][CH2:59][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])=[O:10])=[CH:7][CH:8]=1
Reactant: CCOP(C)(=O)OCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CO)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(C)(=O)OCCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1

Procedure:
1,1-dimethylethyl [2-({[4-(hydroxymethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (140 mg, 0.50 mmol), BOP (440 mg, 0.99 mmol), 4-(2-{[ethoxy(methyl)phosphoryl]oxy}ethyl)benzoic acid (90 mg, 0.33 mmol), and DIPEA (0.17 mL, 0.99 mmol) were stirred in DMF (1.1 mL) at 60° C. for 72 hours. The mixture was then diluted with saturated NaHCO3 solution and extracted with EtOAc. The organic layers were then washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude reaction mixture by MPLC (0-10% MeOH/DCM) resulted in the title compound as a yellow foam. MS cal'd 445 (MH+-Boc), exp 445 (MH+-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]=[CH:7]2.CC[N:17](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([NH2:17])=[O:14])=[CH:5][N:6]=[CH:7]2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cncc2cccc(Cl)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cncc2cccc(Cl)c12
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A 100 mL RBF was charged with 5-chloroisoquinolin-4-carboxylic acid (1 equiv) in dry THF (20 mL), DIPEA (3 equiv), EDC.HCl (1.5 equiv), HOBT (1.5 equiv) under inert atmosphere and the mixture was stirred for 15 mins. To this, corresponding amine (1.2 equiv) was added dropwise and the reaction mixture was stirred overnight. After completion, it was diluted with EtOAc and water. The organic layer was then separated, dried and concentrated under reduced pressure to give the crude product that was purified by column chromatography using 100-200 silica gel (80% Ethyl acetate in Hexanes) to furnish the desired amide derivative in 70-84% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[C:16]([CH3:32])[CH:15]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=[CH:5]1.[CH3:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:33][S:34]([CH2:37][C:38]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:30])([F:31])[F:29])[CH:22]=4)=[C:16]([CH3:32])[CH:15]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=[CH:5]1)=[O:39])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1cc(Nc2ncnc3ccn(CCN)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)CS(C)(=O)=O)c23)ccc1Oc1cccc(OC(F)(F)F)c1
Yield: 41.8 %

Procedure:
A solution of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (174 mg), 2-(methylsulfonyl)acetic acid (54 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0.273 mL) in N,N-dimethylformamide (7.69 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (60 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→92:8), and crystallized from diisopropyl ether to give the title compound (92 mg) as colorless crystals.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43](O)=[O:44])=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:46]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:48][CH2:47]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:43](=[O:44])[NH:52][S:49]([CH:46]4[CH2:48][CH2:47]4)(=[O:51])=[O:50])=[CH:24][C:25]=3[N:26]3[CH2:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]4[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C4CC4)cc3n2C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
1,1′-Carbonyldiimidazole (1.82 g, 11.2 mmol) was added to a slurry of 13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (3.85 g, 8.65 mmol) in THF (15 mL). The reaction mixture was heated at 60° C. for 1.5 h, cooled to rt, treated with cyclopropanesulfonamide (1.36 g, 11.2 mmol), stirred 10 min and then treated with the dropwise addition of a solution of DBU (2.0 mL, 13 mmol) in THF (3 mL). The reaction mixture was stirred at rt overnight, diluted with EtOAc (100 mL) and washed with H2O (˜30 mL), 1N HCl (aq.) (2×50 mL) and brine (˜30 mL). The combined aqueous layers were extracted with EtOAc (100 mL) and the organic layer was washed with 1N HCl (aq.) (˜50 mL). The combined organic layers were washed with brine (˜30 mL), dried (MgSO4), filtered and concentrated. The residue was stirred with Et2O (˜100 mL) for 2 h and the solids were collected by filtration, rinsed with Et2O and dried to yield methyl 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (4.24 g, 7.73 mmol, 89%) as a pale yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.08-2.13 (m, 14H), 2.73-2.87 (m, 1H), 3.13-3.24 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 4.04-4.27 (m, 1H), 5.50-5.71 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.8, 2.6 Hz, 1H), 7.44 (dd, J=8.4, 1.1 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.11 (br s, 1H), 8.78 (br s, 1H). LCMS: m/e 549 (M+H)+, ret time 3.79 min, column B, 4 minute gradient.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[CH2:23][CH2:24][C:25]#[N:26]>>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:25]([NH2:26])[C:24]([CH2:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[CH:4]2)[CH3:12]
Reactant: COc1cccc(OC)c1CCC#N
Reactant: CCOc1ccc(N)c(C=O)c1
Product: CCOc1ccc2nc(N)c(Cc3c(OC)cccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-ethoxybenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[O:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[O:16]=[C:14]([N:28]1[CH2:29][CH2:30][CH:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(Oc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-phenoxypiperidine according to the method described in Example 2. Melting Point: 196-199° C. (diethylether)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][Cl:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCOCCCC1CCCCC1
Solvent: c1ccncc1
Product: ClCCOCCCC1CCCCC1
Temperature: 0 °C

Procedure:
110.4 g of 2-(3-cyclohexylpropyloxy)-ethanol, 2 ml of pyridine and 112 ml of thionyl chloride are boiled under reflux for 30 minutes. The reaction mixture is allowed to cool and is then poured onto 500 g of ice. The mixture is extracted with twice 500 ml of methylene chloride. The combined organic phases are washed with water, with sodium hydrogen carbonate solution, with water again and are then concentrated. The residue is distilled. 119.6 g of 2-(3-cyclohexylpropyloxy)-ethyl chloride are obtained [bp 68°-69° C. at 0.01 mm Hg (1.3 Pa)].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][N:31]([S:37]([NH:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1)(=[O:39])=[O:38])[CH2:32]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=2[C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][N:31]([S:37]([NH:40][C:41]2[S:42][CH:43]=[CH:44][N:45]=2)(=[O:39])=[O:38])[CH2:32]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1nccs1)N1CCc2c(Br)cccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1nccs1)C2
Yield: 31.8 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.023 g, 0.032 mmol), 1-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)-1H-pyrazole (Intermediate O, 0.169 g, 0.481 mmol), 5-bromo-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.120 g, 0.321 mmol), and potassium phosphate (0.272 g, 1.282 mmol) in 2.5 mL dioxane, 1.0 mL water was heated to 100° C. 4 hours. The reaction mixture was diluted with EtOAc and washed with 1 N citric acid solution. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.053 g, 0.102 mmol). [M+H]+=519.8 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.88 (dd, J=8.0, 1.4 Hz, 1H), 7.81 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.09-7.17 (m, 3H), 6.98-7.01 (m, 1H), 6.71 (d, J=4.7 Hz, 1H), 6.00 (d, J=2.0 Hz, 1H), 4.31 (d, J=15.7 Hz, 1H), 4.24 (d, J=15.7 Hz, 1H), 3.30-3.38 (m, 1H), 3.12 (m, 1H), 2.63-2.74 (m, 1H), 2.36-2.46 (m, 1H)
Reaction SMILES: [SH:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][C:8]1C=CC(S(O)(=O)=O)=C[CH:13]=1.C(=O)CCC>C(Cl)Cl>[CH2:8]([CH:13]1[S:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5]1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)CCO
Solvent: CCCC=O
Solvent: ClCCl
Product: CCC1OCCC(C)S1
Temperature: 25 °C

Procedure:
A solution of 3-mercapto-1-butanol (106 g, 1 mol, synthesized as above) and PTSA (paratoluenesulfonic acid monohydrate, 38 g, 0.2 mol, commercially available from Sigma-Aldrich, Inc.) in 400 mL of CH2Cl2 (dichloromethane) were cooled with an ice bath. Butyraldehyde (106 mL, 1,2 mol, commercially available from Sigma-Aldrich, Inc.) was added drop wise to the solution, and the reaction mixture was stirred with cooling for half an hour and at room temperature for another 1 hour. The reaction mixture was washed twice with saturated sodium bicarbonate solution and once with brine. The organic phase was then dried with anhydrous magnesium sulfate. The solvent was removed with a rotary evaporator and the crude product was distilled under vacuum to provide 2-ethyl-4-methyl-1,3-oxathiane (98 g), which had a boiling point of 80° C. at a pressure of 10.4 mmHg.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([O-:38])=[O:37]>C(Cl)(Cl)Cl>[C:22]([CH2:21][N:15]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:20][CH2:19][N:18]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([N+:36]([O-:38])=[O:37])=[CH:40][CH:41]=2)[CH2:17][CH2:16]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To a solution of compound (20) (1.85 g, 4.62 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.93 ml, 1.40 g, 13.86 mmol) and 4-nitrobenzylbromide (0.99 g, 4.62 mmol). After stirring the mixture at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified via alumina (basic) column chromatography. Extraction with ethyl acetate/methanol (10:2) gave a solidified clear oily compound (21) (1.98 g, 80% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([CH3:30])[CH3:29])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].[Se](=O)=[O:32]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([CH3:29])[CH3:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC(C)C)c2)c2cc(OC)c(OC)cc12
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OC)cc12
Yield: 65.8 %

Procedure:
The above 1-(3-isopropoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (2.20 g, 5.38 mmol) was dissolved into 100 ml of ethyl acetate. Then selenium dioxide (1.08 g, 9.73 mmol) was added and the mixture was refluxed for 30 minutes. The reaction mixture was filtered through a thin layer of silica gel. The filtrate was concentrated and then purified through a flash column chromatography using hexane and ethyl acetate (2.5/1 ratio) to give 1-(3-isopropoxybenzoyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester as a solid (1.50 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[S:10][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)(Cl)Cl>[F:25][C:20]1[CH:19]=[C:18]([NH2:17])[CH:23]=[CH:22][C:21]=1[O:24][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[S:10][C:3]=12
Reactant: Nc1ccc(O)c(F)c1
Reactant: Cc1noc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
A 15 mL sealed tube was charged with 7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine (0.113 g, 0.449 mmol), 4-amino-2-fluorophenol (0.071 g, 0.56 mmol), cesium carbonate (0.512 g, 1.57 mmol), and DMF (2.00 ml) and sealed. The reaction mixture was stirred at 90° C. for 18 hours, allowed to cool to room temperature, then diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield a black solid. The product was purified by silica gel chromatography eluting with 3% methanol in methylene chloride to yield 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (0.074 g, 48% yield) as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)sc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2ccccc12
Temperature: 60 °C
Yield: 60.2 %

Procedure:
A mixture of ethyl 2-[bis-(benzenesulphonyl)amino]benzo[b]thiophene-3-carboxylate (Intermediate 4, 0.173 g) and lithium hydroxide mono hydrate (0.043 g) in dioxane (6 ml) and water (3 ml) was stirred and heated at 60° C. for 2.5 hours. After cooling, the mixture was diluted with water and acidified by addition of hydrochloric acid (1M). It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane (5-10%) to give ethyl 2-benzenesulphonylaminobenzo[b]thiophene-3-carboxylate (0.075 g) as a white solid.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=O)[O:17]CC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[NH:21]([C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22].O>CN1C(=O)CCC1>[OH:17][C:16]1[N:22]2[N:21]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:2]=[C:1]2[CH:3]=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)[N:15]=1
Reactant: CCOC(=O)C(=O)NN
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(O)n2n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.24 g (8.4 mmol) of ethyl hydrazino(oxo)acetate are dissolved in NMP (16 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and poured into water (100 ml), and the precipitate is filtered off, washed with water and diethyl ether and dried. 1.90 g (64% of theory) of the crude product are obtained.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:27].O1CCOCC1>C1COCC1>[ClH:27].[ClH:27].[NH2:8][C@@H:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.4 %

Procedure:
(S)—((R)-quinuclidin-3-yl) 2-(tert-butoxycarbonylamino)-2-phenylacetate (0.618 g, 1.715 mmol) was dissolved in THF (6 ml). HCl/dioxane 4M (3 ml, 1.715 mmol) was added, and the reaction was stirred at RT for 30 minutes. The precipitate was filtered, washed with Et2O (10 ml) and dried at RT to give (S)—((R)-quinuclidin-3-yl) 2-amino-2-phenylacetate dihydrochloride (550 mg, 1.65 mmol).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:31])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+]>CO>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:31])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
324 mg of 11β-fluoro-3-hydroxy-7α-(5-pyrrolidin-1-yl-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 10 ml of methanol and mixed with 63 mg of sodium borohydride. After 1.5 hours of stirring at room temperature, the batch is added to semi-saturated common salt solution, extracted 3 times with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a methylene chloride-methanol gradient, 192 mg of 11β-fluoro-7α-(5-pyrrolidin-1-yl)-pentyl)-estra-1,3,5(10)-triene-3,17β-diol with a melting point of 95-118° C. is obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][P:26](=[O:43])([O:35]CC3C=CC=CC=3)[O:27]CC3C=CC=CC=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][P:26](=[O:27])([OH:35])[OH:43])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Solvent: CO
Solvent: O
Product: O=P(O)(O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 1.20 g, (1.73 mmol) phosphoric acid dibenzyl ester (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 40 ml MeOH and 6 ml water was hydrogenated at room temperature (20 bar, 5 h). The reaction mixture was concentrated to 20 ml and 500 ml water were added. The reaction mixture was filtered and the catalyst was washed with water. The filtrate was concentrated under reduced pressure until the product precipitates. The mixture was then cooled to 0° C. and 200 ml MeOH were added dropwise. After two hours the solid was filtered, washed with cold MeOH and dried at 60° C. under high vacuum to give 380 mg (0.83 mmol, 48%) of phosphoric acid mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl} ester as colorless crystalls.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16](=[N:18][OH:19])[NH2:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[C:20](O)(=O)[CH3:21]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16]3[N:17]=[C:20]([CH3:21])[O:19][N:18]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2ccc(C(N)=NO)cc2s1
Reactant: CC(=O)O
Product: CCNC(=O)Nc1nc2ccc(-c3noc(C)n3)cc2s1
Temperature: 110 °C

Procedure:
About 50 mg of 2-[(ethylamino)Carbonyl]amino-1,3-benzothiazole-6-carboxamideoxime was charged into about 1 mL of glacial acetic acid. The mixture was heated to about 110° C. then stirred at this temperature for about 12–20 hours. The solution was cooled to room temperature and the solvent was removed under reduced pressure. The residue was then further purified by preparative HPLC. 1H NMR 1.10 (t, 3H), 2.67 (s, 3H), 3.17 (m, 2H), 6.74 (s, 1H), 7.73 (d, 1H), 7.97 (d, 1H), 8.53 (s, 1H), 10.9 (s, 1H); LC/MS 2.69 min, 304 (M+1), 302 (M−1).