Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].OO.[CH3:5][C:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH:11]=1>CO.O>[CH3:5][C:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][C:11]2=[O:1]
Reactant: CC1=CCCCC1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC12OC1CCCC2=O
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
At room temp., 2N aqueous sodium hydroxide (7.00 mL, 14.0 mmol), followed by 30% aqueous hydrogen peroxide (11.0 mL, 112 mmol) was added to a stirred solution of commercially available 2-methylcyclohex-2-enone (2.20 g, 20.0 mmol) in methanol (250 mL), upon which the resulting red color of the solution faded within 10 min. After stirring at room temp. for 24 h, the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water (200 mL) and dried with sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue purified by chromatography on silica gel [40 g; pentane-Et2O (9:1); Rf=0.29] to furnish 1-methyl-7-oxabicyclo[4.1.0]heptan-2-one (1.18 g, 47%) as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:33]([N:36]=C=O)[CH2:34][CH3:35].C(OC(=O)C)C.C(O)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([NH:36][CH2:33][CH2:34][CH3:35])=[O:32])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCNC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reaction time: 0.5 h

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (example 1, 100 mg, 0.28 mmol) was dissolved in dichloromethane (2 ml) and 1-propyl isocyanate (33.5 mg, 0.39 mmol) was added. The mixture was stirred for 30 min and then the solvent was reduced. After addition of ethylacetate and isopropanol the product precipitated as colourless solid (120 mg, 0.27 mmol, 97%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.O[N:34]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O.N>CN(C)C=O.O>[NH2:34][C:30]([CH:27]1[CH2:26][CH2:25][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:14][CH2:15]3)[S:23][N:22]=2)[CH2:29][CH2:28]1)=[O:32]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylic acid (70.0 mg, 0.153 mmol), 1-hydroxybenzotriazole (23.4 mg, 0.153 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.1 mg, 0.230 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hour. 25% Ammonia water (33.8 mg, 0.497 mmol) was added thereto under ice-cooling, and the resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 52.3 mg (74.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CS(C)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:13][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH3:3]
Reactant: Clc1cnccn1
Reactant: CN(C)CCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cnccn1)c1ccccc1

Procedure:
Following the method of Example 3, reaction of N,N-dimethyl-3-hydroxy-3-phenylpropylamine, sodium hydride and 2-chloropyrazine in DMSO gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][CH:20]2[C:22](Cl)=[O:23])=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:22]([C@@H:20]2[CH2:21][C@H:19]2[C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)=[O:23])[CH:3]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)C1CC1c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccncc3)cc(Cl)n2n1
Yield: 62.1 %

Procedure:
In a 100 mL round-bottomed flask was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 2.74 g, 15.02 mmol) in pyridine (75 ml) to give a yellow solution. Then, at 0° C., 2-(pyridin-4-yl)cyclopropanecarbonyl chloride (7D, 0.19 g, 1.046 mmol) in pyridine (1 ml) was added to give a suspension. After the reaction was complete, saturated NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica using 20% MeOH/CH2Cl2 to provide trans-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(pyridin-4-yl)cyclopropanecarboxamide (7E, 213 mg, 4% for 3 steps) as a yellow solid. 1H NMR (DMSO-d6) δ: 11.43 (s, 1H), 8.46 (d, J=6.1 Hz, 2H), 7.97 (s, 1H), 7.15-7.27 (m, 2H), 6.40 (s, 1H), 2.39-2.46 (m, 4H), 2.28-2.35 (m, 1H), 1.46-1.67 (m, 2H). ESI-MS: m/z 328.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[C:10]1(C#C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(#N)C1C=CC=CC=1>>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccccc1
Reactant: C#Cc1ccc(C)cc1
Solvent: N#Cc1ccccc1
Product: Cc1ccc(C#Cc2ccccc2)cc1
Reaction time: 42 h
Yield: 81 %

Procedure:
The procedure was identical to Example 1, with the exception that 4-ethynyltoluene (0.507 ml; 0.465 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 42 h at 65° C. showed the presence of 1.62 mmol (81% yield) of 1-methyl-4-(phenylethynyl)benzene, and 0.25 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:14]1([CH:2]([CH3:1])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)Cc1c[nH]c2ccccc12
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(Cc1c[nH]c2ccccc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
To a solution of indole-3-acetone (5.0 g, 29 mmol) in anhydrous 1,2-dichloroethane (100 ml) under an atmosphere of nitrogen was added piperidine (2.9 ml, 29 mmol), and glacial acetic acid (1.66 ml, 29 mmol) followed by sodium triacetoxyborohydride (6.8 g, 32 mmol). On complete addition the reaction mixture was stirred at room temperature for 17 hours. The mixture was basified by the addition of a saturated solution of sodium hydrogen carbonate, the layers were separated and the organic layer dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica elution with 5% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title product (3 g, 43%); δH (360 MHz; CDCl3) 0.99 (3H, d, J 6.5 Hz, —CH3), 1.43-1.51 (2H, m, aliphatics), 1.60-1.69 (4H, m, aliphatics), 2.56-2.70 (5H, m, aliphatics+indole CHACHB), 2.87-2.99 (1H, m, indole CHAHBCH (piperidine)), 3.12 (1H, dd, J 13.9 and 3.6 Hz, indole CHACHB), 7.02 (1H, d, J 1.9 Hz, indole H2), 7.09 (1H, m, indole H6), 7.17 (1H, m, indole H5), 7.34 (1H, d, J 8.0 Hz, indole H7), 7.61 (1H, d, J 7.6 Hz, indole H4), 8.01 (1H, bs, indole NH); m/z (ES+) 243 (M++H, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:32])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:27][CH2:28]1)(=[O:44])[CH3:43]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol) was suspended in methylene chloride (5 ml), and diisopropylethylamine (72 μl, 0.41 mmol) and acetyl chloride (29 μl, 0.41 mmol) were added. The mixture was stirred for half an hour at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The solid was suspended in methanol and filtered off to give 7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (117 mg, 71%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:42][C:43](=[O:50])[C:44]1([CH2:49][CH2:48][CH2:47][CH2:46]1)[NH2:45])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:45][C:44]2([C:43]([OH:42])=[O:50])[CH2:46][CH2:47][CH2:48][CH2:49]2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)CCCC1)C1CCCC1
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane at -5° C. 15 mmoles of cycloleucine benzyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystallized from isopropanol and hexane.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.[O-2].[Mn+2]>[CH:2]([C:3]1[CH:4]=[C:5]([CH:9]([S:17][CH2:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (30)-methyl 5-(3-(hydroxymethyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 2) (679 mg) in ethyl acetate (30 mL) was added activated manganese oxide (1.3 g). The suspension was stirred overnight at room temperature. The suspension was filtered on a pad of silica gel and washed with EtOAc. The solvent was evaporated, affording the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[CH:8]1([NH:14][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
Succinic anhydride (2.59 g, 25.9 retool) was dissolved in pyridine (15 ml). Cyclohexylamine was added dropwise to the solution at 0°. Thereafter, the mixture was stirred at room temperature (20°-22°) for 6 h. The pyridine was removed under reduced pressure. The residue was poured into 10% aqueous citric acid. The resulting precipitate was collected, washed thoroughly with 10% aqueous citric acid and then water. The precipitate was dried under vacuum to give the title compound (3.81 g, 74%), mp 168°-170°. The structure of the product was confirmed by NMR.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][C:28]=1OC)C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[CH3:37]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][CH:2]([F:1])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (93%). MS (ESI): m/z=248.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[C:8](#[N:11])[CH2:9]O.CCN(CC)CC>>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([CH2:9][C:8]#[N:11])[CH2:5]1
Reactant: N#CCO
Reactant: COC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC1CN(CC#N)C1
Temperature: 50 °C
Yield: 57.2 %

Procedure:
A solution of 3-methoxyazetidine hydrochloride (275) (MacKenzie et al., PCT Int Appl. WO 9605193, 1996) (3.0 g, 24.4 mmol), aqueous glycolonitrile (55%, 3.4 mL, 34.3 mmol) and Et3N (5.2 mL, 37.3 mmol) was stirred at 20° C. for 3 h, then heated at 50° C. for 1 h. The solution was cooled and partitioned between water (50 mL) and Et2O (50 mL). The organic fraction was washed with water (2×50 mL) and brine (50 mL), dried and the solvent evaporated to give nitrile 276 (1.76 g, 57%) as a colourless oil: 1H NMR δ 4.06 (p, J=5.7 Hz, 1H, CHO), 3.61-3.66 (m, 2H, CH2N), 3.49 (s, 2H, CH2CN), 3.28 (s, 3H, OCH3), 3.22-3.27 (m, 2H, CH2N); MS (APCI) m/z 127 (MH+, 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>>[N:17]([CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Agent: [Na+]
Product: COc1cc(C(=O)CN=[N+]=[N-])cc(OC)c1OC

Procedure:
In a manner similar to Preparation 3 react 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone with NaN3 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(OCC)C>C(Cl)Cl>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: NCCCO
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)NCCCO)c(OC)c1OC
Reaction time: 8 h

Procedure:
2,3,4-Trimethoxybenzene sulfonyl chloride (20.4 g, 0.765 m) in methylene chloride (100 ml) was added dropwise to 3-aminopropanol (17.2 g) in methylene chloride (300 ml). After stirring overnight the reaction was washed with dilute aqueous HCl, dried and stripped to provide a solid. Trituration with diethyl ether provided the product N-(3-hydroxypropyl)-2,3,4-trimethoxy-benzenesulfonamide, m.p. 95°-97° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH:12]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of benzaldehyde (2 g) in EtOH (40 ml) 3 M NaOH solution (3 eq) and 4-chloroacetophenone (2.91 g) were added. The resulting mixture was stirred at rt for 2 h forming a yellow precipitate. The solid was separated by suction filtration and washed with water. The crude was purified by recrystallisation from methanol to give 1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (4.2 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[N:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][N:18]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20]1[CH:19]=[N:18][C:17]([NH2:16])=[N:22][CH:21]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Product: Nc1ncc(-c2cc3c(s2)-c2ccccc2OCC3)cn1

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica and triturating with diethyl ether gave 163. 1H NMR (400 MHz, CDCl3), 3.26 (2H, t, J=5.14), 4.37 (2H, t, J=5.18), 5.16 (2H, Broad s), 7.02-7.09 (3H, m), 7.16-7.22 (1H, m), 7.70 (1H, d, J=7.91), 8.56 (2H, s). MS: (ESI+) 396
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:21])OC2C=CC([N+]([O-])=O)=CC=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:30][C@@H:31]1[C:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[C:39]2[CH:38]=[C:37]([C:45]([NH2:47])=[O:46])[CH:36]=[CH:35][C:34]=2[CH2:33][C@H:32]1[O:48][CH3:49]>CN(C)C=O>[C:1]1([C@H:7]([O:9][C:10](=[O:21])[NH:30][C@@H:31]2[C@@H:32]([O:48][CH3:49])[CH2:33][C:34]3[C:39](=[CH:38][C:37]([C:45](=[O:46])[NH2:47])=[CH:36][CH:35]=3)[C:40]2([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of carbonic acid 4-nitro-phenyl ester (R)-1-phenyl-ethyl ester (102 g, 357 mmol), N,N-dimethylformamide (200 mL) and triethylamine (32.7 mL, 235 mmol) was stirred at room temperature overnight. To the reaction mixture was added trans-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (100 g, 320 mmol), N,N-dimethylformamide (320 mL) and triethylamine (98.0 mL, 703 mmol). The reaction mixture was heated at 85° C. for 5 h and then stirred at room temperature overnight. Approximately 90% of the DMF was removed by distillation at 70° C. and the resulting thick oil was cooled to room temperature and then partitioned between ethyl acetate (1.5 L) and diluted brine (500 mL). The organic layer was washed with 1M NaOH (3×500 mL) and dried with Na2SO4. Most of the solvent was removed by rotary evaporation, 3 volumes ethyl acetate were added and resulting slurry was stirred at room temperature for 30 min, filtered and dried to give the title compound (48 g, >99% chemical and optical purity).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:31][CH:32]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)Cc1ccccc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5ccccc5CS(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(1-methyl-piperidin-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (47.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.016 g, 15%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.97 (d, J=6.6 Hz, 1H), 7.74 (s, 1H), 7.59-7.52 (m, 3H), 7.44-7.37 (m, 2H), 7.23-7.15 (m, 3H), 6.87-6.84 (m, 2H), 6.69 (t, J=7.3 Hz, 1H), 4.45 (s, 2H), 3.01-2.93 (m, 5H), 2.50-2.40 (m, 1H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87-1.74 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[CH2:10]([C@:12]12[CH2:20][CH:19]([OH:21])[C@@H:18]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:17]3[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:31])=[CH:26][C:25](=O)[CH2:24][CH2:23]4)[CH3:11].[OH-].[Na+]>ClCCl.C(O)(=O)C.O>[CH2:10]([C@:12]12[CH2:20][CH:19]([OH:21])[C@@H:18]3[C@@H:22]4[C:27]([CH2:28][CH2:29][C@H:17]3[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:31])=[CH:26][CH2:25][CH2:24][CH2:23]4)[CH3:11]
Reactant: CC[C@]12CC(O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC[C@]12CC(O)[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
A suspension made of sodiumborohydride (152 g) in dichloromethane (0.60 liters) was added to a mixture of trifluoroacetic acid (1.13 liters) in acetic acid (1.13 liters) under stirring at a temperature of 0° C. in about 2 hours. At the end of the addition of the suspension of sodiumborohydride, a solution made of 13-ethyl-11-hydroxy-gon-4en-3,17-dione (201.00 g; 0.66 moles; compound XVIa) in dichloromethane (660 ml) was added to the reaction mixture under stirring at the temperature of 0° C. The reaction mixture was kept under stirring at a temperature of 20° C. for 20′ then it was cooled at the temperature of 0° C. and 4 liters of an aqueous admixture of sodium hydroxide were added (this solution was prepared from 1 liter of water and 3 liters of 30% sodium hydroxide). The reaction was then extracted with dichloromethane (3×2.5 liters), the organic extracts dehydrated on sodium sulfate, filtered and concentrated under vacuum to give 210.20 g of raw 13-ethyl-11-hydroxy-gon-4-en-17-one (compound XIVa). Such a crude may be further purified by silica gel chromatography (1/5 p/p) by eluting under a gradient of polarity, by using an admixture of toluene and ethyl acetate as mobile phase: by eluting with 9/1 toluene/ethyl acetate 144.67 g (0.50 moles; yields 76%) of pure compound XIVa were obtained, with the following analytical characteristics: