Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+:2].CC([OH:6])C.[CH:7]1[N:11]=[CH:10][N:9]([CH2:12][C:13]([P:19]([OH:22])([OH:21])=[O:20])([P:15]([OH:18])([OH:17])=[O:16])[OH:14])[CH:8]=1>O>[CH:7]1[N:11]=[CH:10][N:9]([CH2:12][C:13]([P:15]([O-:18])([OH:17])=[O:16])([P:19]([O-:21])([OH:22])=[O:20])[OH:14])[CH:8]=1.[OH2:6].[OH2:1].[OH2:6].[OH2:6].[Na+:2].[Na+:2]
Reactant: CC(C)O
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (X % v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (13-15 ml) was added drop-wise to a suspension of Zoledronic acid (4.98 g) in a mixture of water (X % v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (70-85 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystal form V.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12]Br)[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:5])[CH3:2].[CH3:28][CH:29]([SH:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C(OCC)(=O)C.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][S:31][CH:29]([CH3:30])[CH3:28])[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CC(C)S
Reactant: CCOC(=O)c1nc(CBr)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(CSC(C)C)c2nc(C(C)(C)C)sc2c1OC(=O)C(C)(C)C

Procedure:
A suspension of the crude 4-bromomethyl-2-tert-butyl-7-(2,2-dimethyl-propionyloxy)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (above), 2-propanethiol (75 μL, 0.8 mmol), and cesium carbonate (130 mg, 0.4 mmol) in 0.8 mL of a 1:1 mixture of THF:ethanol was stirred for 22 h. The resultant reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure to 160 mg of the title compound. MS (ESI+): m/z 452.95 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:34][N:35]([CH3:42])[CH2:36]/[CH:37]=[CH:38]/[C:39]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)=[O:40].[ClH:1]
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL, 0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (94) as an HCl salt (29 mg). MS found for C28H38N8O4 as (M+H)+ 551.3, (M−H)− 549.3. UV: λ=274, 281, 313, 344, 369 nm.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)N=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:30]O.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35]Cl>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:30][C:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH2:35][C:34]([N:33]([CH3:38])[CH3:32])=[O:37])[CH2:28][CH2:29]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:3])[CH3:4]
Reactant: CO
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCNCC3)cc1OCC2
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
Alternatively, a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene hydrochloride (66 mg, 0.12 mmol), in DCM (1 mL), methanol (1 mL) and TEA (0.07 mL) was treated with N,N-dimethyl-2-chloroacetamide (17 mg, 0.14 mmol) and TBAI (5 mg) and then stirred at RT for 48 h then 30° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The aqueous layer was extracted three times with DCM the 10% methanol in DCM, the combined organic extracts dried using a phase separation cartridge before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 278 as a white solid (34 mg, 61%). LCMS: RT=2.26 min, [M+H]+ 465. 1H NMR 400 MHz (DMSO-d6) δ: 9.43 (1H, s), 7.96 (1H, s), 7.92 (1H, s), 6.91 (1H, s), 5.91-5.90 (1H, m), 4.60-4.58 (4H, m), 3.15 (2H, s), 3.06 (3H, s), 2.93 (2H, d, J=11.06 Hz), 2.82 (3H, s), 2.63 (1H, m), 2.15-2.14 (2H, m), 1.82-1.69 (4H, m), 1.50 (6H, d, J=6.60 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].ClC(Cl)C>C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[CH2:6][CH2:7]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2c(c1)NCC2
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(Br)cc32)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
Triacetoxylated sodium borohydride (11.7 g) was added to a mixture of 6- bromoindoline (8.3 g), 1-(t-butoxycarbonyl)-4-piperidone (10 g, [CAS Registry No. 7909-07-3]), acetic acid (14.9 g) and dichloroethane (200 ml) followed by stirring overnight. Then the reaction solution was concentrated under reduced pressure, and the pH value thereof was adjusted to 9 with ethyl acetate, an 8 N aqueous solution of sodium hydroxide and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (10.3 g) (yield: 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([F:16])[CH:3]=1.CCCCCC.C([Li])CCC.[C:28](=[O:30])=[O:29]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[CH2:15])[CH2:12][CH2:13]2)[CH:5]=[C:4]([F:16])[C:3]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: C=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
25 g of 1,3-difluoro-5-(trans-4-vinylcyclohexyl) benzene was dissolved in 100 ml of tetrahydrofuran, and then cooled to a temperature of −70° C. To the solution was then added dropwise 88 ml of a 1.53 mol/l n-hexane solution of n-butyllithium at a rate such that the liquid temperature was kept at −60° C. After 30 minutes of stirring, carbon dioxide was then introduced into the system at a rate such that the liquid temperature was kept at −60° C. When heat generation was terminated, the temperature of the reaction solution was returned to room temperature. To the reaction solution was then added 50 ml of a 10% hydrochloric acid. The reaction solution was then extracted with 250 ml of ethyl acetate. The resulting organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvents were then distilled off to obtain 28.9 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzoic acid.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([NH2:36])[CH2:34][CH3:35])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([NH:36][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)[CH2:34][CH3:35])=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(C(N)CC)cc1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(CC)Nc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
Triethylamine (0.33 g, 3.26 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.40 g, 1.86 mmol) in toluene (10 ml). The mixture was stirred at room temperature. Then, 1-(4-butoxyphenyl)-1-propylamine (0.46 g, 2.22 mmol) was added. After stirring at 80° C. for 3 hours, water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give The desired ethyl 4-(1-(4-butoxyphenyl)-1-propylamino)-6-ethylpyrimidine-5-carboxylate (0.32 g, 44%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]2)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:6].[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1>O1CCOCC1>[N:32]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])[CH:36]=[N:35][CH:34]=[N:33]1
Reactant: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Reactant: c1nc[nH]n1
Solvent: C1COCCO1
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCn3cncn3)ccc2[nH]1
Yield: 30.5 %

Procedure:
1.0 g of 6-{4-[N-(3-chloropropylsulfonyl)-N-benzylamino]butoxy}carbostyril and 600 mg of 1,2,4-triazole were stirred at 140° C. for 3 hours. The reaction mixture was diluted with dioxane. The resulting crystals were collected by filtration and purified by a column chromatography (eluant: 3% methanol/chloroform). The purified crystals were recrystallized from ethyl acetate to obtain 327 mg of 6-[4-{N-[3-(1,2,4-triazol-1-yl)propylsulfonyl]-N-benzylamino}butoxy]-carbostyril.
Reaction SMILES: O[N:2]=[C:3]([NH2:5])[CH3:4].[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8]>CO>[CH3:4][C:3]1[NH:5][C:7]([C:6]([O:10][CH3:11])=[O:9])=[CH:8][N:2]=1
Reactant: C#CC(=O)OC
Reactant: CC(N)=NO
Solvent: CO
Product: COC(=O)c1cnc(C)[nH]1
Temperature: 25 °C

Procedure:
A solution of N′-hydroxyethanimidamide (65 g, 880 mmol) in anhydrous methanol (2 L) was treated with methyl propiolate (100 g, 1.19 mol), and the reaction was heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with diphenyl ether (1 L) and heated at reflux for 4 hours. The hot solution was filtered, and the filtrate was cooled to room temperature and diluted with hexanes (2 L). The resulting solid was washed with diethyl ether (1 L), to afford the product as a brown solid. Yield: 60 g, 430 mmol, 49%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 4.0 g. (0.0125 mole) of ethyl 5-(p-chlorobenzoyl)-1,4 -dimethylpyrrole-2-acetate in 26 ml. of 0.5 N sodium hydroxide (0.013 mole) is heated under reflux for 30 minutes. The resulting solutions is acidified with dilute hydrochloric acid, and the precipitated solid is collected by filtration, air dried and recrystallized from 2-propanol to give 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid as a white crystalline solid, m.p. 178-179° C. Anal. Calcd. for C15H14ClNO3 : C, 61.76; H, 4.83; N, 4.82%. Found: C, 61.68; H, 4.96; N, 4.89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24](=[O:38])[CH2:25][C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])=[CH:29][CH:30]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:38])[CH2:25][C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:19]([C:14]2[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: COc1cc(-c2ccccc2C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)Cc1ccc(-c2ccccc2N)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(-c2ccccc2NC(=O)c2ccccc2-c2cc(OC)c(OC)c(OC)c2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Add a solution of 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (57) (0.18 mmol) in DCM (11.0 mL) to an ice cooled solution of [5-(2-Amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester (36) (46 mg, 0.18 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (0.5 mL). Stir the reaction mixture for 1 h at 0° C. and additional 20 h at rt. Pour the reaction mixture into ice cooled 1 M aqu. HCl, extract with EtOAc (2×) and DCM (2×), wash the combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+2) to obtain (5-{2-[(3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl)-amino]-phenyl}-thiophen-2-yl)-acetic acid methyl ester (58) as a light brown solid (58 mg, 59%). 1H NMR (400 MHz, CDCl3): 3.70 (s, 3H); 3.76 (s, 6H); 3.78 (s, 2H); 3.80 (s, 3H); 6.29 (d, 1H, J=3.4 Hz); 6.60 (s, 2H); 6.75 (d, 1H, J=3.4 Hz); 7.07 (t, 1H, J=7.6 Hz); 7.23 (d, 1H, J=7.6 Hz); 7.31 (t, 1H, J=8.0 Hz); 7.37-7.43 (m, 2H); 7.48 (t, 1H, J=7.6 Hz); 7.52 (s, 1H); 7.69 (d, 1H, J=8.0 Hz); 8.45 (d, 1H, J=8.0 Hz).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCC(=O)CC(=O)OC
Agent: [Ru]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@@H](O)CC(=O)OC
Yield: 95 %

Procedure:
Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of the methyl 3-oxooctadecanoate obtained above and 50 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 12 hours, it was taken out of the autoclave. The reaction product was recrystallized from methanol to obtain 47.8 g of methyl (R)-3-hydroxyoctadecanoate. Yield, 95%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=O)=[CH:19][CH:18]=1.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:25]([CH:26]=[CH:1][C:2]([C:4]3[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=3)=[O:3])=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1cccnc1Nc1ccc(Cl)cc1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)C=Cc2cccnc2Nc2ccc(Cl)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of 3,4,5-trimethoxyacetophenone (135 mg, 0.06465 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 mL) and stirred for 5 minutes. Then added 2-(4-chlorophenylamino)nicotinaldehyde (150 mg, 0.0.6465 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6ax) (232 mg, 85% yield).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH2:13]O)=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.S(Cl)(C)(=O)=O.C(N(CC)CC)C.CCN(C(C)C)C(C)C.[C:36]1([C:42]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:6]1[N:5]=[C:4]2[CH2:13][N:43]([C:42]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C(F)(F)F)nc1CO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 7 mmol (3-hydroxymethyl-6-trifluoromethyl-pyridin-2-yl)-methanol in 20 ml dichloromethane was cooled to 0° C. 0.15 mmol 4-(N,N-dimethylamino)-pyridine and 15 mmol of mesyl chloride was added, followed by careful addition of 28 mmol triethyl amine. After stirring for 1 hour at 0° C., the reaction mixture was extracted with dichloromethane, dried and concentrated. The crude mesylate was dissolved in 10 ml N,N-dimethyl formamide, treated with 21 mmol DIPEA and 9 mmol triphenyl methylamine and hold overnight at 60° C. The resulting mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The crude compound was purified by chromatography (SiO2; ethyl acetate/n-heptane 1:4) to give the title compound as a viscous yellow oil. Yield: 37%.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.O1CCCC1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>O>[OH:17][C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH2:5][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)=[C:2]1[CH3:1]
Reactant: CC1=C(c2cccc3cccnc23)CCC1=O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(c2cccc3cccnc23)CCC1(O)c1ccccc1
Temperature: -90 °C
Yield: 57.9 %

Procedure:
A mixture of 2.4 g (10.75 mmol) of 2-methyl-3-(8-quinolyl)cyclopent-2-enone and 100 ml of tetrahydrofuran was cooled to −90° C., and 7.2 ml of phenyllithium (1.8 M in cyclohexane/diethyl ether, 12.9 mmol) were subsequently added while stirring. The mixture was stirred for a further one hour at this temperature and 1 ml of ethyl acetate was then added. The mixture was then allowed to warm to room temperature while stirring, refluxed for 10 minutes, cooled to room temperature and 100 ml of water were then added. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue was dissolved in 5 ml of toluene and then admixed with 80 ml of hexane. The precipitate formed was filtered off and dried. This gave 1.874 g (6.22 mmol, 57.9% yield) of 3-hydroxy-2-methyl-3-phenyl-1-(8-quinolyl)cyclopentene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][N:12]=[C:11]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:11]([S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[N:12]1
Reactant: Clc1cccc(CBr)c1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
A mixture of 7-(3-chloro-propoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.75 mmoles), 3-chloro-benzylbromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 10 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.87 g, 1.66 mmoles).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[F:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10].N1CCCCC1>CCO>[F:7][C:8]1[C:12]([CH3:13])=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][C:9]=1[CH3:10]
Reactant: CC(=O)C(F)C(C)=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c(C)c1F
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a stirred solution of 2-cyanoacetamide (689 mg, 8.2 mmol) in anhydrous EtOH (7.0 ml) at 75° C., was added 3-fluoropentane-2,4-dione (880 mg, 7.5 mmol), followed by piperidine (96 μl, 0.97 mmol). The reaction mixture was stirred at this temperature for 3 hours and the reaction mixture left to reach room temperature before being stored in the refrigerator for 4 days. The beige solid was collected by filtration and rinsed with cold EtOH (4×0.4 ml) until the filtrate ran clear. The resulting beige solid was dried in-vacuo at 40° C. for 5 hours to give the title compound (733 mg, 58%) as a beige solid. LC-MS 97%, m/z=166.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 13.67 (br. s., 1H) 2.46 (d, J=2.05 Hz, 3H) 2.45 (d, J=2.84 Hz, 3H).