Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:17]1(C)C=CC=C[CH:18]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=C3C4C(=CC=CC=4)C(C4C=CC=CC=4)=C3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.CCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccccc1
Reactant: C=CCCCCCCCC
Reactant: CCCCCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=C2C=C(c3ccccc3)c3ccccc32)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCCCC
Product: CCCCCCCCC=CCCCCCCCC
Temperature: 25 °C

Procedure:
1-Decene (5.00 mL, 26.4 mmol) and hexane (10 mL) were heated to reflux on a heating block kept at 75° C. Then a toluene (2 mL) solution of Neolyst M2 (0.0836 g, 0.0880 mmol) was added. Gas evolution was observed. After 18 hours the mixture was cooled to ambient temperature, and pentane (18 mL) was added. The mixture was passed through a plug of neutral alumina. The volatiles were then removed under reduced pressure to afford a colorless oil of 9-octadecene. Yield: 3.12 g. Proton NMR data shows greater than 95% conversion to homocoupled product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](Cl)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl

Procedure:
In step g of Scheme 1,3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) is acylated with acetylating agents such as acetyl chloride or acetic anhydride, preferably acetic anhydride (Ac2O) to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c). The acylation is conducted in the presence of a base, preferably an inorganic base, such as, sodium bicarbonate (NaHCO3), and preferably, a polar solvent, such as ethyl acetate and/or tetrahydrofuran. This reaction may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C(O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]2[OH:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O
Temperature: 140 °C
Yield: 68.9 %

Procedure:
A mixture of 66.6 g (0.6 mole) of 4-fluoroaniline and 129.79 g (0.6 mole) of diethyl ethoxymethylenemalonate was prepared under a nitrogen atmosphere and heated to 140° C. The ethanol generated was allowed to vaporize during a reaction time of about one hour. To the mixture was added 500 ml of diphenyl ether. The mixture was stirred and heated to its reflux temperature, and maintained at reflux for 15 minutes. The mixture was then cooled, and diethyl ether was added. The product was separated by filtration, washed with diethyl ether and air dried to provide 97.3 g (69% yield) of ethyl 6-fluor-4-hydroxyquinoline-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O.[C:22](O)(=O)[CH3:23]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:3]3[CH2:4][CH2:5][NH:8][CH2:22][CH:23]=3)=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc2c(c1)c(C1=CCNCC1)cn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide (3) (12.3 g) in a mixture of acetic acid (60 mL) and trifluoroacetic acid (15 rnL) was added during 0.5 h to a refluxing solution of 4-piperidon, HCl, H2O (36.6 g) in a mixture of acetic acid (50 mL) and trifluoroacetic acid (100 mL). The reaction mixture was refluxed for 1h, cooled to room temperature and the solvents were removed in vacuo. Water was added and pH was adjusted to 10 by addition of aqueous NaOH. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over MgSO4. Evaporation of the solvents in vacuo afforded the title compound as a foam.Yield 16 g. 1H-NMR (DMSO) 2.48 (s, broad, 2H), 2.80 (d. 3H), 2.98 (t, 2H), 3.50 (d, 2H), 6.40(s, 1H) 7.45 (t, 2H), 7.50 (d, 1H), 7.65 (dd, 2H), 7.70-7.80 (m, 2H), 8.40 (s, 1H), 8.45 (q, broad, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10](Br)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[CH2:22].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:15]1([C:9]2[C:8]3[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:11][C:10]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:21]=[CH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 110 °C
Yield: 83 %

Procedure:
2-bromo-3-cyclohexyl indole-6-carboxylic acid methyl ester (1 eq., prepared as described in WO 2004/087714) was mixed with 2-vinyl benzene boronic acid (1.6 eq.) and bis(triphenylphosphine)palladium dichloride (0.15 eq.) was added. The mixture was degassed and dioxane and 2M aqueous sodium carbonate solution (5 eq.) were added. The mixture was heated under nitrogen atmosphere to 110° C. After 2 h all volatiles were removed in vacuo and the residual material was subjected to flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvent the product was obtained as yellow crystals (83%). MS (ES+): 360.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([CH3:21])=[C:18]([C:22](O)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.CC[N:28]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH:47]1[CH2:51][CH2:50][N:49]=[C:48]1[C:52]1[CH:57]=[CH:56][C:55]([CH:58](N)[CH3:59])=[CH:54][CH:53]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:47]1[CH2:51][CH2:50][N:49]=[C:48]1[C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH:28][C:22]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])[CH3:14])[O:20][C:19]=2[CH3:21])=[O:23])=[CH:54][CH:53]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)c(C)o2)c(C)c1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(N)c1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=NCCN4)cc3)c(C)o2)c(C)c1
Reaction time: 48 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-2-methylfuran-3-carboxylic acid (100 mg, 0.28 mmol) was dissolved in DMF (2 mL) and EDCI (65 mg, 0.34 mmol) and HOAt (46 mg, 0.34 mmol) were added. 1 mL of this solution was added to a flask containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine.HCl (27 mg, 0.13 mmol) and DIPEA (0.024 mL, 0.14 mmol) in DMF (2 mL). The reaction was concentrated and diluted with DCM, then washed with saturated aqueous NH4Cl (2×2 mL) and saturated brine (2 mL), and dried over MgSO4. The filtrate was shaken with Ambersep and PL-MIA resins for 48 h, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH:27][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NOCCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1nc(Cl)c(NC=O)c(NOCCCOCc2ccccc2)n1
Yield: 50.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (5.4 g, 23.0 mmol), 3-benzyloxyprop-1-oxyamine (4.14, 23.0 mmol), triethylamine (10 ml) and dioxan (50 ml) was stirred at reflux temperature for 3 hours, cooled, filtered and evaporated to dryness. Column chromatography on silica gel (eluted with chloroform-ethanol, 25:1) gave the title compound (4.38 g, 50%). IR: υmax (KBr) 3248, 1692, 1589, 1570, 1473, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 1.88 (2H, quintet, J=6.3 Hz, CH2CH2CH2) 3.57 (2H, t, J=6.3 Hz, CH2OCH2Ph), 3.95 (2H, t, 6.3 Hz, CH2ONH), 4.47 (2H, s, CH2Ph), 7.32 (5H, m, Ph), 8.14 (1H, s, CHONH), 9.26 (1H, s, CHONH), 9.42 (1H, br.s, D2O exchangeable, NHOCH2), 10.83 (2H, br.s, 2×NHCHO).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cnc(Br)nc1
Product: CCOC(=O)C(=CNc1cnc(Br)nc1)C(=O)OCC
Temperature: 135 °C

Procedure:
A mixture of 2-bromopyrimidin-5-amine (Krchnak, V.; Arnold, Z. Coll. Czech. Chem. Commun. 1975, 40, 1396-1402) (3.48 g) and diethyl ethoxymethylenemalonate (5.05 mL) is heated to 135° C. for 1 h. The mixture is allowed to cool affording a solid.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][C:21](Cl)=[O:22].O>ClCCl>[Br:18][CH2:19][CH2:20][C:21]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22]
Reactant: CC(C)(C)c1ccccc1N
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccccc1NC(=O)CCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-tert-butylaniline (Aldrich, 24.7 g, 166 mmol) was dissolved in dichloromethane (100 mL) and potassium carbonate (47.0 g, 340 mmol) was added. 3-Bromopropionyl chloride (29.1 g, 170 mmol) in dichloromethane (50 mL) was added dropwise and the mixture stirred for 3 hours at ambient temperature. Water was added slowly to quench the mixture, and the organic layer was separated and washed twice with water, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9H), 2.97 (t, J=6.44 Hz, 2H), 3.74 (t, J=6.27 Hz, 2H), 7.00-7.06 (m, 1H), 7.16-7.25 (m, 2H), 7.36-7.42 (m, 1H), 9.35 (s, 1H). MS (DCI) m/z 284.0 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][CH:20]4[CH2:21][O:22][C:24]([CH3:29])([CH3:25])[O:23]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CC(O)CO)cnc21
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CC1(C)OCC(Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 810.9 %

Procedure:
A solution of 3-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-propane-1,2-diol (1.67 g, 5.03 mmol), p-toluene sulfonic acid (96 mg, 0.5 mmol) and 2,2-dimethoxy-propane (3.1 mL, 25.2 mmol) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (1.51 g, 81%) as a white solid: LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.0.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:18][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[O:7])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)NCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
Mono-methyl isophthalate (1 g, 5.55 mmol), amino acetaldehyde dimethyl acetal (569 μL, 5.28 mmol) and EDCI (1.52 g, 7.92 mmol) were dissolved in 55 mL DCM, followed by the addition of DIPEA (1.84 mL, 10.56 mmol). The reaction was allowed to stir at room temperature for 2 hours. It was then taken up in 50 mL of DCM, washed with saturated NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford the crude product (1.48 g) as a clear oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-fluoro phenyl isocyanate (0.036 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 50 as a colorless solid (0.037 g, 32%). LCMS m/z (%)=449 M+H+ (81Br, 58), 447 M+H+ (79 Br, 63), 1H NMR (400 MHz, CDCl3) δ: 7.5 (s, 1H), 7.346 (d, 1.95 Hz, 2H), 7.326 9bs, 1H), 7.151 (d, J=4.77 Hz, 1H), 7.124 (t, 1H), 6.995 (d, J=1.87 Hz, 2H), 6.869 (d, J=5.42 Hz, 1H), 6.847 (d, J=4.71 Hz, 1H), 4.045 (m, 1H), 3.651 (s, 3H), 1.333 (d, J=6.61 Hz, 3H), 1.160 (d, J=6.61 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Al](C)C.C[O:21][C:22]([C@H:24]1[CH2:28][C@H:27]([OH:29])[C@@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[CH2:25]1)=O.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([C@@H:24]1[CH2:25][C@H:26]([NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[C@@H:27]([OH:29])[CH2:28]1)=[O:21]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a stirred suspension of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (296 mg; CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) at r.t. in dioxane (3 ml) under an argon atmosphere was added carefully trimethyl aluminium solution (0.72 ml; 2M in heptane). After stirring for 2 hrs at r.t., a solution of (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentane-carboxylic acid methyl ester (110 mg) in dioxane (3 ml) was added. The mixture was heated to 100° C. and stirring at that temperature was continued for 24 h. The mixture was cooled to r.t. and water (0.8 ml) was added. After 15 min stirring, MgSO4 was added and stirring was continued for another 15 min. The solids were filtered off and washed with dichloromethane. The filtrate was concentrated. The crude product was isolated by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentyl}-amide (81 mg) as light yellow solid. MS: 476.0 ([M+H]+).
Reaction SMILES: BrC1C=CC([C@H]2C3C(=CC=C(OCCCN4CCCCC4)C=3)[C@@H]3CCC(=O)[N:10]3[CH2:9]2)=CC=1.[C:32]1([C@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH2:49][CH2:50][CH2:51][N:52]4[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]4)[CH:46]=3)[C@@H:41]3[CH2:58][CH2:59][C:60](=O)[N:40]3[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[N:52]1([CH2:51][CH2:50][CH2:49][O:48][C:45]2[CH:46]=[C:47]3[C:42](=[CH:43][CH:44]=2)[C@@H:41]2[CH2:58][CH2:59][CH2:60][N:40]2[CH2:39][C@H:38]3[C:32]2[CH:33]=[CH:34][C:35]([C:9]#[N:10])=[CH:36][CH:37]=2)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: O=C1CC[C@H]2c3ccc(OCCCN4CCCCC4)cc3[C@H](c3ccc(Br)cc3)CN12
Reactant: O=C1CC[C@H]2c3ccc(OCCCN4CCCCC4)cc3[C@H](c3ccccc3)CN12
Product: N#Cc1ccc([C@@H]2CN3CCC[C@H]3c3ccc(OCCCN4CCCCC4)cc32)cc1

Procedure:
Cis-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared as described in Example 42, Step 13, on a 1.23 mmol scale to yield 308.1 mg of a mixture of the desired product and cis-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:28]([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])C)C.CO.C1C[O:40][CH2:39][CH2:38]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:39]([C:38]4[CH:31]=[CH:29][N:28]=[C:32]([CH3:33])[CH:34]=4)=[O:40])=[N:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a solution of 0.35 g (0.97 mMol) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 20 ml THF were added 0.365 ml ethyl diisopropyl amine and 0.2 g (1.10 mMol) 4-(2-chloromethyl)-isonicotinic acid chloride, dissolved in 10 ml dichloro methane. The reaction mixture was stirred at room temperature for 72 h. Then 5 ml methanol were added. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate) to yield 0.32 g (69%) of 4-{4-methoxy-2-[(2-methyl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a dark brown solid. ES-MS m/e (%): 481 ([M+H]+, 100).
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>>[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[C@H]1CO1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1Cl

Procedure:
86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=C(C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33]([C:36]1C=C[CH:39]=[C:38](C(C)C)[C:37]=1CC(Cl)=O)(C)[CH3:34].C(Cl)(=O)CCCCCCCCCCC>>[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)(=[O:15])[CH2:13][CH2:5][CH2:4][CH2:2][CH2:1][CH2:34][CH2:33][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Agent: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with dodecanoyl chloride; 1H NMR (DMSO-26):δ 7.09 (s, 3H), 3.65 (heptet, 2H), 2.05 (t, 2H), 1.48--1.15 (m, 18H); 1.10 (d, 6H), 0.86 (t, 3H) ppm.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][C:14]([CH3:17])=[N:15][CH:16]=[C:11]2[C:10]([C:18]#[N:19])=[N:9]1.[Cl-].[NH4+:26].C(O)(=O)C>CO>[F:4][C:5]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][C:14]([CH3:17])=[N:15][CH:16]=[C:11]2[C:10]([C:18](=[NH:26])[NH2:19])=[N:9]1
Reactant: [NH4+]
Reactant: Cc1ncc2c(C#N)nn(Cc3cccc(F)c3F)c2n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 0.73 ml (3.35 mmol) of a 25% sodium methoxide solution was initially charged in methanol, and 1.040 g (purity 92%, 3.35 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile dissolved in 4 ml of absolute methanol were added. The mixture was stirred at RT for 1 h. Subsequently, 215 mg (4.03 mmol) of ammonium chloride and 786 mg (13.08 mmol) of acetic acid were added and the mixture was heated to reflux for 2 h. The reaction mixture was concentrated, and the residue was admixed with 10 ml of ethyl acetate and 15 ml of water and basified (pH=10) with 2N sodium hydroxide solution. The mixture was stirred at RT for 1 h, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate, concentrated and dried under high vacuum. 840 mg (purity 85%, 70% of theory) of the target compound were obtained.