Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]Cl.[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[Si](CC)(CC)CC)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CO.C1COCC1.F[B-](F)(F)F.[Ag+]>[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[I:1])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Reactant: ClI
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1cnc2[nH]c(I)c([C@H](C)COCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of iodine monochloride (2.83 g, 17.4 mmol) in MeOH (25 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred mixture of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (6.00 g, 13.4 mmol) and silver tetrafluoroborate (3.39 g, 17.4 mmol) in MeOH/THF (1:2; 75 mL) at 0° C. After an additional 0.5 h, the reaction was quenched with 1M Na2S2O3, warmed to room temperature and filtered through celite® washing copiously with ethyl acetate. The filtrate was concentrated under reduced pressure, poured into 1M Na2S2O3 and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) to give the title compound as a colourless solid (5.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:12][NH:11][C:10]=1[NH2:13]
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1[nH]nc(-c2cccc(Cl)c2)c1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a stirring solution of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine (1.53 g, 7.9 mmol) in THF (32 mL) was added N-bromosuccinimide (1.55 g, 8.7 mmol). The reaction mixture was stirred for 5 h at room temperature, then absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 1.73 g (80%) of 4-bromo-5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a brown solid. 1H NMR (d6-DMSO) δ: 12.2 and 12.4 (2 broad s, 1H, NH+tautomer), 7.77 (s, 1H), 7.73 (broad s, 1H), 7.48 (broad s, 1H), 7.43 (broad s, 1H), 5.30 (broad s, 1H, NH), 4.82 (broad s, 1H, NH); HPLC/MS m/z: 272 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([O:12]C)=[O:11])[C:3]1=[O:14].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]1=[O:14]
Reactant: COC(=O)c1ccc(SC)n(C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)O)c(=O)n1C
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Methyl 1,2-dihydro-1-methyl-6-methylthio-2-oxopyridine-3-carboxylate (2.1 g, 9.8 mmol) and lithium hydroxide monohydrate (0.50 g, 12 mmol) were dissolved in a mixed solvent of THF (30 mL) and water (2 mL), and stirred for a day at room temperature. The reaction mixture was concentrated under reduced pressure. To thus obtained residue, a mixed solution of aqueous saturated sodium bicarbonate and ethyl acetate was added, and then liquid separation and extraction were subjected. The obtained liquid layer was added with diluted hydrochloric acid to give a pH of 3 to 4, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain 1.6 g of a desired product (yield: 82%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].[Br:11][C:12]1[CH:25]=[CH:24][C:15]([NH:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18])=[CH:14][CH:13]=1>C(O)(=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][S:17]([C:20]2[C:21](=[O:22])[O:10][C:3]3[C:4]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:2]=3[Br:1])(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(Br)c1O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=c1oc2c(Br)cccc2cc1S(=O)(=O)Nc1ccc(Br)cc1

Procedure:
A solution of 3-bromosalicylaldehyde (1 mmol) and 4-bromoanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 206-208° C.
Reaction SMILES: [CH:1](/O)=[CH:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:39]>>[Cl:39][CH2:1]/[CH:2]=[CH:3]\[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC/C=C\C=C/O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCl
Temperature: 23 °C
Reaction time: 9 h
Yield: 92 %

Procedure:
A mixture of (Z,Z)-undecadien-1-ol (3.42 g, 20.4 mmol) and triphenylphosphine (7.5 g, 28.6 mmol) in dry CCl4 (25 ml) was refluxed with stirring for 9 h. The reaction mixture was allowed to cool to 23° C., hexane (60 ml) was added, and stirring was continued for an additional 10 minutes. The precipitate of triphenylphosphine oxide was filtered and washed with hexane. The solvent was removed from the combined filtrate at 40° C./~30 mmHg. Evaporation distillation of the resulting residue at 125°-130° C./0.3 mmHg gave 3.5 g (92%) of (Z,Z)-1-chloro-2,5-undecadiene as a colorless liquid.
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (1.0 g, 2.2 mmol) and 4-hydroxy phenyl boronic acid (0.37 g, 2.7 mmol) in 1,4-dioxane (30 mL) is added K2CO3 (0.91 g, 6.6 mmol). The mixture purged with nitrogen for 10 minutes. Pd(PPh3)2Cl2 (0.14 g, 0.2 mmol) is added and the mixture is heated at 100° C. for 12 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAc (2×10 mL). The filtrate is dried over anhydrous sodium sulphate, filtered, and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash using 24 g redisep column) eluting with 15-20% EtOAc/hexane to give the title compound (0.75 g, 73.52%). LCMS m/z 456.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])/O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(/C(O)=C\c2ccnc(Cl)n2)c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: 60 °C
Yield: 77 %

Procedure:
A tautomeric mixture of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-fluorophenyl)benzamide and 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-N-(2,6-difluorophenyl)benzamide (5.73 g, 14.8 mmol) was dissolved in 150 mL of DCM with stirring. NBS (2.63 g, 14.8 mmol) was added in a single portion, and the reaction was stirred for 15 minutes. The reaction was concentrated in vacuo. Dioxane (100 mL) was added to dissolve the residue with stirring. 2-Aminopyridine (4.18 g, 44.4 mmol) was added, and the reaction was heated to 60° C. for 16 hours. The reaction was cooled to rt and poured into half-saturated NaHCO3 solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The mixture was purified by flash chromatography to afford 5.26 g (77%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.40 (d, J=7.0 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.66-7.54 (m, 2H), 7.89 (m, 1H), 7.27-7.15 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1nn(C)c2c(Cl)ncnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C)c2c(NC3Cc4ccccc4C3)ncnc12
Yield: 62 %

Procedure:
7-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidine (28 mg, 0.15 mmol) (see J. Med. Chem.,31, 454 (1988)), 2-aminoindan (66 mg, 0.50 mmol), and triethylamine (30 μl, 0.2 μmol) in dry methylene chloride (1 ml) were heated to reflux for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:4) to obtain the title compound (26 mg, 0.093 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:24]=12
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(NS(C)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 54 %

Procedure:
A solution of 3-Methanesulfonylaminophenylboronic acid (32 mg, 0.15 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA38 (24.3 mg, 54% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>C(O)C.N1CCCCC1>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14](=[S:15])[NH2:16])#[N:12]
Reactant: N#CCC(N)=S
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(N)=S
Temperature: 0 °C
Yield: 40.9 %

Procedure:
To 0.83 g (6mmol) 3,4-dihydroxybenzaldehyde and 0.7 g (7 mmol) cyanothioacetamide in 30 ml ethanol was added 4 drops of piperidine. The mixture was refluxed for 1 hour, poured into ice water, filtered and dried, giving 0.54 g (41% yield) of an orange solid, m.p. 213° C. Calculated analysis for C10H8N2O2S: C=54.54, H=3.64, N=12.73; found: C=54.44, H=3.87, N=12.91.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:21][NH2:22].O>C1C=CC=CC=1>[C:1]([CH:5]=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=CCOc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C=CCOc1ccc(CC(C)NCC(O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 1-(4-(3-carbomethoxyprop-2-eneoxy) phenyl) propan-2-one (2.27 g) and 2-hydroxy-2-(4-chlorophenyl) ethanamine (1.57 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water using a Dean and Stark trap. The solution was evaporated, the residue dissolved in methanol (50 ml), cooled in ice and sodium borohydride added. The solution was stirred for 1 hour at 0° C., the methanol evaporated, and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was dried (MgSO4) and evaporated to give a cream solid (3.1 g) which was crystallised from ethyl acetate m.p. 120°-122°. as a 0:100 mixture of diastereoisomers. Recrystallisation of the mother liquors from hexane gave a 70:30 mixture of diastereoisomers, m.p. 55°-65°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([CH:18]=O)[CH2:14][CH2:15][CH:16]=O)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]21[CH2:18][N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[CH2:16][CH2:15][CH2:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(C=O)CCC=O
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of [(1R,2S)-2-formyl-2-(3-oxo-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.73 g, 16.7 mmol) and 4-fluorobenzylamine (2.3 g, 18 mmol) in dichloromethane (50 mL) was cooled in an ice bath and treated with sodium triacetoxyborohydride (10.1 g, 48 mmol). The resulting mixture was then stirred at room temperature overnight. The mixture was treated with 1.0 N aqueous sodium hydroxide (25 mL) and stirred at room temperature for 1 hour. The organic phase was removed and washed with water and saturated aqueous sodium chloride. The solvent was removed under vacuum to give a residue. The residue was purified by chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to give an oil (6.3 g). 1H NMR (300 MHz, CDCl3) δ7.31-7.24 (m, 2H), 6.97-6.94 (m, 2H), 4.82 (bm, 1H), 3.62 (m, 1H), 3.37 (bs, 2H), 2.42 (m, 1H), 2.20 (m, 3H), 1.69-1.21 (m, 12H), 1.45 (s, 9H). Mass spec (ES+) m+/z 377.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH3:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[C:15](=O)[CH3:16]>B(F)(F)F.CCOCC.C1C=CC=CC=1>[CH3:16][C:15]1([CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH3:13])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)NC(C)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)NC(C)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of indole-3-ethanol (16.1 g), benzene (1200 ml), N-(1-methyl-2-oxopropyl)-acetamide[12.7 g, described by A. Triebs and W. Sutter, Chem. Ber. 84, 96(1951)] and boron trifluoride-etherate (5 drops) is refluxed using a water separating condenser for 60 minutes. After cooling, the mixture is washed with concentrated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a residue of the title compound as a 1:1 mixture of diastereoisomers:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[CH2:35][NH:34][CH2:33][CH2:32]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:35]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 59.6 %

Procedure:
The procedure of Example 39 is repeated using 2.12 g of 4-[6-Bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene and 2.3 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 1.6 g of the desired product as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]([NH2:27])=[O:26]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)[NH:24][C:25](=[O:26])[N:27]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3ccc(OCC(=O)O)cc3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
(E)-2-(4-[3-(4-Hydroxy-3-methylphenyl)-3-oxoprop-1-enyl]phenoxy)acetic acid (10.0 g, 32.0 mmol) and urea (5.9 g, 0.10 mol) was suspended in 150 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 100 mL of 2-propanol and heated in a 90° C. oil bath for 10 minutes, then let it cooled down to room temperature by itself. The suspension was filtered, washed with 50 mL of 2-propanol and dried in the air. 4.0 g (35%) of yellow powder was obtained. 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.94 (d, 1H), 7.46 (s, 1H), 7.13 (d, 2H), 7.03 (d, 1H), 7.03 (d, 1H), 4.86 (s, 2H), 2.21 (s, 3H). MS (EI): 353 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:12]2[CH:13]=[C:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=4)=[O:19])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.C1COCC1>[Cl:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]3[O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:30])=[O:3])[C:12]=3[CH:13]=1)=[O:19])=[CH:28]2
Reactant: CCOC(=O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN1CCCOc2ccc(NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid ethyl ester (10 mg, 0.023 mmol, 1 eq.) was dissolved in a mixture of 1 mL of MeOH and 1 mL of THF and treated with 1 mL 1N NaOH. The reaction was stirred at room temperature for 3 hrs at which time the solvents were removed by evaporation and the residue acidified with 1N HCl. The precipitate was collected on a filter, dried and purified on preparative TLC in 9:1 CH2Cl2/MeOH to afford 9 mg of the product as a white solid. LC MS: AP+ 400/402,
Reaction SMILES: [C:1]1([C@:7]23[CH2:12][C@H:11]2[CH2:10][O:9][C:8]3=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.C1COCC1>[CH2:18]([N:25]([CH3:26])[C:8]([C@@:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][C@H:11]1[CH2:10][OH:9])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccccc1
Reactant: O=C1OC[C@@H]2C[C@]12c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)[C@@]1(c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of (1S,5R)-1-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (10.5 g, 60.0 mmol) in CH2Cl2 (200 mL) was added AlCl3 (16.0 g, 120 mmol) and then the mixture was cooled to 0° C., and then benzyl methyl amine (240 mmol, as a 2.0M solution of benzyl methyl amine in THF) was added slowly. The mixture was stirred at room temperature for 24 h, and then the reaction was quenched with saturated aqueous NH4Cl. After addition of CH2Cl2 and H2O, the resulting mixture was partitioned. The organic layer was washed with 1N HCl and brine, dried (Na2SO4), evaporated, and purified by column chromatography (silica gel; AcOEt/hexane, 1:4) to give (1S,2R)-2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH3:16])[NH:13][C:12](=[O:14])[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[C:10]2=[O:15])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(c2cc(F)cc(F)c2)NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)(c3cc(F)cc(F)c3)C2=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-5-(3,5-difluorophenyl)-5-methylimidazolidine-2,4-dione from Step A (6.53 g, 28.9 mmol) in DMF (60 mL) was added potassium carbonate (4.39 g, 31.8 mmol) and 4-methoxybenzyl chloride (3.92 mL, 28.9 mmol). The reaction was stirred at ambient temperature for 16 h and at 50° C. for 1 h and then quenched with H2O (100 mL). The resulting precipitate was filtered and rinsed with water to provide the title compound. MS: m/z=347 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH3:11])[C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:17]([C:30](O)=[O:31])=[CH:16]2>>[CH3:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH:1][C:30]([C:17]3[N:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([F:12])=[CH:21][CH:20]=4)=[O:31])[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cn1cnc2cc(N)cnc21
Product: Cn1cnc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21

Procedure:
Compound 7 is synthesized according to a process similar to that described in Example 1.2, starting with 6-amino-3-methyl-3H-imidazo[4,5-b]pyridine, described in the preceding step, and 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, described in step 1.1.