Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)(Cl)Cl>[C:23]1([CH2:22][O:21][C:19](=[O:20])[NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
A solution of 5.00 g (36.7 mmol) of 2-(4-aminophenyl)ethylamine in 100 mL of chloroform was cooled to 0° C. and 3.72 g (5.20 mL, 36.8 mmol) of triethylamine was added. A solution of 6.26 g (5.2 mL, 36.8 mmol) of benzyl chloroformate in 40 mL of chloroform was then added dropwise over a 30-min period. The reaction was allowed to stir at 0° C. for 2 h. It was diluted with 100 mL of chloroform, washed with 100-mL portions of water and brine, dried over sodium sulfate and concentrated. The residue was dissolved in 50% ethyl acetate/hexane and stirred with 30 g of silica gel, filtered, and concentrated. Further purification by recrystallization from ethyl acetate/hexanes gave 4.82 g (49%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) 7.33 (s, 5H), 6.94 (d, 2H, J= 8.2 Hz), 6.60 (d, 2H, J=8.2 Hz), 5.07 (s, 2H), 4.84 (broad s, 1H), 3.55 (broad s, 2H), 3.37 (m, 2H), 2.67 (t, 2H, J=6.9 Hz). FAB MS m/z 271 (M+1).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([OH:27])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CS(C)=O>[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([O:27][CH2:2][C:3]#[N:4])=[O:26])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
2-Bromoacetonitrile (4.35 ml, 62.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.651 ml, 3.74 mmol) were added to a solution of (S)-4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-ID) (1.00 g, 3.12 mmol) in DMSO (4.35 ml), and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→40/60) to afford (S)-cyanomethyl 4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-ID) (885.2 mg, 79%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28].O>C1C=CC=CC=1>[Si:1]([O:14][C:15]1[C:16]([CH3:30])=[C:17]([CH3:29])[C:18]2[O:22][CH:21]([CH2:23][CH2:24][CH2:25][I:26])[S:20][C:19]=2[C:27]=1[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCI)O2
Temperature: 50 °C

Procedure:
5.2 g of t-butyldimethylsilyl chloride and 4.6 g of imidazole were dissolved in 80 ml of benzene, and then the reaction mixture was heated for 1 hour at 50° C., after which a solution of 6.3 g of 5-hydroxy-2-(3-iodopropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Examples 74 and 75) in 10 ml of benzene was added and the reaction mixture was allowed to react for 8 hours at 40°-45° C. The reaction product was cooled, poured into water, and then extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography and the title compound was obtained from the fraction eluted with a 9:1 by volume mixture of cyclohexane and benzene.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O>>[C:1]([OH:19])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: CC(C)=O
Reactant: C#CCCCCC#CCCCCCCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C#CCCCCC#CCCCCCCC(=O)O
Yield: 87 %

Procedure:
Oxidation of pentadeca-8,14-diyn-1-ol (3.0 g, 13.69 mmol) using Jones reagent as described above and purification by SiO2 column chromatography using 15% EtOAc/hexanes as eluent gave pentadeca-8,14-diynoic acid (2.80 g, 87%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.33; 1H NMR (400 MHz, CDCl3) δ 2.34 (t, J=7.0 Hz, 2H), 2.10-2.18 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.55-1.67 (m, 6H), 1.33-1.49 (m, 6H).
Reaction SMILES: [C:1]([C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>O.C(O)COCCO>[CH2:1]([C:9]1[C:17]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1C(=O)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzoyl-3-n-butoxy-5-sulfamylbenzoic acid (0.94 g), 98% aqueous hydrazine hydrate (1.5 ml), potassium hydroxide (0.5 g) in water (1.0 ml) and diethylene glycol (6.5 ml) is stirred at about 130° C. for 3 hours. The temperature is then slowly raised to 215° C. allowing volatile material to distil off. The stirring at 215° C. is continued for a further 2-3 hours until the nitrogen evolution has ceased. After cooling and dilution with water (10 ml), the resulting solution is acidified with conc. hydrochloric acid (1 ml). The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzyl-3-n-butoxy-5-sulfamylbenzoic acid is obtained with a melting point of 228°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Cn2ccc3cc(F)ccc32)c1
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To a solution of 3 g (22.2 mmol) of 5-fluoroindole in 90 ml of dry DMF was added 8.28 g (23 mmol) NaH and 4.51 g (23 mmol) of 3-bromomethyl benzonitrile. The mixture was stirred overnight at and thereafter distributed between water and dihcloromethane. The water layer was extracted twice with dichloromethane, and the combined organic extracts were washed with brine, dried and evaporated. The oily residue was subjected to flash chromatography eluting with dichloromethane/hexane (1/1), to give 5.75 g (76%) of the subtitle product.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][O:35][CH2:36]Cl>CN(C)C=O>[CH3:34][O:35][CH2:36][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Cc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 7-hydroxy-8-methyl-2-oxo-2H-chromen-3-ylcarbamate 7 (975 mg, 3.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (1.01 mL, 7.5 mmol) over 5 minutes at room temperature. The resulting solution was stirred for 30 minutes and cooled to 0° C. To it was added methoxymethylchloride (1.25 mL, 7.5 mmol) dropwise and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched by water and the precipitate was filtered, washed with diethyl ether and dried under vacuum to give compound 8 as a white amorphous solid (931 mg, 82%). 1H NMR (500 MHz, acetone-d6) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.42 (m, 6H), 7.15 (d, 1H, J=8.7 Hz), 5.34 (s, 2H), 5.26 (s, 2H), 3.49 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, acetone-d6) δ 158.8, 157.2, 154.2, 149.9, 137.4, 129.3, 129.0, 128.9, 126.2, 123.1, 112.8, 115.0, 114.9, 112.3, 95.6, 67.6, 56.4, 8.3. IR (KBr) νmax 3321, 2948, 2931, 28591, 1724, 1693, 1608, 1541, 1367, 1213, 1155, 898 cm−1. HRMS (ESI+) m/z [M+Na+] calcd for C20H19NNaO6 392.1110. found 392.1104.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:14]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][C:22]1[CH:21]=[CH:20][C:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCCCCc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCc1ccc(OC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
9.50 g of 3-methyl-4-nitrobenzoic acid (52.5 mM) were dissolved in 400 ml of THF and 53.1 g of triethylamine (525.0 mM). The solution was cooled to −30° C. and 6.01 g of methansulfochloride (52.5 mM) were added. The mixture was stirred for 1 h at this temperature, then a solution of 8.21 g of 4-pentylphenol (50.0 mM) in 20 ml of THF was added, followed by 100 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the mixture was filtered through a pad of celite filter aid, evaporated to dryness. The residue was flash chromatographed on silica gel using cyclohexane/ethyl acetate: 1/1 as eluent to afford 4-pentylphenyl 3-methyl-4-nitrobenzoate as a yellow oil. Yield: 16.2 g (49.5 mM, 99%).
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:26])[N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:20]=[C:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[CH2:8][CH2:7]1)C.[NH2:28][OH:29].Cl.[OH-].[K+].CO>CO>[C:21]1(=[CH:20][C:14]2[CH:13]=[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([C:5](=[O:26])[C:4]([NH:28][OH:29])=[O:3])[CH2:7][CH2:8]3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NO
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(OC)c(C=C3CCCC3)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)C(=O)NO)CC2)cc1C=C1CCCC1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-[4-(3-cyclopentylidenemethyl-4-methoxy-phenyl)-piperidin-1-yl]-oxo-acetic acid ethyl ester (0.4 mmol, 0.150 g) in methanol (5 mL) was added hydroxylamine.HCl (1.6 mmol, 0.111 g), followed by potassium hydroxide/methanol solution (5 M solution; 0.4 mL) dropwise at room temperature. A white solid precipitated out of solution as this reaction stirred for 3 hours. The reaction went to completion as seen by TLC. The reaction mixture was diluted with H2O (100 mL), acidified with 1N HCl and extracted with EtOAc (3×100 mL). Each organic phase was washed with H2O (1×50 mL) and the combined organics were dried (Na2SO4) and concentrated in vacuo to a white solid. The solid was triturated in Et2O/hexane to afford pure white crystals which were dried overnight at 45° C. to give the title compound, mp 127°-128° C. (0.3 mmol, 0.017 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH2:32][O:33][CH3:34])#[N:2].CO.[OH-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:16]3[C:11]([C:12]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:13]=4[CH2:14][CH2:15]3)=[N:10]2)=[CH:5][C:4]=1[CH2:32][O:33][CH3:34])#[N:2]
Reactant: CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(COC)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 18 %

Procedure:
A mixture of 4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride, Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (209 mg, 0.73 mmol) and ethanol (4 mL) was stirred under argon at 80° C. for four hours. The mixture was cooled to room temperature and concentrated to give ethyl 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate as a yellow solid. The ester was suspended in tetrahydrofuran (4 mL), methanol (1 mL) and treated with 2.5 N sodium hydroxide (1 mL) at room temperature. After four hours the mixture was concentrated to half the original volume, treated with 6 N Hydrogen chloride (2 mL), dimethylsulfoxide (24 mL) and purified by reversed-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow/orange solid, 65 mg, 0.015 mmol, 18% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 7.80-7.87 (m, 2H), 7.60 (d, J=8.86 Hz, 1H), 7.35 (d, J=2.15 Hz, 1H), 7.18 (dd, J=8.86, 2.15 Hz, 1H), 4.92 (dd, J=9.80, 5.51 Hz, 1H), 4.50 (s, 2H), 3.59 (ddd, J=13.83, 9.40, 4.70 Hz, 1H), 3.36 (s, 3H), 3.06-3.15 (m, 1H), 2.82-2.96 (m, 1H), 2.19-2.29 (m, 1H), 2.00-2.13 (m, 1H), 1.65-1.89 (m, 2H), 1.14-1.54 (m, 7H). ES-MS m/z 430 (M+H)
Reaction SMILES: [CH:1]1([N:7]([CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>C1C=CC=CC=1>[CH:1]1([N:7]([CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[S:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CN(C(=S)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Yield: 200.6 %

Procedure:
A solution of 13.7 g of 6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]carbostyril and 4.45 g of phosphorus pentasulfide in 200 ml of benzene was refluxed for 5 hours. The reaction mixture was allowed to cool. The insolubles were removed by filtration. The filtrate was subjected to distillation to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluant: 5% methanol/dichloromethane) to obtain 7.2 g of 6-[3-(N-cyclohexyl-N-methylaminothiocarbonyl)propoxy]carbostyril.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Br-].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][Zn+]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[N:9][C:2]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:35])=[C:27]([F:26])[CH:28]=3)=[C:3]([CH:6]=2)[C:4]#[N:5])=[CH:23][CH:22]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: Fc1ccc(C[Zn+])cc1F
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a dried round bottom flask was added THF (1 mL), the product of Example 36 (0.050 g; 0.127 mmol), 3,4-diflourobenzylzinc bromide (0.27 mL of a 0.5 M solution in THF; 0.134 mmol), and tetrakis(triphenylphosphine) palladium (0) (0.008 g; 5 mol %). The reaction was evacuated and purged with nitrogen several times and stirred at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution (3×), and brine. The organic portion was dried (Na2SO4), filtered, and concentrated in vacuo. Purification done by MPLC (silica gel; 0-10% ethyl acetate/hexane gradient) afforded the desired product: m/e=487 (M+3); Rt=4.8 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[NH:10])=[CH:4][CH:3]=1.[O-][CH2:13][CH3:14].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[N:11]=[C:8]([C:14]3[CH:13]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH:5]=[CH:6][N:10]=2)=[CH:6][CH:7]=1
Reactant: CC[O-]
Reactant: N=C(N)Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(Cc2nccc(-c3ccc(Br)cc3)n2)cc1
Yield: 154.7 %

Procedure:
To a stirred mixture of 4-bromophenyl-acetamidine (11.25 g, 0.04 mole) and 1-dimethylamino-3-dimethylimonio-1-(4-bromophenyl)-1-propane perchlorate (15.25 g, 0.04 mole) in 100 mL of dry ethanol is added 0.04 mole sodium ethoxide (prepared from 0.92 g Na and 65 mL ethanol). After stirring for 30 min at room temperature a further equivalent of sodium ethoxide is added, and the mixture is heated under reflux for 2 hr. The solvent is removed under reduced pressure, and the yellow-brown residue triturated with 150 mL water. The solid is filtered, washed with water, dried in air and recrystallized from ether:hexane (1:3) to give 12.5 g (77%) of a pale yellow crystalline solid, mp 93°-94° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[Cl-].[NH4+]>O.CN(C)C=O>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1)[CH3:16]
Reactant: CCOC(CCl)OCC
Reactant: Oc1cc(O)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1cc(O)cc(Cl)c1)OCC
Temperature: 90 °C

Procedure:
The monosodium salt of 3-hydroxy-5-chlorophenol (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reacton vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-diethoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 3-(2,2-diethoxyethoxy)-5-chlorophenol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1C#N.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:6](=[O:7])[NH:8][C:9]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[C:20]([F:30])([F:29])[F:19])=[CH:18]2
Reactant: CNC(=O)c1cc(N2CCOCC2)c(Cl)cc1C
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2cc(Cl)c(N3CCOCC3)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
167 μl of a 1.8 M lithium diisopropylamide THF solution (0.3 mmol) was diluted with 1.5 ml of THF. Thereafter, 1 ml of a THF solution containing 27 mg (0.10 mol) of the 4-chloro-2,N-dimethyl-5-morpholin-4-ylbenzamide prepared in Step B was added dropwise to the diluted solution at −78° C. Thereafter, 1 ml of a THF solution containing 17 mg (0.10 mmol) of 2-(trifluoromethyl)benzonitrile was further added thereto, and the obtained mixture was then stirred at −78° C. for 1 hour. The temperature of the reaction solution was increased to 0° C., and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Thereafter, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1), so as to obtain 5.4 mg (13%) of 6-chloro-7-morpholin-4-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid.
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:35]([NH2:37])[CH3:36]>C(Cl)Cl.[Pd]>[C:1]([C:5]1[C:9]([CH2:10][NH:37][CH2:35][CH3:36])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)cc1C=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(C)(C)C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
2-(2-(3-Tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.66 g, 3.84 mmol) was dissolved in DCM (40 mL) and acetic acid (20.98 g, 20 mL, 349 mmol). Ethylamine (2M in THF, 7.68 mL, 15.35 mmol) was added and the mixture was stirred for 90 min. A slurry of palladium on charcoal (10%, 1.51 g, 1.420 mmol) in DCM (30 mL) was added and the mixture hydrogenated at 4 barr for 72 h at 20° C. The catalyst was filtered through dicalite and the dicalite washed with water, DCM and MeOH. All volatiles were removed under reduced pressure and the aqueous residue was basified to pH 8 using sodium bicarbonate. The crude product was extracted with EtOAc. The organics were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography (DCM, 0-30% MeOH/DCM and 0-20% 7 N NH3 in MeOH/DCM). Concentration in vacuo yielded a white solid (800 mg, 1.73 mmol, 45%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].[ClH:16]>CN(C)C=O>[ClH:16].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C(=Cc1ccncc1)C(C)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution containing 1.1 g of pyridine-4-carboxaldehyde and 1.0 g of 2,4-pentanedione in 10 ml of N,N-dimethylformamide was saturated with hydrogen chloride gas at 20° C. The solution was stirred for 1 h at 20° C. and then for 2 h at 80° C. The solvent was evaporated in vacuo and the residue was crystallized from ethanol. Yield 0.17 g, mP 175°-186° C.