Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[N:1]=[C:2]2[N:7]=[CH:6][CH:5]=[N:4][N:3]2[CH:9]=1)=[O:12])[CH3:15]
Reactant: Nc1nccnn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2nccnc2n1
Temperature: 25 °C
Yield: 1.8 %

Procedure:
A solution of 3-amino-1,2,4-triazine (5.0 g, 52 mmol) and ethyl bromopyruvate (11 mL, 88 mmol) in ethanol (50 mL) was heated to reflux for 20 minutes. The reaction was cooled to room temperature, and then partitioned between 200 mL of EtOAc and 200 mL of water. The layers were separated, and the organic layer was dried over MgSO4. The solids were removed by filtration, and then the solvent was removed by rotary evaporation. The residue was purified by chromatography (90 g SiO2, 50 to 70% EtOAc in hexanes) to give the desired product (181 mg, 1.8%). MS (ESI): 192.4 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:2]([O:26][C:25]2[CH:20]=[CH:21][C:22]([CH3:27])=[CH:23][CH:24]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:15]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)C(Br)CCCCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)Oc1ccc(C)cc1

Procedure:
A mixture of 5.6 g (17 mmol) of ethyl 2-bromo-7-(4-chloro-phenyl)heptanoate, 1.82 g (17 mmol) of p-cresol, 7.0 g (50 mmol) of potassium carbonate and 70 ml of butanone is heated for 36 h at the refluxing temperature. Then the inorganic precipitate is removed on a suction filter and the filtrate is concentrated. The residue is taken up in ether, the solution washed twice with 0.5N caustic soda solution, dried and concentrated by evaporation. The residual oil is chromatographed with toluene on silica gel. 5.3 g (86% of theory) is obtained of ethyl 7-(4-chloro-phenyl)-2-(4-methylphenoxy)heptanoate, a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([OH:14])=[C:12]([N+:15]([O-])=O)[CH:11]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:13]=1[OH:14]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)c(O)c(-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 85.1 %

Procedure:
The solution of methyl 4′-fluoro-6-hydroxy-5-nitrobiphenyl-3-carboxylate (13.0 mg, 45.0 μmol) and palladium (10% on carbon; 4.75 mg, 4.46 μmol) in ethanol (5 mL) was degassed and stirred under hydrogen at 1 atm. After 1 h, the mixture was filtered and washed with ethanol. The filtrate was concentrated to dryness to give the title compound (10 mg). LC-MS [M+1]=262.1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:4].C=O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:21][C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[S:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(SCCNC(=O)C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)C(F)(F)F)CCS2
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of compound 12 (100 mg), paraformaldehyde (100 mg), p-toluenesulfonic acid (60 mg) in toluene (10 mL) was stirred at 80° C. overnight. Filtration, followed by washing with sat. NaHCO3 solution gave crude product 13 in an estimated yield of ˜70% by TLC and NMR.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.NN>C(O)CO>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:7][C:8]1=[O:11]
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: NN
Solvent: OCCO
Product: O=C1Cc2ccccc2N1

Procedure:
In still a further embodiment, a process is provided for preparing 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile including reacting 7-fluoro-1H-indole-2,3-dione and aqueous hydrazine in ethylene glycol to form the 2-oxindole; alkylating the 2-oxindole at the 3-position; brominating the alkylated 2-oxindole; reacting the brominated 2-oxindole with 5-[1,3,6,2]dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile, sodium carbonate, and PdCl2(PPh3)2; removing residual PdCl2(PPh3)2 or a by-product thereof using N-acetyl-L-cysteine; and isolating 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile. See, Scheme 6.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[CH2:12][C:13](=O)[CH3:14].[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[OH:19]>>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([CH:18]([OH:19])[CH2:17][NH:16][CH:13]([CH3:14])[CH2:12][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][N:2]2[CH3:1])=[CH:25][CH:24]=1
Reactant: NCC(O)c1ccc(O)cc1
Reactant: CC(=O)CC1c2ccccc2CCN1C
Product: CC(CC1c2ccccc2CCN1C)NCC(O)c1ccc(O)cc1
Yield: 47 %

Procedure:
The same procedure as described in Example 1 was repeated, using (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetone [Synthesis, 1001 (1988)]and 2-amino-1-(4-hydroxyphenyl)ethanol, to give crude crystals. The crude crystals were washed with ether to give crystals of Compound 31 in a yield of 47%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:2]=[CH:1]/[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[O:11]1
Reactant: C#Cc1cccnc1
Reactant: CC1(C)OBOC1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2cccnc2)OC1(C)C
Temperature: 50 °C
Yield: 49.8 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 3-ethynyl pyridine (104 mg, 1 mmol), toluene (4 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.73 mL, 5 mmol). The mixture was purged with argon for 15 min HRuCl(CO)(PPh3)3 (73 mg, 0.05 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (10 mL) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 1:1) to give the title compound as a white solid (115 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H) 8.52 (d, 1H, J=4.8 Hz), 7.81 (d, 1H, J=7.8 Hz), 7.38 (d, J=18.6 Hz, 1H), 7.28-7.26 (m, 1H), 6.26 (d, 1H, J=18.5 Hz), 1.33 (s, 12H).
Reaction SMILES: [Sn].[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N+:14]([O-])=O)([CH3:4])[CH3:3].Cl.C(O)(=O)C>CCOCC>[CH:2]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH2:14])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(C(C)C)c1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)c1ccc(N)c(C(C)C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Mossey Tin (22 g, 184.5 mmol) was added to a solution of Intermediate 32 (25 g, 120 mmol), followed by conc. HCl (150 mL). After heating at 100° C. for 1 hour, acetic acid (50 mL) was added to the mixture and it was heated for another 30 minutes. After stirring at room temperature overnight, the reaction mixture was diluted with ether (500 mL), washed with water (50 mL) and transferred to a 500 mL beaker. Solid potassium carbonate was carefully added until all acids were quenched (˜80 g). The mixture was then extracted with ether (3×100 mL), washed with brine (1×20 mL), dried (Na2SO4) and concentrated to give the title compound in a crude form as a brown oil that was taken to the next step without further purification:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:18]2[CH2:23][CH2:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:19][CH2:20][N:21]([S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(=NCCc2ccccc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(NCCc2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 73.5 %

Procedure:
A mixture of 10.0 g (0.022 mol) of α-(4-fluorophenyl)-N-(2-phenylethyl)-1-(phenylsulfonyl)-4-piperidinemethanimine and 1.0 g (0.025 mol) of LiAlH4 in 200 mL of dry THF was stirred at room temperature for 8.5 hr. A 10 mL solution of 10% NaOH was slowly added followed by 100 mL of water. The mixture was extracted with CH2Cl2, and the solution was dried (MgSO4). The solvent was removed in vacuo to give an oil. This was crystallized from 200 ml of methanol to give 7.32 g (72.9%) of a white crystalline solid, mp 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:32]=[CH:31][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[CH:28]3[CH2:30][CH2:29]3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH:28]3[CH2:29][CH2:30]3)=[CH:31][CH:32]=2)=[O:10])=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyclopropylphenyl)acetate (70 mg, 0.146 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.293 ml, 1.46 mmol) and water (300 μL). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-cyclopropylphenyl)acetic acid (50 mg, 75.9% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.65 (d, 2H), 7.30 (d, 2H), 7.15 (d, 2H), 7.10 (d, 1H), 6.90 (m, 4H), 3.65 (t, 2H), 3.60 (s, 2H), 2.90 (t, 2H), 2.05 (m, 1H), 0.80 (m, 2H), 0.62 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:19])[CH:5]=[C:6]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[Cl:19][C:4]1[CH:5]=[C:6]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1cc(Cl)cc(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cc(Cl)cc(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(5-bromo-3-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 following the procedure described in Example 10 to give N-(3-(3-chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a pale yellow oil. Yield (1.02 g, 66%):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:4]1[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1cccc(-c2ccc3ccccc3c2)c1
Temperature: -10 °C
Yield: 67.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 212 g (748 mmol) of 2(3-bromophenyl) naphthalene and 3 L of dehydrated THF was cooled down to −10 degrees C., and added with 600 ml (948 mmol) of hexane solution of 1.6M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at 0 degree C. The reaction solution was further cooled down to −78 degrees C., and added with 450 g (2.39 mol) of triisopropyl borate in drops. Subsequently, the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. The reaction mixture was further added with 3 L of toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 3-(2-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: C1([C:7]2[C:8]([NH2:19])=[N:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)C=CC=CC=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[N:19]=[C:8]3[CH:7]=[CH:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:10][N:9]3[CH:21]=2)=[CH:25][CH:26]=1
Reactant: Nc1ncc(-c2ccccc2)cc1-c1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Yield: 82 %

Procedure:
Dissolving crude 3,5-diphenyl-2-amino-pyridine obtained and 5.5 g (20 mmol) of 2,4′-dibromo acetophenone into 80 milliliter of ethanol, adding 3.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 6.9 g of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine (yield: 82%).
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][N:4]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH-].[Na+].C1(C)C=CC=CC=1>[CH3:16][C:2]1([CH2:3][N:4]([S:12]([CH3:15])(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)[O:19][CH2:18][CH2:17][O:1]1
Reactant: CC(=O)CN(c1ccc(Cl)cc1)S(C)(=O)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(CN(c2ccc(Cl)cc2)S(C)(=O)=O)OCCO1

Procedure:
A mixture of N-(2-oxopropyl)-4'-chloromethanesulphonanilide (6.0 g), ethane-1,2-diol (10 ml), 4-toluenesulphonic acid (0.1 g) and toluene (75 ml) was stirred and boiled under reflux with water separation by means of a Dean and Stark receiver. After 3 hours the reaction mixture was cooled and poured into water (about 200 ml) containing a few drops of sodium hydroxide solution. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to a brown oil, which gave fawn coloured crystals from a solution in toluene/80°-100° petrol. Yield 6.0 g (86%). Melting point 84°-85°.
Reaction SMILES: [H-].[Na+].[CH2:3](O)[C:4]#C.Cl[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH2:10]([O:9][CH2:8][C:3]#[CH:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCOCc1ccccc1
Reactant: C#CCO
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C#CCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4.6 g (192 mmol) of sodium hydride was charged in a 200 ml three-necked flask provided with a 100 ml dropping funnel with a bypass and vacuum-dried in nitrogen stream. Then, thereto was added 100 ml of tetrahydrofuran, followed by cooling to 0° C. Furthermore, 11.2 ml (192 mmol) of propargyl alcohol diluted with 100 ml of tetrahydrofuran was gradually added thereto. After stirring at this temperature for 30 minutes, 22.3 ml (160 mmol) of chloromethylbenzyl ether diluted with 20 ml of tetrahydrofuran was added dropwise, followed by stirring for 30 minutes. After further stirring for 1 hour at room temperature, the reaction was stopped by saturated aqueous ammonium chloride solution and the reaction mixture was rendered weakly acidic with 3N aqueous hydrochloric acid solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation and then the ether (1) was obtained by vacuum distillation. Boiling point: 80-83° C./ 0.5 mmHg, Yield: 90%
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH3:32][NH:33][C:34]([C:36]1[C:41](=[O:42])[C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:49]([F:51])[F:50])[CH:44]=2)=[C:39]([CH3:52])[N:38]([CH:53]([C:55]2[CH:60]=[CH:59][C:58](Br)=[CH:57][N:56]=2)[CH3:54])[CH:37]=1)=[O:35]>>[CH3:32][NH:33][C:34]([C:36]1[C:41](=[O:42])[C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:49]([F:51])[F:50])[CH:44]=2)=[C:39]([CH3:52])[N:38]([CH:53]([C:55]2[CH:60]=[CH:59][C:58]([C:1]#[N:2])=[CH:57][N:56]=2)[CH3:54])[CH:37]=1)=[O:35]
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O

Procedure:
Example 16 is prepared as described for Example 15, substituting preparation 15b with preparation 16c. ESI mass spectrum: [M+H]+=423; Retention time HPLC: 0.94 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)cc(Cn2c3cccc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 69 %

Procedure:
A suspension of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (18 mg, 0.043 mM) and 0.043 mL (0.043 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 42 hours at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 12 mg (67%) of the {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-7.3 (m, 4H), 7.1 (m, 2H), 6.9 (s, 1H), 6.8 (s, 2H), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.35 (s, 2H), and 2.2 (s, 6H). IR (KBr, cm−1) 3385, 1663, 1616, 1575, 1498, 1456, 1412, and 1330. MS (ES) m/e 401, 403.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[N:8][CH:7]=1)=O)C.[H-].COCCO[Al+]OCCOC.[Na+].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[N:8][CH:7]=[C:6]2[CH2:4][OH:3]
Reactant: CCOC(=O)c1cnc(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A slurry of 41.1 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid ethyl ester in 250 ml of dry tetrahydrofuran was chilled to 0° and treated dropwise over 30 minutes with 62.8 ml of 3.5M sodium bis-(2-methoxyethoxy)aluminum hydride in toluene solution. After stirring at 0° for three hours, 60 ml of saturated aqueous sodium sulfate solution was cautiously added and the mixture was stirred until granular. The supernatant solution was decanted, the residue was extracted with warm methylene chloride, and the combined organic solutions were evaporated in vacuo. The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, and concentrated. Crystallization from methylene chloride/ethyl acetate provided 26.7 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol as a white solid, mp 140°-146°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)CI
Reactant: OCCc1cccc(F)c1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1cccc(F)c1

Procedure:
In analogy to the procedure described in example 78.1, 2-(3-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(3-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=227.2 [M+H+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:16][CH:15]=1>>[N:24]1([CH2:23][CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:8]3[S:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:9]=3)=[CH:15][CH:16]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OCc1cnc(-c2cccs2)s1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: c1csc(-c2ncc(COc3ccc(CCCCn4ccnc4)cc3)s2)c1
Yield: 86 %

Procedure:
In substantially the same manner as in Working Example 159, 2-(2-thienyl)-5-thiazolylmethanol was chlorinated and then reacted with 1-[4-(4-hydroxyphenyl)butyl]imidazole to obtain 5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 86%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 128-129° C.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:31])[S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CN(C)C=CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 42.5 %

Procedure:
A mixture of 0.134 g (1.24 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.43 g (1.24 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 205 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-methyl-benzenesulfonamide as a yellow solid (yield 42%).