Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CC#N.[Br:19][CH:20](Br)[CH3:21]>CCOCC>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(Br)Br
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: O=Cc1cccc(OCCBr)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (5.17 g, 42.33 mmol), K2CO3 (58.5 g) and CH3CN (100 ml) was stirred at room temperature for 15 minutes, then dibromoethane (18.3 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 3-4 hours. Additional dibromoethane was added and then the reaction mixture was refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate was stripped to afford an oil. The oil was dissolved in ether (300 ml), washed with 5N NaOH (2×75 ml) and the ether layer was dried over MgSO4 and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 5.23 g of 3-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([F:40])[CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:32][C:33]=2[F:40])[CH:11]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1F
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2F)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
To mixture of 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (21.0 g), 4-benzyloxy-2-fluorophenylboronic acid (16.8 g) and potassium carbonate (8.7 g) in DME/water (v/v=2/1, 300 mL) at r.t. under Ar-atmosphere palladium(0) bis(tri-tert-butylphosphine) (0.99 g) was added and the mixture was stirred at 85° C. for 90 min. To the mixture water was added and it was extracted with ethyl acetate. The organic phase was washed several times with water, finally with brine. Methanol was added and the precipitate formed was filtered off, dried in air to give 6-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (23.0 g, 82%). This material was dissolved in isopropanol (100 mL), and 1N sodium hydroxide solution (140 mL) was added. The solution was stirred overnight, filtered, then the filtrate was adjusted to pH 2-3 and the precipitate formed was dried in air giving 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (18.0 g, 83%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(O)c2C1

Procedure:
Synthesis worked according to the preparation of A7-1 when using 76 mg (0.23 mmol) (S)-N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine ((S)-A5-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using hexane/ethyl acetate 10/1 in the presence of 1% (v/v) of dimethylethylamine to achieve compound 1b.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=1>>[I:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[O:10][C:9]1=[O:11]
Reactant: OCc1cccc(I)c1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Product: Cc1ccc2oc(=O)n(Cc3cccc(I)c3)c2n1

Procedure:
Reaction of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one with (3-iodophenyl)-methanol under Mitsunobu conditions gives 3-(3-iodobenzyl)-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one; ESI: 367 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](OB=O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]=1[C:13]1[N:7]2[CH2:6][C:5]3[C:9]([C:8]2=[N:11][N:12]=1)=[CH:10][C:2]([C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[CH:3][CH:4]=3
Reactant: O=BOc1ccncc1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3ccncc3)cc1-2
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (220 mg) (prepared as in Example 4), 4-pyridylboranic acid (295 mg), Cs2CO3 (1.26 g/l ml H2O), and DME (3 ml) was degassed with a stream of N2 for 0.5 h. Bis(triphenylphosphine)palladium(II) chloride (42 mg) was added and the reaction heated to 100° C. for 5 h. The reaction mixture was cooled, poured into H2O and extracted into CH2Cl2, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica, eluting with 3% MeOH/CH2Cl2, and recrystallised from CH2Cl2/hexane to give the title compound (50 mg, 21%). 1H NMR (360 MHz, CDCl3) δ 8.72 (2H, d, J=4.5 Hz), 8.29 (1H, d, J=1.3 Hz), 7.67 (1H, dd, J=8.0, 1.7 Hz), 7.57–7.53 (4H, m), 7.48–7.39 (4H, m), 4.07 (2H, s), 2.73 (3H, s), m/z (ES+) 392 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:14]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[C:13]([C:14]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(-c2nc3ccccc3[nH]2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of 1,2-phenylenediamine (30 mmole, 3.24 g) and 3,4,5-trimethoxybenzaldehyde (30 mmole, 5.89 g) in acetonitrile (75 ml) is added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (30 mmole, 6.81 g), and the mixture is stirred 18 hours at room temperature. Sodium hydroxide (0.5M, 120 ml) is added, and the mixture is stirred over night at room temperature. The dark precipitate is filtered off and is digested with ethanol (30 ml) to give the title product as a brown solid (14%). (R1=hydrogen, R2=3,4,5-trimethoxyphenyl, n=0). 1H-NMR (DMSO, TMS, δ): 3.74 (s, 3H, OCH3), 3.91 (s, 6H, OCH3), 7.20 (m, 2H, ar), 7.54 (s, 2H, ar), 7.61 (m, 2H, ar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[C:6]([CH2:8][CH2:9][N:10]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH:7]=1.[OH-].[Na+].ClCCl>CO>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)([OH:17])=[O:16]
Reactant: COC(=O)CCCCN(CCc1cc(F)ccc1OCc1ccc(-c2ccc(C)cc2)cc1)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2ccc(COc3ccc(F)cc3CCN(CCCCC(=O)O)Cc3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.45 g (0.69 mmol) of methyl 4-{[(2-{5-fluoro-2-[(4′-methyl-1,1′-biphenyl-4-yl)methoxy]phenyl}ethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 185 is dissolved in 8 ml of methanol. 0.5 ml of aqueous sodium hydroxide solution (45%) and 1.5 ml of dichloromethane are added, and the solution is stirred at RT for 8 hours. The reaction is extracted with diethyl ether, the aqueous phase is acidified using sulphuric acid and extracted with ethyl acetate and the extract is filtered through Extrelut and concentrated.
Reaction SMILES: [Br-].[NH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2CC2C=CC=CC=2)=[CH:5][C:4]=1[C:21]([O:23]CC)=O.[CH3:26][N:27](C=O)C.C(O)=O>C(N)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:3]2[N:2]=[CH:26][N:27]=[C:21]([OH:23])[C:4]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2cccc[n+]2Cc2ccccc2)[nH]c1N
Reactant: CN(C)C=O
Agent: [Br-]
Solvent: NC=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccccn3)cc12

Procedure:
Under a protective gas, 27.07 g of 2-(5-amino-4-ethoxycarbonyl-1H-pyrrol-2-yl)-N-benzyl-pyridinium bromide in 195 ml of formamide are heated for 16 hours at 150° C. with 97.6 ml of DMF (dried over 4A molecular sieve) and 48.8 ml of formic acid. When the dark-brown reaction mixture is cooled in an ice-bath, the title compound crystallizes and can be filtered off and washed with isopropanol and diethyl ether; 1H-NMR (300 MHz, DMSO-d6): 12.5 and 11.9 (2s, 2H), 8.60 (d, J=7, 1H), 8.05-7.8 (m, 3H), 7.28 (dd, J1 =7, J2 =9, 1H), 7.20 (s, 1H); FAB-MS: (M+H)+ =213.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=NO)[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(OCC(=NO)c2ccc(N3CCCC3)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(OCC(=O)c2ccc(N3CCCC3)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to that of Example 1.h, by reaction of 210 mg (0.5 mmol) of methyl 4-[2-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-2-hydroxyiminoethoxy]benzoate with 100 mg (2.5 mmol) of sodium hydroxide. A white solid is obtained after recrystallization (m.p.=235° C., m=44 mg, yield=22%); (1H NMR (DMSO): 1.35 (s, 9H); 1.86 (s, 4H); 2.89 (s, 4H); 5.29 (s, 2H); 7.04-7.06 (d, J=7.65 Hz, 2H); 7.40-7.42 (d, J=7.4 Hz, 1H); 7.49-7.51 (d, J=7.4 Hz, 1H); 7.65 (s, 1H); 7.86-7.88 (d, J=7.4 Hz, 2H); 11.9 (s, 1H); 12.6 (s, 1H)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.S(Cl)(Cl)(=O)=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CC1Sc2ccccc2N(C)C1=O
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)C(C)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzothiazine (4.8 g) in methylene chloride (25 ml), sulfuryl chloride (3.5 g) is added under ice-cooling. The mixture is stirred for 30 minutes, and added into a solution of phenol (2.4 g) and aluminum chloride (3.3 g) in methylene chloride (20 ml) with stirring under ice-cooling. The mixture is stirred for 1 hour under ice-cooling, and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution is dried over anhydrous sodium sulfate and concentrated in vacuo. A mixture of benzene and n-hexane (1:1) is added to the residue and the separated crystals are collected by filtration to give 6.4 g (90.2%) of the titled compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([S:27]([N:30](CC2C=CC(OC)=CC=2OC)[C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1F)#[N:19].Cl>CN(C)C(=O)C.O1CCOCC1.CS(C)=O>[C:18]([C:20]1[CH:21]=[C:22]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11])#[N:19]
Reactant: FC(F)(F)c1ccccc1S
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Sc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Trifluoromethylthiophenol (0.0615 g, 0.345 mmol) and potassium carbonate (0.100 g, 0.724 mmol) were stirred in N,N-dimethylacetamide (3 mL). After 5 minutes, 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.150 g, 0.345 mmol) was added to the reaction mixture and the mixture stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, followed by brine, then dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was then dissolved in 1,4-dioxane (1 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a residue. The residue was solubilised in dimethylsulfoxide (1 mL) and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: O=C(CCl)Nc1c(CCl)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(C(F)(F)F)c1NC(=O)CCl
Yield: 105 %

Procedure:
A solution of 8.01 g (0.0262 mol based on 93.5% assay) of 2'-(chloromethyl)-6'-(trifluoromethyl)-2-chloroacetanilide (prepared as in example 6) and 4.0 ml (0.029 mol) of triethylamine in 60 ml of ethanol was shaken with 0.160 g of 10% Pd/C under 20-50 psi of H2 pressure at room temperature. When H2 uptake was complete (4.0 hr.), the mixture was filtered to remove catalyst and partitioned between 100 ml of methylene chloride and 50 ml of water. The organic phase, combined with a small methylene chloride wash of the aqueous phase, was washed with two 50 ml portions of water and was dried using magnesium sulfate. Solvent removal in vacuo provided 6.92 g of white 2'-methyl-6'-(trifluoromethyl)-2-chloroacetanilide assaying 92.1% for a yield of 96.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH2:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2]
Reactant: CCOC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 92.9 %

Procedure:
Using the procedure described in Example 161C, 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-amine (0.429 g, 1.75 mmol) and phenyl chloroformate (0.329 g, 2.1 mmol) were reacted in the presence of K2CO3 (0.415 g, 3 mmol) in THF (15 mL), and purified by silica gel chromatography with 15-35% EtOAc/hexane as eluants to afford phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as solid (0.594 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 5H), 7.41-7.48 (m, 4H), 7.14-7.38 (m, 2H), 6.6 (s, 1H), 3.37 (q, 2H), 1.59 (s, 6H), 1.14 (t, 3H); LC-MS (ESI) m/z 320 (M−OEt)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][NH:17][CH:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: CC1=NCCn2c1cc1c2-c2ccccc2C(C)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC1Cc2cc3n(c2-c2ccccc21)CCNC3C
Yield: 81 %

Procedure:
5,6,10,11-Tetrahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole (2.0 g) was dissolved in a mixture of 80 ml of methanol and 8 ml of water under argon. The solution was treated portionwise with 0.9 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the solvent was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 100 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 2.0 g of yellow-brown oil, was dissolved in a 25-fold amount of hot ethanol and treated with 1.1 equivalents of a hot saturated solution of fumaric acid in ethanol. There were obtained 2.4 g (81%) of 5,6,8,9,10,11-hexahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 196°-199° C.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[N:4]1.S(Cl)([Cl:12])=O>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][Cl:12])[N:4]=1)#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccn(CO)n1
Solvent: ClCCl
Product: N#Cc1ccn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.89 g of 1-(hydroxymethyl)-3-cyano-1H-pyrazole was dissolved to 30 ml of dichloromethane. 1.6 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.00 g of 3-cyano-1-(chloromethyl)-1H-pyrazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[C:20]1([CH:24]2[C:25]3[N:16]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[CH:12][CH:11]=4)[S:15][C:26]=3[CH2:27][CH2:28][CH2:29]2)[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: NC(=S)Nc1ccc(-c2ccncc2)cc1
Solvent: CCO
Product: c1ccc(C2CCCc3sc(Nc4ccc(-c5ccncc5)cc4)nc32)cc1
Yield: 20.1 %

Procedure:
A solution of (4-pyridin-4-yl-phenyl)-thiourea (100 mg, 0.44 mmol) and 2-bromo-6-phenyl-cyclohexanone (116 mg, 0.46 mmol) in ethanol (5 ml) was heated to reflux over night. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as the eluent to yield the title compound (34 mg, 20%) as a yellow solid. MS ISP (m/e): 384.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.61 (d, 2H), 7.59 (d, 2H), 7.46 (d, 1H), 7.18-7.33 (m, 5H), 7.13 (d, 2H), 4.08 (m, 1H), 2.75 (m, 2H), 2.18 (m, 1H), 1.7-1.98 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20]C=O)[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
A mixture of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (15.0 g) and conc. hydrochloric acid (9.5 g) in methanol (75 ml) was stirred at ambient temperature for 2.5 hours. Water (100 ml) was added to the reaction mixture and the solution was adjusted to pH 3.0 with 10% aqueous solution of sodium hydroxide under stirring. The precipitates were collected by filtration, washed with water and diisopropyl ether and dried to give 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl) acetic acid (syn isomer) (12.7 g).
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:22])=[CH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([Br:21])=[CH:16][CH:15]=4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCCCCCCBr
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: CCCCCCCOc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 78.6 %

Procedure:
Following the procedure of Example 8(b), but reacting 3.4 g (9.5 mmol) of 3-(1-adamantyl)-6-bromo-2-naphthol with 2.05 g (11.4 mmol) of 1-bromoheptane, 3.4 g (79%) of 7-(1-adamantyl)-6-heptyloxy-2-bromonaphthalene were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14].[NH:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)ccc1OCCBr
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCCN1C(=O)CCC1=O

Procedure:
B method: 11.66 g (45 mmol) of 4-(2-bromo-ethoxy)-3-methoxy-benzaldehyde (6.2) and 4.46 g (45 mmol) pyrrolidine-2,5-dione (7.2) is heated with 8.28 g (60 mmol) K2CO3 in 200 ml of acetonitrile for 8 h. After same isolation procedure as in A method 4.1 is given with same purity.