Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:15])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CI
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxy-2-nitro-phenylamine (5.0 g, 0.029 mol) in DMF (25 ml) was added NaH (0.9 g, 0.035 mol) at 0° C. and stirred at that temperature for 30 min. Methyl iodide (2.17 ml, 0.035 mol) was added and the resulting solution was stirred at room temperature for 30 min. The reaction was quenched with ice-water and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the title compound (4-methoxy-2-nitro-phenyl)-methyl-amine as a red solid. C8H10N2O3; 1H NMR (400 MHz, CDCl3), δ: 8.00 (brs, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.18 (dd,1=9.2 Hz, J2=2.0 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 3.81 (d, J=14.8 Hz, 3H), 3.02 (s, 3H). MS (M+1): 183.1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2Cl)CC1)c1ccccc1
Yield: 78.2 %

Procedure:
0.14 g (0.00062 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 0.17 ml (0.00123 mol) of triethylamine were dissolved in 6.2 ml of toluene, treated with 0.09 ml (0.000776 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.16 g (78%) of 1-(2-chloro-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O.C(O)C>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[C:11]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:10]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)n1nc(CC2CCCCC2)c(C#N)c1N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)n1nc(CC2CCCCC2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To potassium hydroxide (4.95 g, 0.09 mol) in 50% water/ethanol (83 ml) was added 30% hydrogen peroxide (6.7 ml, 0.06 mol) followed by 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carbonitrile (2.8 g, 0.01 mol). The reaction mixture was stirred at room temperature for 24 hours, then was heated on a steam bath for 4 hours. More 30% hydrogen peroxide was added (6.5 ml, 0.057 mol) and the reaction mixture was heated for an additional 2 hours. The solvent was removed in vacuo, water was added and the residue was extracted with ethyl acetate (2×). The organic layer was washed with brine, dried over anhydrous MgSO4 and the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography on silica eluting with ethyl acetate (100%) to afford 0.34 g (11%) of 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carboxamide as an amber oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.O=P(Cl)(Cl)Cl.[NH2:13][C:14](=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:15].[O-]CC.[Na+].Cl>ClCCCl>[OH:23][C:22]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:15])[N:13]=[C:3]2[N:2]([CH3:1])[CH2:6][CH2:5][C:4]=12
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)N
Reactant: CN1CCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1c(C)nc2c(c1O)CCN2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A solution of 1-methylpyrrolidin-2-one (14.81 ml, 154 mmol) in anhydrous 1,2-dichloroethane (DCE) (250 ml) under a nitrogen atmosphere was added drop wise POCl3 (28.5 ml, 307 mmol) over a 10 min period and the mixture was stirred at ambient temperature. After 1 h, a solution of diethyl 2-(1-aminoethylidene)malonate (30.9 g, 154 mmol) in DCE (10 mL) was added and the mixture was heated to 40° C. After 18 h, the reaction mixture was partitioned between sat. aq. NaHCO3 and DCM. The organic later was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo, The residue was dissolved in N,N-dimethylformamide (DMF) (150 ml) and treated dropwise with sodium ethoxide (172 ml, 461 mmol) and heated to 100° C. After 3 h, the reaction mixture was cooled to ambient temperature and the pH was adjusted to pH 7 with 1M HCl. The mixture was partitioned between water and EtOAc and the organics washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 0-25%) to afford ethyl 4-hydroxy-1,6-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (11.0 g, 30.3% yield) as a white solid. 1H NMR (CHLOROFORM-d) δ: 11.89 (s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.54 (t, J=8.7 Hz, 2H), 2.87-3.05 (m, 5H), 2.64 (s, 3H), 1.41 (t, J=7.1 Hz, 3H); LC/MS (m/z) ES+=237.1 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([O:13]C)=O)[NH2:9])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C[O-].[Na+]>C(#N)C>[CH3:15][N:16]1[C:11](=[O:13])[CH2:10][N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[NH:9][C:17]1=[O:18]
Reactant: COC(=O)CN(N)c1ccc(C)cc1
Reactant: CN=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(N2CC(=O)N(C)C(=O)N2)cc1

Procedure:
To a solution of methyl [1-(4-methylphenyl)hydrazino]acetate (2.25 g) in acetonitrile (10 ml) was added methyl isocyanate (2 ml) and the mixture was heated under reflux for 30 min. The solvent was removed in vacuo to give a solid which was treated with a solution of sodium methoxide (27 ml; from sodium (4 g) and methanol (200 ml)) according to the method of Example 3 to give a solid which was purified by trituration with System A (1:1) to give the title compound (1.51 g), m.p. 193°-194°, t.l.c. (ether) Rf 0.56.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][C:2]1([CH2:5][O:6][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=2[C:12]#[N:13])[CH2:4][CH2:3]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC1(CO)CC1
Product: CC1(COc2cccc([N+](=O)[O-])c2C#N)CC1
Yield: 65 %

Procedure:
Prepared as in Example 166d from (1-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.44-0.46 (m, 2H), 0.57-0.59 (m, 2H), 1.22 (s, 3H), 4.06 (s, 2H), 7.67 (dd, J=1.6 Hz, J=8.0 Hz, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.C[O:16]B(OC)OC.C(OO)(=O)C>CCOCC.CCCCCC>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([OH:16])=[CH:8][CH:9]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cn1
Agent: CC(=O)OO
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(O)cn1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M hexane solution of n-butyllithium (23 mL, 58 mmol) was added over 30 minutes to a −78° C. solution of 5-bromo-2-methoxypyridine (10 g, 53 mmol) in ether (120 mL), keeping the temperature below −65° C. The slurry was stirred for 30 minutes, and then trimethylborate (6.1 mL) was added quickly to the reaction solution. Again the temperature was maintained below −65° C. The solution was stirred for 10 minutes, warmed to 15° C. and then cooled to −78° C. Peracetic acid (56 mmol) was added dropwise, while the temperature was kept at or below −65° C. After addition, the reaction was warmed briefly to −50° C., cooled back to −65° C., then stirred at approximately 25° C. overnight. The reaction was quenched with water (100 mL), and then extracted with ether (3×150 mL). The organic portions were combined and washed with aqueous NaHSO3 solution and brine. The organic portions were extracted two times with 2N aqueous NaOH solution. The pooled basic aqueous fractions were washed with Et2O and then acidified with NaHSO4. The product precipitated out as oil; the aqueous mixture was extracted three times with Et2O, the pooled ether fractions were dried with Na2SO4, and stripped of solvent in vacuo. Yielded 3.6 g of a brown solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[N+:8]([CH2:11][CH2:12][CH3:13])([O-:10])=[O:9].Cl>C(#N)C.O>[CH3:4][CH:3]([CH:11]([N+:8]([O-:10])=[O:9])[CH2:12][CH3:13])[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: CCC[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCC(C(C)CC(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
A solution of 4 g (40 mmol) of methyl crotonate and 4.72 g (53 mmol) of 1-nitropropane in 20 mL of acetonitrile was treated with 6 mL (40 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). After stirring for 22 h at room temperature the reaction mixture was diluted with water and acidified with 2N HCl. The solution was extracted with Et2O and the Et2O layer was washed with brine, dried and concentrated. The residue was chromagraphed on a flash column using 10% Et2O-Hexane to isolate 6.41 g (85%) of the title compound.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([O:9][C:10]([C:12]1[S:13][C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=1)=[O:11])[CH3:8].[N-:20]=[N+:21]=[N-:22].[Na+]>CC(C)=O.O>[N:20]([C:17]([C:14]1[S:13][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[N:16][CH:15]=1)=[O:19])=[N+:21]=[N-:22]
Reactant: CCOC(=O)c1ncc(C(=O)O)s1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ncc(C(=O)N=[N+]=[N-])s1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Ethyl chloroformate (9.8 g, 83.6 mmol) was added to a solution of 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (Intermediate X, 13 g, 64.67 mmol), TEA (9.79 g, 97.01 mmol) in acetone (130 mL) at −20° C., stirred for 1 h, then a solution of NaN3 (5.4 g, 83.6 mmol) in water (15 mL) was added and stirred at RT for 30 mins. After completion, the solvent was evaporated, the crude residue was diluted with water (150 mL) and extracted with EtOAc (2×150 mL). The combined extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford Ethyl 5-(azidocarbonyl)thiazole-2-carboxylate (11 g crude) as brown liquid. The crude was carried to next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[O:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:32][CH:30]1[O:31][CH:26]([CH3:25])[CH2:27][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:29]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC1CNCC(C)O1
Product: CC1CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)CC(C)O1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 2,6-dimethylmorpholine to give a yellow solid. MS m/z: 433.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20](Cl)=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>ClCCl>[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:1][CH2:2][CH2:3][OH:4])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.25 h

Procedure:
2-Aminoethanol (1.2 g, 19.7 mmol) in dry dichloromethane (5 ml) was added dropwise to a solution of 9-fluorenylmethylchloroformate (5.0 g, 19.3 mmol) together with pyridine (1.5 g, 19.4 mmol). The mixture was stirred for a total of 1.25 hours then diluted with dichloromethane (50 ml), washed with water (25 ml), a saturated solution of ammonium chloride (25 ml), the organic phase was separated dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give a white solid. This material was crystallised from dichloromethane to give 2-(9-fluorenylmethoxycarbonyl)aminoethanol.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN1CCOCC1.[NH2:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)=[O:10]
Reactant: NCC1CC1
Reactant: Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1ccccc1C(=O)NCC1CC1
Yield: 72 %

Procedure:
A 100 ml, round bottom flask was charged with anthranilic acid (500 mg, 3.65 mmol), added DMF (15 mL) under nitrogen atmosphere and stirring. Then, added N-methylmorpholine (1 mL, 9.12 mmol), aminomethylcyclopropane (311 mg, 4.38 mmol), N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI) (840 mg, 4.38 mmol) and HOBt (670 mg, 4.38 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (50 mL×2). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to afford amorphous colorless 2-amino-N-(cyclopropylmethyl)benzamide (500 mg, 72% yield), which was checked by NMR and used for next step without further purification. 1H-NMR (Bruker 300 MHz, DMSO-d6) δ 0.20-1.01 (m, 4H), 1.01-1.04 (m, 1H), 3.06-3.11 (m, 2H), 6.37-8.21 (m, 7H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[CH2:35][OH:36]>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:36][CH2:35][C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: OCc1ncccn1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ncccn2)c(-c2ccc(OC(F)(F)F)cc2)n1

Procedure:
In analogy to example 64, however by starting from 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide (example 21e) and pyrimidin-2-yl-methanol the title compound was obtained as an off-white solid. MS (ISP) (M+H+)=490.2.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)=O>[CH2:20]([N:27]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:1]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Yield: 24.9 %

Procedure:
A mixture of ethyl 4-benzoylbenzoate (13.7 g, 54 mmole), benzylhydrazine (8 g, 65 mmole), ethanole (50 mL) and HOAc (1 mL) was refluxed for 12 hours and then treated with the procedure described in Example 1 to yield a crude product that was purified by column chromatography (silica gel-benzene), and recrystallized from n-hexane to give 4.8g 1-benzyl-3-(4′-ethoxycarbonylphenyl)indazole in a yield of 25.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([NH:15]C(=O)C)=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([NH2:15])=[C:13]([F:19])[C:12]([F:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)ccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 90 °C

Procedure:
A round bottom flask containing N-(6-benzyloxy-2,3-difluorophenyl)-acetamide (1.0 g), potassium hydroxide (1.0 g), water (2 mL) and ethanol (10 mL) are heated at 90° C. for 10 h. The mixture is then concentrated and extracted twice with EtOAc and water. The combined organic layers are dried over MgSO4, filtered and concentrated. The product is used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[F:20][C:21]([F:37])([F:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.ClCC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:37])([F:20])[F:36])=[CH:27][CH:26]=3)[S:29][CH:30]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OC(C)C
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(F)c1)OC(C)C

Procedure:
In analogy to the procedure described in example 1 d], [rac]-3-(3-fluoro-4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester [example 54 c]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (example 18 a]and 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[Br:11]N1C(=O)CCC1=O.C(OCC)(=O)C.II>C(#N)C>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nc[nH]c2nccc1-2
Agent: II
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 4-chloropyrrolo(2,3-d)pyrimidine (30.0 g, 195 mmol) in acetonitrile (300 mL) at 85° C. was added N-bromosuccinimide (34.8 g, 195 mmol) portion-wise during a period of 10 minutes and the reaction mixture was stirred at 40° C. for 1 hour, then at room temperature for another 30 minutes. The reaction progress was monitored by TLC using 30% ethyl acetate in petroleum ether with iodine and 254 nm UV light to visualize the spot. The reaction mixture was allowed to stand for 1 hour so that precipitation occurred completely. The resulting solid was filtered and washed with chilled water (250 mL), then dried under high vacuum to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as brown solid. LRMS (ESI) calc'd for C6H4BrClN3 [M+H]+, 232; found 232. 1H NMR (400 MHz, DMSO-D6,) δ: 12.98 (s, 1 H), 8.60 (s, 1H), 7.96 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([Cl:28])[CH:20]=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:4](=[CH:3][N:2]([CH3:10])[CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:24])=[C:21]([Cl:28])[CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
30.2 g of ethyl 3-dimethylaminoacrylate and 29.3 ml of triethylamine were dissolved in 180 ml of toluene and heated to reflux. At this temperature there was added dropwise thereto a solution of 53 g of 4-bromo-2-chloro-benzoyl chloride in 50 ml of toluene over 30 min. and the mixture was subsequently stirred at reflux for a further 1 hr. The mixture was left to cool to room temperature and was stirred in an ice bath for a further 30 min. The suspension was filtered and the triethylamine hydrochloride was washed with 40 ml of ice-cold toluene. The filtrate was concentrated to half of the volume and then, for crystallization, diluted with 100 ml of hexane and stirred in an ice bath for a further 1 hr. 51.2 g (67%) of ethyl 2-(4-bromo-2-chlorobenzoyl)-3-dimethylamino-acrylate were obtained as white crystals. M.p. 101°.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:21])[CH3:20])(=[O:6])=[O:5].C([Li])CCC.CCCCCC>C1COCC1>[C:3]([S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:21])[CH3:20])(=[O:6])=[O:5])#[CH:2]
Reactant: Cc1cc2c(cc1S(=O)(=O)C=C(Cl)Cl)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 5(b), by reaction at −78° C. of 6-(2,2-dichlorovinylsulphonyl)-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (8 g, 24.3 mmol) in 200 ml of THF with 2.5 M n-butyllithium/hexane (21.4 ml, 53.5 mmol), 2.08 g (33%) of the expected alkyne are obtained in the form of a yellow solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:53]([C:52]3[CH:56]=[CH:57][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)=[O:54])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added 4-methoxybenzoyl chloride (0.068 g, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 66% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.11 (d, 1H), 8.03 (d, 2H), 7.93 (d, 1H), 7.10 (m, 2H), 7.53 (t, 1H), 7.09 (d, 2H), 3.85 (s, 3H); ES-MS (m/z) 411 [M+1]+.