Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:8][S:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5].CC(C[AlH]CC(C)C)C.CC(O)C.C(=O)=O>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:7]2[C:6]([CH:4]=[O:5])=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9][N:8]=2)=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 14 (359 mg) in 4 ml of THF is cooled to −78° C. under N2 and to this is added 1.5 ml of DIBALH (1M in hexane). After stirring for 30 min at −78° C., only starting material is observed. The iPrOH/CO2 bath is replaced for an ice bath and stirring is continued at 0° C. for 2 h. TLC shows complete conversion. The mixture is re-cooled to −78° C. and the reaction mixture is quenched with 1N HCl (5 ml). The cooling bath is removed and the reaction mixture is diluted with 1N HCl (50 ml) and EtOAc (50 ml). The layers are separated and the organic layer is washed once more with 1N HCl (50 ml). The organic layer is washed with brine, dried and concentrated. 286 mg of 15 are obtained as a white solid with melting point: 148-149° C.
Reaction SMILES: [C:1]([O-:8])(=O)/[CH:2]=[CH:3]\C([O-])=O.[N:9]1([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C1OC2C=CC(C(Cl)=O)=CC=2O1>CN(C)C=O>[C:1]([N:12]1[CH2:13][CH2:14][N:9]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:11]1)(=[O:8])[CH2:2][CH3:3]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 130 °C

Procedure:
5.6 g of acid maleate of 2-(1-piperazinyl)pyrimidine are dissolved in 80 ml of dimethylformamide, then 5.6 ml of triethylamine and 3.8 g of 3,4-methylenedioxy benzoyl chloride are added. The mixture is heated for 12 hours at 130° C. then the solvent is evaporated to dryness in vacuo. The residue is taken up in a dilute solution of hydrochloric acid and washed with ether. The aqueous phase is rendered alkaline by a sodium carbonate solution and extracted with ethyl acetate. The solution is dried over sodium sulfate and the solvent is evaporated to dryness.
Reaction SMILES: [CH3:1][NH2:2].[O:3]([CH2:10][CH2:11][CH2:12]Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][NH:2][CH2:12][CH2:11][CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: BrCCCOc1ccccc1
Solvent: C1CCOC1
Product: CNCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.57 g of methylamine is condensed in a solution of 1.6 ml of 3-phenoxy-propylbromide in 15 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium chloride solution, extracted with ether, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 2.01 g of methyl-(3-phenoxy-propyl)-amine is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]4[C@H:26]([CH2:29][C:30]([O:32]C)=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:36])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:35]=[CH:34][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a solution of methyl [(3S)-6-({4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.358 g, 0.707 mmol) in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous sodium hydroxide solution (0.750 mL), and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.309 g, yield 89%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][CH:5]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a solution of 100 g (386.5 mmol) 4-(3-chloro-propoxy)-5-methoxy-benzoic acid methyl ester in 300 ml acetic acid was added dropwise 100 ml of 70% nitric acid. The mixture was heated to 50° C. for 1 hr and then poured into ice water. The mixture was extracted with chloroform. The organic solution was washed with dilute sodium hydroxide and then dried over magnesium sulfate. The solvent was removed. Ether was added an the mixture was stirred until solid was deposited. The solid was collected by filtration giving 98 g of 4-(3-Chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester as white crystals: mass spectrum (electrospray, m/e,): M+H 303.8; 2M+NH4623.9.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N>CO.[Ni]>[NH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)NC(=O)c1ccc(CN)cc1
Yield: 108.9 %

Procedure:
Combine N-tert-butyl-4-cyano-benzamide (0.4 g, 1.78 mmol), Raney® 3201 nickel (slurry in water, 0.03 g), 2N ammonia in methanol (20 mL) and hydrogenate at 50 psi for 1 h. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a colorless oil (0.4 g, 95%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCBr
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Dimethylaniline (100 grams), the dihexyl acetal of 2-bromoacetaldehyde (70 grams) and sodium carbonate (32 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then distilled under vacuum to yield the desired product the dihexyl acetal of 2-(2,6-dimethylanilino)acetaldehyde as the residue.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[CH:25])[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C#Cc1ccc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(C#Cc2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3 g (8.8 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyphenylacetylene, 1.8 g (9.7 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 160 mg (1.7 mmol) of palladium(II) acetate and 350 mg (1.3 mmol) of triphenylphosphine were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)OCc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10.0 g 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml DMF were added 7.1 ml benzyl bromoacetate and 24.0 g cesium carbonate. After stirring for 16 h at RT the suspension was filtered, washed with DMF and concentrated. The residue was taken up with ethyl acetate and extracted with aqueous LiCl (4%). Evaporation of the solvent yielded the crude product which was used in the subsequent debenzylation. Yield: 15.5 g yellow oil.
Reaction SMILES: [BrH:1].C[O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3=[N:20][N:21]=[CH:22][N:12]3[N:11]=2)=[CH:6][CH:5]=1>>[BrH:1].[N:20]1[N:21]=[CH:22][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([OH:3])=[N:9][CH:8]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=12
Reactant: COc1ccc(-c2nn3cnnc3c3ccccc23)cn1
Agent: Br
Product: Oc1ccc(-c2nn3cnnc3c3ccccc23)cn1

Procedure:
47% hydrobromic acid was added to 141 mg of 6-(6-methoxypyridin-3-yl)-[1,2,4]triazolo[3,4-a]phthalazine, and refluxed for 4 hours. The reaction liquid was concentrated under reduced pressure, and ether was added to the resulting residue. The resulting solid was taken out through filtration to obtain 250 mg of 5-[1,2,4]triazolo[3,4-a]phthalazin-6-ylpyridin-2-ol hydrobromide as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[S:22][C:15]=12)=[O:8].Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]([O:25][CH2:30][CH2:31][CH2:32][OH:33])=[O:24])[S:22][C:15]=12)=[O:8]
Reactant: OCCCBr
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)O)sc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc3cc(C(=O)OCCCO)sc23)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.30 mmol) in anhydrous DMF (10 ml) were added 3-bromo-1-propanol (63 mg, 0.45 mmol) and potassium carbonate (83 mg, 0.60 mmol). The mixture was heated at 50° C. for 5 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give 3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as white solid. Yield: 25 mg, 18%.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.I[C:12]1[CH:13]=C(C=C[C:20]=1CCC)C(O)=O>>[C:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)#[C:12][CH3:13]
Reactant: CCCc1ccc(C(=O)O)cc1I
Reactant: O=C(O)c1ccc(I)nc1
Product: CC#Cc1ccc(C(=O)O)cn1
Yield: 45 %

Procedure:
When 6-iodonicotinic acid was substituted for the 3-iodo-4-propylbenzoic acid in Example 47, Step B, the similar process afforded the title compound in 45% yield, as yellow solid. 1H-NMR (CDCl3) 2.12 (s, 3H); 7.25 (broad s, 1H+H2O); 7.46 (dd, 1H, J=0.6, 7.6 Hz); 8.2 (dd, 1H, J=2.16, 6 Hz); 9.23 (dd, 1H, J=0.8, 1.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[CH:15]([F:21])[C:16](OCC)=[O:17]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:15]1[C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(F)Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2OC1F
Temperature: 60 °C
Reaction time: 44 h
Yield: 41.8 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (1.98 g) and potassium fluoride (2.24 g) in N,N-dimethylformamide (40 mL) was added ethyl bromofluoroacetate (2.85 g), and the mixture was stirred at 60° C. for 44 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→1/1) and triturated with n-hexane/diisopropylether to give 2-fluoro-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.14 g) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH3:28])=[CH:18]1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 63.1 %

Procedure:
Under an atmosphere of nitrogen, (E)-Methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (0.606 kg, 2.65 mol) and (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (33% w/w solution in toluene, 2.0 kg, 2.65 mol) were charged to a 20 L vessel followed by toluene (4.22 L). Acetic acid (304 ml, 5.31 mol) was added to the vessel. The mixture was agitated and heated to 80° C. The mixture was agitated at 80° C. overnight before being cooled to 20° C. A solution of potassium carbonate (0.916 kg, 6.63 mol) in water (3.3 L) was added to the mixture. The mixture was stirred for 10 minutes before the agitator was switched off and the layers were allowed to separate. The aqueous layer was removed and discarded. Water (3.3 L) was charged to the reactor. The mixture was agitated for 10 minutes then allowed to stand for 10 minutes. The lower aqueous phase was removed and the organic layer was allowed to stand at room temperature overnight. The batch was heated to 80° C. Heptane (4.61 L) was added to the hot solution over 35 minutes. The stirred mixture was held at approximately 80° C. for 1 hour. The mixture was cooled to 30° C. over 2 hours during which time the product crystallised. The slurry was stirred at 30° C. for 2.5 hours. The solid was isolated by filtration. The reactor vessel walls were washed with heptane and the washings were used to wash the filter cake. The solid was dried in vacuo to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate as a pink solid (0.763 kg, 61%). 1H NMR (400 MHz, DMSO, 27° C.) δ 1.06 (3H, d), 1.13 (3H, d), 1.21 (3H, d), 2.35 (1H, dd), 2.58 (1H, dd), 2.8-2.98 (2H, m), 3.44-3.61 (1H, m), 3.74 (3H, s), 5.24 (1H s), 6.80 (1H, d), 6.9-7.05 (2H, m), 7.19 (1H, d), 7.41 (1H, d), 7.50 (2H, d), 7.63 (1H, d), 10.58 (1H, s). m/z: ES+ [M+H]+ 457.
Reaction SMILES: S(=O)(=O)(O)O.C(O[C:13](CC)([CH2:38]C)[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=2)=[C:16]([CH:35]([CH3:37])[CH3:36])[CH:15]=1)(=O)CC([O-])=O.[C:42]([OH:45])(=[O:44])C>O>[CH:20]([C:18]1[CH:19]=[C:14]([CH:13]([CH3:38])[C:42]([OH:45])=[O:44])[CH:15]=[C:16]([CH:35]([CH3:36])[CH3:37])[C:17]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=1)([CH3:21])[CH3:22]
Reactant: CC(=O)O
Reactant: CCC(CC)(OC(=O)CC(=O)[O-])c1cc(C(C)C)c(Oc2ccc([N+](=O)[O-])c(OC)c2)c(C(C)C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Oc2c(C(C)C)cc(C(C)C(=O)O)cc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Sulphuric acid (1.0 mL, 20%) was added to a mixture of diethyl(3,5-diisopropyl-4-[3-methoxy-4-nitrophenoxy]benzyl) malonate (1.4 g), acetic acid (5 mL) and water (5 mL). After heating for 8 hours at 80° C., the reaction mixture was concentrated and ethyl acetate was added to the residue. The organic phase was washed with water and brine. After recrystallization (ethyl acetate/petrolium ether), 1.1 g of 3,5-diisopropyl-4-(3-methoxy-4-nitrophenoxy)phenylpropionic acid was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Product: Fc1ccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:11]([C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1)[CH3:12].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:18][C:15]2[CH:14]=[C:13]([CH2:11][CH3:12])[NH:17][N:16]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Temperature: 105 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
A 350-mL sealed tube equipped with a magnetic stirring bar was charged with 3,5-dibromo-1-methyl-1H-pyridin-2-one (3.2 g, 0.012 mol), 5-ethyl-1H-pyrazol-3-amine (2.0 g, 0.018 mol), Pd2(dba)3 (0.55 g, 0.60 mmol), 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (0.49 g, 0.00084 mol), Cs2CO3 (7.8 g, 0.024 mol), and 1,4-dioxane (80 mL). After the reaction mixture was stirred at 105° C. for 16 h, it was cooled to room temperature, partitioned between dichloromethane (50 mL) and water (30 mL), and the organic phases were extracted with dichloromethane (30 mL×3). The combined organic phases were washed with water (30 mL×2) and brine (20 mL×1), dried (Na2SO4), and filtered through a pad of Celite, and the resulting filtrated was concentrated. To the crude product were added dichloromethane (20 mL) and ether (100 mL). The mixture was sonicated for 10 min., and the resulting precipitates were filtered to give 42% yield (1.5 g) of 5-bromo-3-(5-ethyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one (125a) as a solid.
Reaction SMILES: [H-].[K+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCC1(Cc1cccnc1)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
In a 1-liter three-necked flask provided with magnetic stirring and a condenser, under an inert nitrogen atmosphere, potassium hydride 32% (25 g; 200 mmoles; 1.1 eq.) is suspended in anhydrous THF (200 mL). The reaction mixture is cooled to −78° C. and then benzyl 2-oxocyclopentanecarboxylate (39.7 g; 182 mmoles) is added dropwise whilst keeping the temperature below −78° C. The reaction mixture is stirred for 1 hour at ambient temperature. A solution of 3-(chloromethyl)-pyridine base (38.7 g; 226 mmoles; 1.24 eq.) in 100 mL of anhydrous THF is added to the clear yellow solution. The reaction mixture is stirred at reflux for 12 hours. After coming back to ambient temperature, the reaction mixture is evaporated to dryness and taken up in 80 mL of water and 500 mL of ethyl acetate. The aqueous phase is extracted three times with 50 mL of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and then dried over MgSO4, filtered and concentrated. The product is purified on silica gel using a mixture of dichloromethane/ethanol (gradient of 98/2 to 95/5) as eluant to yield the expected product in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>>[CH2:20]([N:23]([CH2:24][CH2:25][CH3:26])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1)[CH2:21][CH3:22]
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: CCCNCCC
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1h-indazol-5-yl)-amide (Intermediate 16) and dipropylamine (Aldrich), the title compound was obtained as a white solid.