Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[OH:1][CH2:2][CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OCC1C2CCC(O2)C1Cc1cc(F)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCC1C2CCC(O2)C1Cc1cc(F)ccc1OCc1ccccc1
Yield: 94.5 %

Procedure:
To a solution of [1S-(1α, 2α, 3α, 4α)]-2-[[3-[hydroxymethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-4-fluoro-phenol (0.71 g, 2.8 mmol) in ethanol (30 mL) was added potassium hydroxide (0.173 g, 3.08 mmol) and the resulting mixture was refluxed until the potassium hydroxide dissolved. Then benzyl bromide (0.332 mL, 2.8 mmol) was added and the reaction was left to reflux for 16 h. After this time, the reaction was stopped and the solvent was evaporated under vacuum. The crude product was partitioned between ethyl acetate (30 mL) and 2M HCl (15 mL). The organic phase was separated; washed with a sat. solution of sodium bicarbonate (15 mL), brine (15 mL), dried (MgSO4), filtered and the solvent was evaporated “under vacuum” to give the crude product as an oil. The crude product was purified by chromatography column on a 20G SPE cartridge using ethyl acetate/hexane 1:2 as eluent to isolate 0.906 g (94%) of titled product as an oil. 1H-NMR (CDCl3, 300 MHz) δ 7.37(m, 5H, ArH), 6.86 (m, 3H, ArH), 5.08 (s, 2H, —OCH2Ph), 4.56 (d, 1H, J=4.9 Hz, —CH—O—), 4.27 (d, 1H, J=4.9 Hz, —CH—O—), 3.74 (m, 2H, —CH2OH), 2.86 (dd, 1H, J=4.4, 13.9 Hz, —CH—), 2.53 (dd, 1H, J=11.3, 13.7 Hz, —CH—), 2.29 (m, 1H, —CH2—), 2.08 (m, 1H, —CH2—), 1.80-1-32 (m, 4H, —CH2—CH2—)
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([C:16]2[C:17]([O:22][C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:8]([F:32])[CH:7]=1.[OH-].[Li+]>O1CCCC1.CO>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([O:22][C:17]3[C:16]([C:14]([NH:13][CH2:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][C:8]=4[F:32])=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
To a stirred solution of [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester (0.40 g, 0.88 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added aqueous lithium hydroxide (2 mL, 1 M, 2 mmol). The reaction was stirred at room temperature 1 hour. The solvents were stripped in vacuo and the residue partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous was extracted with 2 aliquots ethyl acetate and the pooled organics were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a yellow solid. The crude product was recrystallized from ethyl acetate to afford 80 mg of a white crystalline solid (0.18 mmol, 21% yield). mp 180° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[O:36]=[C:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17]([N:45]3[CH2:44][CH2:43][CH:42]([N:38]4[CH2:39][CH2:40][CH2:41][C:37]4=[O:36])[CH2:47][CH2:46]3)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Reactant: O=C1CCCN1C1CCNCC1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Yield: 8 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (51.5 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (50.5 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.2 mg, 8%).
Reaction SMILES: C(OC([O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9])C)C.[H-].[Na+].CO[C:17](=[O:28])[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH2:9][C:22]([C:21]1[CH:20]=[CH:19][C:18]([C:17](=[O:28])[CH2:9][C:8](=[O:10])[C:7]([CH3:11])([OH:6])[CH3:12])=[CH:27][CH:26]=1)=[O:24]
Reactant: CCOC(C)OC(C)(C)C(C)=O
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)O)cc1
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 9.9 gm (57 mmol) of above-mentioned 3-(1-ethoxyethoxy)-3-methyl-butane-2-one, 2.3 gm (57 mmol) of 60% sodium hydride, 5.0 gm (25 mmol) of dimethylterephthalate and 50 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The reaction mixture was stirred at room temperature while adding 30 ml of methnol with ten drops of 2N hydrochloric acid. A mixed solvent of acetone-chloroform was added to the crude product, and recrystallization afforded 4.1 gm of the title compound as pale yellow crystals (yield: 48%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:19](=O)([O-])O.[Na+].CI>CN(C)C=O>[CH3:19][O:13][C:12](=[O:14])[CH:11]([O:15][CH2:16][CH2:17][CH3:18])[CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Crude rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid was dissolved in 5 ml N,N-dimethylformamide, 0.54 g of sodium hydrogencarbonate was added followed by 0.32 nm of methyl iodide. The mixture was stirred at r.t. for 7 hours, then poured into ice water and extracted 3 times with ethyl acetate; after drying over MgSO4 and evaporation, the crude product was purified by chromatograph) (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 0.47 g of rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester as light yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Yield: 89.9 %

Procedure:
In a manner similar to the method described in example 32a, 1,4-dioxa-spiro[4.5]decan-8-ol (5.1 g, 32 mmol) (Alfa) was reacted with methanesulfonyl chloride (3.7 g, 32 mmol, Aldrich) and triethylamine in dichloromethane to give methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester as a light yellow oil (Yield 6.8 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[NH2:13][NH2:14]>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([NH:13][NH2:14])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: N#Cc1nc(F)c(F)c(N)c1Cl
Reactant: NN
Product: N#Cc1nc(NN)c(F)c(N)c1Cl

Procedure:
reacting the fluoro substituent in the 6-position of 4-amino-3-chloro-5,6-difluoropicolinonitrile (Formula C) with hydrazine to produce 4-amino-3-chloro-5-fluoro-6-hydrazinopicolinonitrile (Formula D)
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31]>>[Cl:39][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[NH:29][CH2:28][CH2:27][OH:26])=[CH:37][C:36]=1[NH:38][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)NCCO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 594.1.2 [(M−H)−]; mp 209° C.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][CH2:20][CH2:21][NH:22][C:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Reactant: NCCNc1ccccc1
Product: O=C(NCCNc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenylaminoethylamine to give the title compound as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([O-:10])[O:7][CH2:8][CH3:9])[CH3:4].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Br.C(OP([O-])OCC)C.[Na+]>O1CCCC1>[CH2:3]([O:5][P:6]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][Br:11])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccccc1CBr)OCC
Yield: 16.1 %

Procedure:
A suspension of sodium hydride (60% in oil, 1.4 g, 35 mmol) in anhydrous tetrahydrofuran (75 ml) is stirred under a nitrogen atmosphere and a solution of diethylphosphite (4.82 g, 34.9 mmol) in tetrahydrofuran (20 ml) is added dropwise. The reaction mixture is stirred an additional 20 minutes. A solution of 1,2-bis(bromomethyl)benzene (10.56 g, 40 mmol) in anhydrous tetrahydrofuran (150 ml) is treated dropwise with the solution of sodium diethylphosphite generated above. The reaction mixture is stirred 6.5 hours at room temperature, and then quenched with water and diluted with diethyl ether. The diethyl ether layer is separated, washed with water (2×100 ml), and dried over magnesium sulfate. After filtration and evaporation, the residue is chromatographed over silica gel (ethyl acetate as eluant) to give a clear oil (1.8 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1/[CH:12]=[C:4]1\[C:5](=[O:11])[NH:6][C:7]2[C:3]\1=[C:2]([C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=1)[CH:10]=[CH:9][CH:8]=2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3cccc(C(F)(F)F)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A suspension of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30 mg, 0.089 mmol) (Starting Material 1), K2CO3 (25 mg, 0.180 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 3-(trifluoromethyl)phenylboronic acid (20 mg, 0.110 mmol) (Aldrich) in 2.5 mL of a 1.5:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 14 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes then 40% ethyl acetate-hexanes elution) to yield pure (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-4-(3-trifluoromethylphenyl)-2H-indol-2-one (yield 18 mg, 56%) as a yellow solid (mp 197-198° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=1)=[O:18])[CH3:13])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=1)=[O:18]
Reactant: CN(CCCCNC(=O)OC(C)(C)C)CCNC(=O)c1nc(Cl)c(N)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
[4-({2-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-amino)-butyl]-carbamic acid tert-butyl ester (0.54 g, 2.2 mmol) in DCM (10 mL) and TFA (2 mL) is stirred at RT for 1 h. The solvent is removed in vacuo and the resulting oil is dissolved in saturated aqueous sodium carbonate solution. The mixture is concentrated in vacuo and the residue is dissolved in MeOH and filtered to remove the sodium carbonate. The filtrate is concentrated in vacuo to afford the title compound. [M+H]+ 316
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]=[C:8]([C:5]3[CH:4]=[C:3]([CH:2]=[CH:7][CH:6]=3)[C:19]([OH:21])=[O:20])[C:12]=2[CH:13]=1
Reactant: O=C=O
Reactant: Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2occ(-c3cccc(C(=O)O)c3)c2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The product of step B in 150 ml. of tetrahydrofuran is added to 5 g. of magnesium turnings in 25 ml. of tetrahydrofuran at a rate sufficient to sustain refluxing. Refluxing is continued for an additional three hours, then the mixture is stirred overnight at about 20° C. To this reaction mixture is added gaseous carbon dioxide over a period of one hour. The mixture is maintained at reflux during the second half hour. The reaction mixture is cooled and cautiously added to 50 ml. of 6N hydrochloric acid. The reaction mixture is evaporated to provide a residue which is recrystallized from acetic acid to provide tan crystals of 3-(5-methyl-3-benzofuranyl)benzoic acid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[OH:26][C:25]([CH3:28])([CH2:27][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]

Procedure:
2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenylamino)propionamide was prepared as described in Example 52 starting from 4-(trifluoromethyl)aniline and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.51 (3H, s), 3.23 (1H, dd, J=13.3 Hz, J=5.0 Hz), 3.51 (1H, dd, J=13.3 Hz, J=7.0 Hz), 6.06 (1H, s), 6.18 (1H, m), 6.77 (2H, d, J=8.4 Hz)), 7.31 (2H, d, J=8.4 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: FC1(F)CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4,4-difluoropiperidine (0.141 g, 0.894 mmol) and triethylamine (0.138 mL, 0.993 mmol) in acetonitrile (4 mL) was heated in a microwave at 150° C. for 12 h. Further portions of 4,4-difluoropiperidine (4 eq.) and triethylamine (5 eq.) were added and the reaction heated at 150° C. for 1 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give a yellow gum which was purified by column chromatography. Elution with 0-100% EtOAc/hexane gave a colourless gum which was a mixture (˜9:1) of the title compound and unreacted D109 (0.0485 g). MS (ES): MH+ 544.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]1=[O:13]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2CC1Br

Procedure:
Analogously to Example 1 (a), reaction of 12.39 g (70.0 mmoles) of 6-nitro-1-indanone in 130 ml of glacial acetic acid, containing 0.5 ml of 48% strength aqueous hydrobromic acid, and 11.2 g (70 mmoles) of bromine in 70 ml of glacial acetic acid, in accordance with the instructions indicated above, gives 2-bromo-6-nitro-1-indanone of melting point 102°-105° C. which, as the pure product after reprecipitation from ethanol/water, has a melting point of 114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=C[C:29]=2N=N1.C1CCN2C(=NCCC2)CC1.[O-]CC.[Na+]>CCO>[CH2:29]([O:18][C:4]1[C:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:30]
Reactant: Nc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOc1nc(N)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (50 mg, 0.19 mmol) and BOP (110 mg, 0.25 mmol) in EtOH (1 ml) was added DBU (43 μl, 0.29 mmol). The resulting mixture was heated at 60° C. for 4 hours. After cooling down to room temperature, sodium ethoxide (26 mg, 0.38 mmol) was added. The mixture was again heated at 60° C. overnight. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) yielding the title compound as a white solid (30 mg, 54%). mp 142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C:11](=[CH2:15])[C:12]([OH:14])=[O:13].C(N(CC)CC)C>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[C:4]2[S:9][CH2:10][CH:11]([C:12]([OH:14])=[O:13])[CH2:15][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(CSc1ccccc1OC)C(=O)O
Solvent: Clc1ccccc1Cl
Solvent: CCN(CC)CC
Product: COc1cccc2c1SCC(C(=O)O)C2

Procedure:
A mixture 22.5 g of α-(o-methoxyphenylthiomethyl)-acrylic acid, 2.53 g of triethylamine and 200 ml of o-dichlorobenzene is heated for 12 hours at 195°. After dilution with ether the products are extracted with sodium bicarbonate solution. Acidification of the basic extracts affords 8-methoxy-3,4-dihydro-2H-[1]-benzothiopyran-3-carboxylic acid, m.p. 138°-144°.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH:37]=[O:38])[CH2:31][CH2:30]1.[CH3:39][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[OH:38][CH:37]([CH3:39])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (841 mg) in tetrahydrofuran (15 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (2.2 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (387 mg, 76%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[C:23]1[S:24][C:25]2[C:26]([NH2:33])=[N:27][CH:28]=[C:29]([F:32])[C:30]=2[N:31]=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[NH:33][C:26]1[C:25]2[S:24][C:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])=[N:31][C:30]=2[C:29]([F:32])=[CH:28][N:27]=1
Reactant: Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
To a solution of methyl chloroformate (18 mg, 0.191 mmol) and DIPEA (42 μL, 0.24 mmol) in THF (1.0 mL) was added 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine (50 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then heated at 50° C. for 2 hours and left standing at room temperature for 18 hours. The crude reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a white solid (12 mg, 20%). 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.77-7.65 (m, 3H), 3.73 (s, 3H). LCMS (Method C): RT=4.74 min, m/z: 372 [M+H+].