Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:43]>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:43])=[C:8]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(CCC(=O)OC)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
3-(3-Diethoxyphosphoryl-4-hydroxymethyl-phenyl)propionic acid methyl ester (330 mg, 1 mmol), PPh3 (289 mg, 1.1 mmol) and CBr4 (365 mg, 1.1 mmol) were dissolved in 5 mL dry THF. The reaction mixture was stirred at 25° C. for 1 hr. The mixture turned cloudy. Solid was filtered and the filtrate was concentrated. The residue was further purified by flash column chromatography on silica gel (EtOAC/hexane 3/1, Rf=0.40). Pure product was obtained as an oil 150 mg (yield 38%).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:10]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:3]=1
Reactant: C1CCC2NCCCC2C1
Reactant: O=C(O)c1csc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 8 h

Procedure:
5-Bromo-thiophene-3-carboxylic acid (0.44 g, 2.18 mmol) was dissolved in acetonitrile (3 mL) and decahydroquinoline (a 3:2 mixture of cis- to trans-isomers; 2 mL) then HATU (2.18 mmol) was added. The reaction mixture was stirred overnight, and then the solvent evaporated and the residue purified by flash chromatography on silica eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired cis-product were concentrated under vacuum to give the title compound (0.63 g) as a colourless gum. LCMS m/z 330.36 [M+H]+ R.T.=4.09 min. (Analytical Method 5).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccc(CCl)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at 0° C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 mM) was added and the resultant mixture stirred at 0° C. for 3 h, then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 502.3 mg (37%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow foam. 1H NMR (CDCl3) δ 7.4-7.2 (m, 4H), 6.9 (m, 1H), 6.7 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[N:31]=[C:32]([C:37]4[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][C:38]=4[CH3:47])[S:33][C:34]=3[CH2:35][CH3:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][C:21]=3[C:30]3[N:31]=[C:32]([C:37]4[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=4[CH3:47])[S:33][C:34]=3[CH2:35][CH3:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCc1sc(-c2ccc(C(=O)OC)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc(-c2ccc(C(=O)O)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate (11 mg, 0.015 mmol) in 1,4-dioxane (0.4 mL) and water (0.4 mL), was added 1N LiOH (0.151 mL, 0.151 mmol). The mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water containing 0.1% TFA. The fractions were collected and lyophilized to give 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoic acid. LCMS calc.=717.1; found=717.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H); 7.99 (d, J=8.1 Hz, 1H); 7.89 (d, J=8.1 Hz, 1H); 7.87 (s, 1H); 7.78 (s, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.71 (s, 2H); 7.57 (d, J=7.9 Hz, 1H); 5.61 (d, J=8.0 Hz, 1H); 4.94 (d, J=15.7 Hz, 1H); 4.25 (d, J=15.7 Hz, 1H); 4.04-3.98 (m, 1H); 2.89-2.76 (m, 2H); 2.69 (s, 3H); 1.37 (t, J=7.5 Hz, 3H); 0.60 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([OH:19])[CH:15]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:33]1[CH2:42][CH2:41][C:36]2([O:40][CH2:39][CH2:38][O:37]2)[CH2:35][CH2:34]1)(=O)=O.O>CN(C)C=O>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:19][CH:33]3[CH2:42][CH2:41][C:36]4([O:40][CH2:39][CH2:38][O:37]4)[CH2:35][CH2:34]3)[CH:15]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
20.00 g 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one in 150 ml N,N-dimethylformamide are heated to 50° C., then 16.00 g potassium carbonate and 20.00 g 1,4-dioxa-spiro[4.5]dec-8-yl methanesulphonate are added and the reaction mixture is stirred overnight at 80° C. Then another 6.00 g potassium carbonate and 8.00 g 1,4-dioxa-spiro[4.5]dec-8-yl methanesulphonate are added and the mixture is stirred for a further 4 h at 80° C. Within the next 24 h a total of a further 6.00 g potassium carbonate and 10.00 g 1,4-dioxa-spiro[4.5]dec-8-yl methanesulphonate are added batchwise until the reaction is complete. After cooling to ambient temperature a total of 450 ml of water are very slowly added dropwise with stirring, whereupon a precipitate is formed which is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:26][CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:26]([N:18]([CH2:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)C(C)C

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide (example 49, step 2) was reacted with 1-iodo-2-methylpropane and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid isobutyl-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as an off-white solid. MS: 441.3 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:33][C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=[CH:36][CH:35]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1cccc2ccccc12
Product: O=C(NCc1cccc2ccccc12)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(aminomethyl)naphthalene as in General Procedure 10 to give the title compound. LCMS: m/z=586.95 (M+H+); retention time=1.01 minutes.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16](Cl)=[O:17])[O:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[O:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(C1CCCCC12OCCO2)N1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Pyrrolidine (0.21 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aquous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (97 mg, 41%) as a white solid. MS ISP (m/e): 240.3 (100) [(M+H)+].
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]4[C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:16][C@@H:15]2[NH:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].Cl>CO.O1CCCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]4[C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:16][C@@H:15]2[NH:34][CH:35]([CH2:36][CH3:37])[CH2:38][CH3:39])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@@H](NC(CC)CC)C3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@@H]2NC(CC)CC)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A 2 N aqueous lithium hydroxide solution (439 μL, 0.877 mmol) was added to a mixed solution of ethyl 2-{(3S,4R)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidin-1-yl}-1,3-benzothiazole-7-carboxylate obtained in Example (202f) (48.0 mg, 0.088 mmol) in methanol (0.3 mL) and tetrahydrofuran (0.3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. The reaction solution was concentrated under reduced pressure and water was added. The aqueous layer was washed with diethyl ether. A 1 N aqueous hydrochloric acid solution (877 μL, 0.877 mmol) was added to the aqueous layer, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 42 mg of the title compound (92%) as a pale yellow solid.
Reaction SMILES: COC([CH:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:20][C:6]1=2)=O.C(O)(=O)C.Cl.[OH2:32]>>[O:32]=[C:5]1[CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[CH:18][C:19]([CH:21]([CH3:26])[C:22]([OH:24])=[O:23])=[CH:20][C:6]1=2
Reactant: O
Reactant: COC(=O)C(C)c1ccc2c(c1)C(C(=O)OC)C(=O)c1ccccc1S2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccccc1S2

Procedure:
Methyl 2-(10,11-dihydro-1i-methoxycarbonyl-10-oxodibenzo[b,f]thiepin-2-yl)propionate (prepared in Example 22, 18 mg, 0.040 mmol.), acetic acid (0.3 mL) and 6N hydrochloric acid (0.3 mL) were mixed, and the mixture was heated for 2 hours under reflux. To the reaction mixture was added water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The residue was dissolved in toluene and concentrated under reduced pressure to give 14 mg of the desired compound as a white crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
64 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 64 mg (0.23 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred for 1 h at RT. Then 40 mg (0.15 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].Cl>O>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid compound of formula-8 (200 g) and 40% solution of methyl amine (660 ml) was taken into autoclave and heated to 85-90° C. and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25-35° C. Water was added to the reaction mixture and acidified with hydrochloric acid. Filtered the precipitated solid, washed with water and then dried to get title compound.
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1>O>[Br:1][C:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)[C:8]([OH:7])=[N:9][CH:10]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(Br)cnc(O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A mixture of bromine (940 mg) and acetic acid (10 mL) was added dropwise to a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.2 g) and acetic acid (50 mL) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain methyl 4-bromo-1-hydroxyisoquinoline-7-carboxylate (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:20])[C:15](=[CH2:19])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O>O>[O:20]=[C:14]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:12]=2[Cl:13])[CH2:19][CH:15]1[CH:16]([CH3:17])[CH3:18]
Reactant: C=C(C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl)C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,3-Dichloro-4-(2-methyleneisovaleryl)phenoxyacetic acid (8.8 g., 0.0278 mole) is added to concentrated sulfuric acid (50 ml.). The mixture is stirred and heated at 60° C. for two hours and then at 80° C. for three hours. The dark solution is cooled and added dropwise with stirring to water (1 l.). A pale yellow gum separates and after 16 hours at 20°-25° C. changes to a cream colored powder (8.6 g., m.p. 161°-164° C.) which is recrystallized from acetic acid-water (1:1) to afford 6.9 g. of (1-oxo-2-isopropyl-7,8-dichloro-5-indanyloxy)acetic acid, m.p. 166°-167.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9](N2CCOCC2)[N:8]=[C:7]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[C:6]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38].C[Si]([C:43]#[N:44])(C)C>C(N(CC)CC)C>[C:21]([C:26]1[CH:25]=[C:24]([C:9]2[N:8]=[C:7]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:20])[C:6]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[C:5]([O:4][CH2:3][CH2:2][OH:1])[N:10]=2)[CH:23]=[CH:43][N:44]=1)#[N:22]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(N2CCOCC2)nc1OCCO
Solvent: CCN(CC)CC
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccnc(C#N)c2)nc1OCCO

Procedure:
reacting the product of step e) with trimethylsilylcyanide and triethylamine to form 5-isopropyl-pyridine-2-sulphonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl-amide, and
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]([CH2:30][C:31]3[CH:32]=[C:33]4[C:48]([CH3:49])=[N:47][N:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:34]4=[N:35][C:36]=3[N:37]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:12][CH:13]=2)=[N:4]1.[CH3:54]I.O>CN(C=O)C>[F:27][C:26]([F:28])([F:29])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][N:14]([CH2:30][C:31]1[CH:32]=[C:33]2[C:48]([CH3:49])=[N:47][N:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:34]2=[N:35][C:36]=1[N:37]([CH2:42][CH:43]1[CH2:45][CH2:44]1)[CH2:38][CH:39]1[CH2:41][CH2:40]1)[C:11]1[N:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][N:3]([CH3:54])[N:4]=2)=[CH:13][N:12]=1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(-c4cc[nH]n4)cn3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(-c4ccn(C)n4)cn3)cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.008 g, 0.21 mmol) in DMF (2 ml) was added dropwise with stirring to 5-(((5-(1H-pyrazol-3-yl)pyrimidin-2-yl)(3,5-bis(trifluoromethyl)benzyl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine, obtained in Example 8 (0.03 g, 0.042 mmol). The reaction mixture was stirred for 20 min at 0° C. CH3I was added at this temperature and the mixture was stirred for an hour at 20-35° C. The reaction mixture was then treated with water and the mixture was extracted three times with ethyl acetate (50 ml). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get the crude product. The crude product was further purified by column chromatography using 60-120 silica gel and 35% EtOAc in petroleum ether as eluent to afford the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29].[Se](=O)=[O:31]>C(OCC)(=O)C.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]([C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=1)=[N:11][CH:10]=[C:9]2[CH:28]=[O:29]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-(3-bromo-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (70 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-bromo-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (62 mg, 88% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH2:5][C:4]([C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:21].Cl.C[OH:24]>ClCCl>[CH3:1][N:2]1[CH:6]([CH3:7])[CH2:5][C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[OH:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]1=[O:21]
Reactant: CC1CC(c2ccccc2)(c2ccc(O)cc2)C(=O)N1C
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: CC1CC(c2ccccc2)(c2ccccc2O)C(=O)N1C
Temperature: -60 °C

Procedure:
(+/-)-1,5-dimethyl-3-(p-hydroxyphenyl)-3-phenyl-2-pyrrolidone (from Example 1), 1.5 g, was dissolved in 30 mL dichloromethane. The flask was flushed with argon and chilled in an acetone/dry ice bath to -60° C. I M boron tribromide in dichloromethane, 10 mL, was then added drop-wise over 18 min with stirring. The reaction was allowed to come to room temperature and stirred for 22 h. Methanol, 10 mL, was then added slowly to quench the reaction. The resultant solution was rotary evaporated to give an oil redissolved in 10 mL methanol and rotary evaporated a second time. The oil was diluted with 20 mL water to give a precipitate. 6 N hydrochloric acid, 6 mL, was added followed by 50 mL dichloromethane. Mixing gave a biphasic solution. The phases were separated and the upper aqueous phase was reextracted twice with 25 mL portions of dichloromethane. The combined dichloromethane extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to give a foam residue.