Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:60][C:61]([F:65])([F:64])[CH2:62][NH2:63]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([NH:63][CH2:62][C:61]([F:65])([F:64])[F:60])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCC(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)NCC(F)(F)F)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2,2,2-trifluoroethylamine (56 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (102 mg, yield 60%) as a pale-yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.O.[CH:18]1[CH:23]=CC=C[CH:19]=1>C(O)(C)C>[CH:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11])([CH3:23])[CH3:19]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Br)ccc1C(=O)OC(C)C

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid (Aldrich, 5.4 g, 25 mmol) in benzene (75 mL) and isopropanol (75 mL) was treated with concentrated sulfuric acid (1.5 mL) and heated to reflux over 4 days using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and saturated, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a clear oil that was used as such for the next step (6.12 g, 95%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH3:26][C@@H:21]1[CH2:22][CH2:23][C@@H:24]([CH3:25])[N:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: CCNCC
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Product: CCN(CC)CCCOc1ccc(-c2ccc(C(=O)N3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 4A and diethylamine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10]
Reactant: COc1ccccc1CN
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: COc1ccccc1CNc1nc(Cc2ccsc2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (038 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 521 mg (3.80 mmol) of 2-methoxybenzylamine to give 62 mg (46% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[CH3:27][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=1)([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CI
Reactant: CC(C)OC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A 250-mL round bottom flask was charged with diisopropyl 2-(4-nitrobenzyl)malonate (1.61 g, 4.98 mmol) in DMF (24 mL). To this solution at 0° C. was slowly added NaH (60% suspension, 0.24 g, 5.97 mmol). After 30 minutes, iodomethane (0.37 mL, 5.97 mmol) was added in one portion. The reaction was stirred for 21 h, at which time, the reaction was warmed to rt. The reaction was diluted in water (250 mL) and extracted with methyl tert-butylether (3×75 mL). The combined extract was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 8:2) as eluent to afford the title compound (1.44 g, 86%) as a white solid. MW=337.37. 1H NMR (CDCl3, 300 MHz) δ 8.16-8.09 (m, 2H), 7.37-7.30 (m, 2H), 5.05 (sept, J=6.3 Hz, 2H), 3.30 (s, 2H), 1.33 (s, 3H), 1.27-1.20 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](Cl)=[O:20])=[CH:5]2.C(N(CC)CC)C.Br.Br.[NH2:31][C:32]1[CH:33]=[C:34]2[CH2:40][C:39](=[O:41])[NH:38][C:35]2=[N:36][CH:37]=1.O>ClCCl>[O:41]=[C:39]1[NH:38][C:35]2=[N:36][CH:37]=[C:32]([NH:31][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:33]=[C:34]2[CH2:40]1
Reactant: Nc1cnc2c(c1)CC(=O)N2
Reactant: O=C(Cl)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1.3 g (4.25 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid chloride, prepared in the preceding step, 2.1 mL (14.9 mmol) of triethylamine and 1.45 (4.68 mmol) of 5-amino-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine dihydrobromide (US 2005/256 125) in 42.5 mL of dichloromethane is stirred for 24 hours at room temperature. After this time, the mixture is poured into 200 mL of water. 100 mL of dichloromethane are added and the organic phase is then separated out, washed with twice 50 mL of water and concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and dichloromethane. The product thus purified is taken up in 100 mL of hot methanol, and the resulting suspension is filtered. The filtrate is concentrated under reduced pressure, thus allowing 0.4 g of the expected product to be isolated.
Reaction SMILES: [CH:1]1([CH:4]([CH2:11][C:12](OCC)=[O:13])[CH2:5][C:6](OCC)=[O:7])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)C.Cl>C1COCC1>[CH:1]1([CH:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(CC(=O)OCC)C1CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: OCCC(CCO)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 g (14.02 mmol) of diethyl 3-cyclopropylpentanedioate were dissolved in 24.7 ml of abs. THF, and, after cooling to −10° C., 25.2 ml (25.2 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise. The reaction mixture was stirred at RT overnight. After cooling to 0° C., 100 ml of isopropanol were carefully added dropwise. The mixture was acidified by addition of 1 N hydrochloric acid and mixed with Celite. After filtration through Celite and washing with ethyl acetate and water, the filtrate was saturated with sodium chloride and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→2:1). This gave 1.35 g of the target product (66.8% of theory).
Reaction SMILES: C1CCCCC=1.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]3[N:30]=[C:29]([CH3:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[CH:20][C:19]([CH:38]=[CH2:39])=[CH:18][N:17]=2)=[CH:11][CH:10]=1.C1C[O:43]CC1>>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([CH2:38][CH2:39][OH:43])=[CH:20][C:21]=2[C:22]2[N:30]=[C:29]([CH3:31])[N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: C1=CCCCC1
Product: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.0 mL) and cyclohexene (0.42 mL, 4.15 mmol) were cooled in an ice water bath under nitrogen, and borane-dimethyl sulfide complex (0.19 mL, 2.0 mmol) was added via syringe. The reaction was allowed to warm to room temperature while being stirred under nitrogen over 90 minutes, resulting in a suspension. In a separate flask, N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (185.4 mg, 0.418 mmol) was dissolved in THF (6.0 mL), and to this solution was added 1.6 mL of the suspension generated in the first flask. The addition occurred via syringe dropwise, resulting in gas evolution. The reaction was stirred at room temperature under nitrogen for 40 minutes and then cooled in an ice/water bath and quenched with MeOH (4.0 mL), 2N aqueous NaOH (4.8 mL), and 30% aqueous H2O2 (6.5 mL), all added via syringe. The reaction was stirred while being allowed to warm to room temperature. After 75 minutes, more 2N aqueous NaOH (1.2 mL) and 30% aqueous hydrogen peroxide (3.5 mL) were added, and stirring was continued. Then, 3 hours after that, 5N aqueous NaOH (1.60 mL) and 30% aqueous hydrogen peroxide (8.0 mL) were added, and stirring was continued for another hour. Then, the reaction was diluted with water (20 mL), DCM (20 mL), and MeOH (about 1 mL), and allowed to stand at room temperature overnight. Then, the layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. The organic extracts were combined, concentrated, and taken on to step 2.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15](OC)=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].OC(CC1C=CC([Cl:37])=CC=1Cl)C(C1C=CC=CC=1)=O.OC(CC1C=CC(N(C)C)=CC=1)C(C1C=CC=CC=1)=O.OC(CC1C=CC(OC)=C(OC)C=1)C(C1C=CC=CC=1)=O.OC(CC1C=CC(N(CC)CC)=CC=1)C(C1C=CC=CC=1)=O.OC(CC1C=C(C)C(N(C)C)=CC=1)C(C1C=CC=CC=1)=O.OC(CC1C=C(Cl)C(N(C)C)=CC=1)C(C1C=CC=CC=1)=O.OC(CC1C=CC(Cl)=CC=1)C(C1C=CC=CC=1)=O.OC(CC1C=CC=CC=1OC)C(C1C=CC=CC=1)=O>>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[C:16]([Cl:37])[CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccccc1)C(O)Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC(O)C(=O)c2ccccc2)cc1
Agent: CCN(CC)c1ccc(CC(O)C(=O)c2ccccc2)cc1
Agent: CN(C)c1ccc(CC(O)C(=O)c2ccccc2)cc1
Agent: CN(C)c1ccc(CC(O)C(=O)c2ccccc2)cc1Cl
Product: O=C(c1ccccc1)C(O)Cc1cccc(Cl)c1

Procedure:
The following compounds were prepared in a similar manner: 2-hydroxy-β-(4-methoxyphenyl)-propiophenone of melting point 51°-54° C.; 2-hydroxy-β-(2,4-dichlorophenyl)-propiophenone of melting point 106° C.; 2-hydroxy-β-(4-dimethylaminophenyl)-propiophenone of melting point 69°-71° C.; 2-hydroxy-β-(3,4-dimethoxyphenyl)-propiophenone of melting point 84°-87° C.; 2-hydroxy-β-(4-dimethylaminophenyl)-propiophenone of melting point 62° C.; 2-hydroxy-β-(4-diethylaminophenyl)-propiophenone of melting point 49°-51° C.; 2-hydroxy-5-methyl-β-(4-dimethylaminophenyl)-propiophenone of melting point 90°-92° C. and 2-hydroxy-5-chloro-β-(4-dimethylaminophenyl)-propiophenone of melting point 99° C.; 2-hydroxy-β-(4-chlorophenyl)-propiophenone, C15H13ClO2 (260.72); oily: calculated: C: 69.10; H; 5.03; Cl: 13.60; found: C: 69.5; H: 5.4; Cl: 13.2; and 2-hydroxy-β-(2-methoxyphenyl)-propiophenone, C16H16O3 (256.30); oily: calculated: C: 74.98; H: 6.29; found: C: 74.7; H: 6.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:22]=[CH:21][N:20]=1
Reactant: COc1ccnc(Nc2cc(C)cc(Br)c2)n1
Reactant: Nc1cc(B(O)O)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(Nc2cc(C)cc(-c3ccnc(N)c3)c2)n1
Temperature: 100 °C

Procedure:
A mixture of N-(3-bromo-5-methylphenyl)-4-methoxypyrimidin-2-amine (125 mg, 0.425 mmol), 2-aminopyridine-4-boronic acid (103 mg, 0.467 mmol), PdCl2(dppf)-CH2Cl2 adduct (35 mg, 0.042 mmol) and sodium carbonate (425 μL, 0.850 mmol) in dioxane (3 mL) was heated to 100° C. for 14 hours. The reaction mixture was filtered through a CELITE pad and washed with dioxane (3×). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (methanol/ethyl acetate) to give N-[3-(2-aminopyridin-4-yl)-5-methylphenyl]-4-methoxypyrimidin-2-amine as a tan solid. MS ESI calc'd for C17H18N5O [M+H]+ 308. found 308. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.95-7.88 (m, 2H), 7.61 (s, 1H), 7.00 (s, 1H), 6.69 (d, J=5.4 Hz, 1H), 6.64 (s, 1H), 6.28 (d, J=5.6 Hz, 1H), 5.95 (s, 2H), 3.92 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH:10][CH2:11][CH:12]=[CH2:13])[CH:8]=[CH2:9]>>[CH2:7]([N:10]([CH2:11][CH:12]=[CH2:13])[C:4](=[O:5])[CH2:3][CH2:2][Cl:1])[CH:8]=[CH2:9]
Reactant: O=C(Cl)CCCl
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)C(=O)CCCl

Procedure:
comprises first reacting 3-chloropropionyl chloride (CPC) with diallylamine to form N,N-diallyl-3-chloropropaneamide, then reacting this product with RF-iodide followed by eliminating HCl and Hl by dehydrohalogenating with a base such as an alkali metal hydroxide. The product of the formula IIa is then washed with water followed by separating the aqueous layer.
Reaction SMILES: [OH:1]C1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.S(Cl)(Cl)(=O)=O.[N-:23]=[N+:24]=[N-:25].[N-:26]=[N+:27]=[N-:28].[C:29]1(=O)[C:38]2[C:33]([C:34](=[O:39])[CH:35]=[CH:36][CH:37]=2)=[CH:32][CH:31]=[CH:30]1.C(N(CC)CC)C>O1CCOCC1>[N-:23]=[N+:24]=[N-:25].[N-:26]=[N+:27]=[N-:28].[C:37]1(=[O:1])[C:38]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34](=[O:39])[CH:35]=[CH:36]1
Reactant: O=C1C=CC=C2C(=O)C=CC=C12
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [N-]=[N+]=[N-]
Solvent: O=S(=O)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)c2ccccc21
Temperature: 40 °C

Procedure:
11.4 g (0.05 mol) of bisphenol A (result of calculation of dipole moment based on MOPAC-97=2.1 debye) and 34.9 g (0.13 mol) of 5-naphthoquinone diazide sulphonyl chloride were dissolved in 400 g of 1,4-dioxane under a current of dry nitrogen, and then warmed to 40° C. To this there was added, dropwise, 13.1 g (0.13 mol) of triethylamine mixed with 40 g of 1,4-dioxane, and then naphthoquinone diazide compound (4) was obtained in the same way as in Synthesis Example 1. (As an average, 1.3 of the Q groups=5-naphthoquinone diazide sulphonyl groups and 0.7=hydrogen.)
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])([O-])=O.[K+].[K+]>CCO>[CH:2]1([NH:7][N:8]=[C:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][CH2:18]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NNC2CCCC2)CC1

Procedure:
A mixture of cyclopentylhydrazine hydrochloride (1.07 g, 7.83 mmol), Boc-4-piperidone (1.57 g, 7.86 mmol) and K2CO3 (2.2 g, 16 mmol) in EtOH (20 mL) is heated at reflux for 3 hr. The mixture is filtered and the filtrated is concentrated to give the title compound as an oil that is used in the next step without further purification. MS (M+1): 282.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10](I)[C:5]2=[CH:4][CH:3]=1.[CH:18]1([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26](B4OC(C)(C)C(C)(C)O4)[CH:27]=3)[C:22]2=[O:39])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([C:26]3[CH:27]=[C:28]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:39])[N:21]([CH:18]3[CH2:20][CH2:19]3)[CH2:29]4)[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Product: O=C1c2ccc(-c3nn(C4CCCCO4)c4nc(Cl)ccc34)cc2CN1C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 72, Step 3 starting from 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (Example 72, Step 2) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=409.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1nc2c(s1)CCCC2
Reactant: S=C=NCCC1=CCCCC1
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2c(s1)CCCC2
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4,5,6,7-tetrahydrobenzothiazole (1.54 g, 10 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 120 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, the residue taken up in ethyl acetate and washed with 1N HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 426 mg (13%) of the titled product:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH2:38])=[S:37])[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:37])[CH3:28]
Reactant: CCc1ccccc1NC(N)=S
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CCc1ccccc1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-ethylphenyl)thiourea and isolated as an off-white solid (0.152 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[CH3:41][NH:42][CH3:43].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](=[O:29])[N:42]([CH3:43])[CH3:41])([CH3:26])[CH3:27])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N(C)C)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 23.3 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), dimethylamine hydrochloric salt (8.2 mg, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 10 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:38])=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
A solution of triphenylphosphine (105 mg, 0.403 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.336 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminothiazole (74 mg, 0.739 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was treated with a solution of hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate). The pure 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (93 mg, 73%) was obtained as a pale yellow foam: mp 68-72° C. (foam to gel); EI-HRMS m/e calcd for C17H18ClN3O3S (M+) 379.0757, found 379.0760.