Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.ClC(OC(Cl)(Cl)Cl)=O.[C:14]([NH:33][C:34]1[S:35][CH:36]=[C:37](/[C:39](=[N:43]/[O:44][CH3:45])/[C:40]([OH:42])=O)[N:38]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:47][CH:48]1[C:76](=[O:77])[N:50]2[C:51]([C:60]([O:62][CH:63]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[S:61])=[C:52]([CH:55]3[CH2:59][CH2:58][O:57][CH2:56]3)[CH2:53][S:54][C@H:49]12>ClCCl.O.C(O)(=O)C>[C:14]([NH:33][C:34]1[S:35][CH:36]=[C:37](/[C:39](=[N:43]/[O:44][CH3:45])/[C:40]([NH:47][CH:48]2[C:76](=[O:77])[N:50]3[C:51]([C:60]([O:62][CH:63]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[S:61])=[C:52]([CH:55]4[CH2:59][CH2:58][O:57][CH2:56]4)[CH2:53][S:54][C@H:49]23)=[O:42])[N:38]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOC3)CS[C@H]12
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C3CCOC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Vilthmyer reagent was prepared from dimethylformamide (52 mg) and trichloromethyl chloroformate (60 mg) in dichloromethane (1 ml) according to standard method. The Vilsmier reagent as prepared was cooled to -40° C., to which was then added a suspension of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (266 mg) in dichloromethane (2 ml) and the resulting mixture was further stirred at -20° C. for 30 minutes to give a first solution. On the other hand, the diphenylmethyl 7-amino-3-(tetrahydrofuran-3-yl)thio-3-cephem-4-carboxylate hydrochloride (255 mg) was suspended in dichloromethane (2 ml), to which was added N,O-bistrimethylsilylacetamide (0.25 ml) to give a second, clear solution. The latter, second solution was added to the former, first solution, i.e. the solution containing the acetic acid derivative as activated with the Vilthmyer reagent as above, and the resulting mixture was stirred under ice-cooling for 60 minutes to effect the N-acylation reaction. The resulting reaction solution, after adding ice-cooled water thereto, was stirred well and then separated into organic and aqueous layers.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30][NH2:31])[CH2:25][CH2:26][CH3:27].Cl>C(#N)C.C(OCC)(=O)C>[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:29][CH2:30][NH:31][CH:13]1[CH2:12][C:11](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:14]1=[O:15])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCN)CCCC
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCCN1C(=O)CC(NCCN(CCCC)CCCC)C1=O
Reaction time: 6 h

Procedure:
N-nonyl maleimide (0.02 mM) prepared as described in Example 12 above in 2 ml of acetonitrile was treated with one equivalent of triethylamine and one equivalent of N,N-dibutylethylenediamine. The reaction mixture was stirred for six hours and then the acetonitrile was evaporated. The residue obtained was treated with cold aqueous dilute hydrochloric acid solution and ethyl acetate, with stirring for one hour. The ethyl acetate layer was then separated and concentrated to give the desired product.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@@H:37]([CH3:40])[CH2:38][OH:39]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@@H](C)CO)nc2n(C)c1=O
Yield: 74.2 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (S)-2-aminopropan-1-ol (0.036 g, 0.48 mmol) were combined in THF (1 mL) to provide (S)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a white solid (0.062 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H) 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.10-4.06 (m, 1H), 3.65-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J=6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Br)=[O:30])=[CH:25][CH:24]=1.O>ClCCl>[Br:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Br)c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Br)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 10 ml of triethylamine in 50 ml of dichloromethane under argon is added 3 g of 6-bromopyridine-3-carbonyl bromide. The mixture is stirred at room temperature for 16 hours and then poured into 100 ml of water. The organic layer is separated and washed with 2% HCl, water, saturated NaHCO3 and dried (Na2SO4), the solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:19][C:20]1[NH:21][C:22]([NH2:25])=[N:23][N:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:23]3[N:24]=[C:20]([CH3:19])[N:21]=[C:22]3[NH:25][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1nnc(N)[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nc(C)nn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (381 mg, 1.6 mmol) and 5-methyl-4H-1,2,4-triazole-3-amine (200 mg, 2.0 mmol, 1.3 eq.) were dissolved in DMF (4 ml), and solid sodium bicarbonate (659 mg, 7.8 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (300 mg, 46% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH:7]=[C:6]2[C:23]1[N:32](S(C2C=CC(C)=CC=2)(=O)=O)[C:26]2=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]2[CH:24]=1.[OH-].[K+].ClCCl.CO>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[CH:7]=[C:6]2[C:23]1[NH:32][C:26]2=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]2[CH:24]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 61 %

Procedure:
But using 0.82 g of 2-[5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine dissolved in 100 ml of methanol and 2 g of potassium hydroxide dissolved in 7 ml of water. After flash chromatography on a silica column [eluent: dichloromethane/methanol (70/30 by volume)], 0.37 g of 2-{5,6-dimethoxy-1-[2-(4-methyl-piperazin-1-yl)ethyl]-1H-indol-3-yl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(N(CC)CC)C.[CH2:19]([C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25])[CH2:20][CH2:21][CH3:22].[P:30](Cl)([O-:32])[O-:31].P(Cl)([O-])[O-:35]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:19]([C:23]([CH2:28][CH3:29])([CH2:24][OH:25])[CH2:26][OH:27])[CH2:20][CH2:21][CH3:22].[P:30]([O-:32])([O-:35])[O-:31]
Reactant: [O-]P([O-])Cl
Agent: CC1(C)CC(O)CC(C)(C)N1
Agent: CCCCC(CC)(CO)CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [O-]P([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a one liter, four-necked, round-bottom reaction flask was weighed 69.2 grams (0.44 mole) of 2,2,6,6-tetramethylpiperidin-4-ol, 101.2 grams (1.00 mole) of triethylamine and 250 grams of toluene. The flask was equipped with a stir shaft and paddle, temperature probe, dropping funnel, and nitrogen inlet. The reaction mixture was placed under a nitrogen blanket. Most of the 2,2,6,6-tetramethylpiperidin-4-ol was soluble in the solvents at room temperature. 2-Butyl-2-ethyl-1,3-propanediol-chlorophosphite (89.9 grams (0.40 mole)) was weighed into the dropping funnel and then slowly added to the reaction flask. White solids formed immediately. The chlorophosphite was added at a rate of addition such that the reaction temperature stayed between 18 and 22° C. Occasional cooling with an ice bath was necessary to keep the temperature under control. The total addition time was 30 minutes. The ice bath was removed and the mixture was allowed to warm slowly to room temperature. Fifty grams of additional toluene was added to rinse the dropping funnel. The white solids were waxy and difficult to stir at 18° C. After two hours, the mixture was heated to a temperature of 65° C., and stirring was continued for another hour. The mixture was then heated to 80° C. and held there for one hour to ensure the reaction is complete. The mixture was cooled to room temperature and vacuum-filtered to remove any solids. The clear filtrate was evaporated to dryness under vacuum. The product was obtained as a pale yellow liquid. (Yield: 122.8 grams) (GC Purity: 98%). The product was analyzed by 31P-NMR analysis, giving a characteristic signal with a shift of δ=125 ppm.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[N:23]=[CH:22][N:21]([C:24]4[CH:25]=[C:26]([NH:38][C:39](=[O:41])[CH3:40])[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=5[F:37])[CH:29]=4)[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:28]1[CH:29]=[C:24]([N:21]2[C:18]3=[N:19][CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=4)[CH:16]=[C:17]3[N:23]=[CH:22]2)[CH:25]=[C:26]([NH:38][C:39](=[O:41])[CH3:40])[CH:27]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)cnc32)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(=O)[nH]c4)cnc32)c1
Yield: 84.3 %

Procedure:
A solution of N-(5-(6-(6-(benzyloxy)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (0.10 g, 0.182 mmol) in TFA (4 ml) was stirred at RT for 16 h. The mixture was concentrated on vacuo, quenched with sodium bicarbonate and extracted as in Example 1(d). The solvent was distilled off to give the product in 84.3% yield (0.70 g)1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.98 (s, 1H), 8.68-8.67 (D, 1H), 8.43 (d, 1H), 8.31 (s, 1H), 7.99-7.96 (dd, 1H), 7.89 (s, 2H), 7.76-7.70 (m, 2H), 7.49-7.43 (m, 1H), 7.31-7.26 (m, 1H), 6.51-6.48 (d, 1H), 2.13 (s, 3H); LC-MS (ESI): Calculated mass 457.43: Observed mass: 458.1[M+H]+ (rt: 0.68 min).
Reaction SMILES: [C:1]([C:5]1[C:14]([O:15]C(=O)C(C)(C)C)=[CH:13][C:8]2[CH2:9][CH:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[C:1]([C:5]1[C:14]([OH:15])=[CH:13][C:8]2[CH2:9][CH:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1Cc2cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CC1Cc2cc(O)c(C(C)(C)C)cc2O1
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Under a nitrogen stream, 0.15 g of 6-t-butyl-2-methy-5-trimethylacetoxy-2,3-dihydrobenzofuran was dissolved in 3 ml of n-hexane at room temperature, 1.55 ml of diisobutylaluminium hydride (1M in n-hexane) was added dropwise, and the mixture was stirred overnight. After the reaction was quenched with 5% hydrochloric acid, the mixture was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified on a short column of silica gel (in n-hexane containing 5% ethyl acetate) to give 0.09 g of 6-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a white solid (yield 84%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:35][CH3:36])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[CH2:35]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1)[CH3:36]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (4.5 mL) was added to a methylene chloride (2.0 mL) solution of methyl 4-(2-((tert-butoxycarbonyl)(ethyl)amino)phenyl)-2-nitrobenzoate (0.39 g) at room temperature, followed by stirring at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-85% hexane/ethyl acetate] to obtain 0.27 g of methyl 4-(2-(ethylamino)phenyl)-2-nitrobenzoate as an orange oily substance.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:29])[CH2:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])=[C:11]([CH3:30])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]([N:16]([CH3:29])[CH2:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:15])=[C:11]([CH3:30])[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)sc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)sc1C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
The compound (129 mg, 0.292 mmol) obtained in Example 30c was dissolved in methylene chloride (3 mL), trifluoroacetic acid (1.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, toluene (×2) was added to the resulting residue, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methylene chloride (3 mL), triethylamine (0.318 mL, 2.29 mmol) and di-tert-butyl dicarbonate (244 mg, 1.75 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (78 mg; yield, 78%) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:22]1([NH:21][C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=c1c(Nc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 110 °C
Yield: 85.5 %

Procedure:
53 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one and 23 mg of aniline were dissolved in 10 ml of toluene, to which 2 mg of palladium acetate, 7 mg of 1,1′-bis(diphenylphosphino)ferrocene and 23 mg of sodium tert-butoxide were added, and the mixture was stirred at 110° C. for a night. The reaction solution was cooled to room temperature, filtered by silica gel and washed with ether, and the filtrate was distilled under a vacuum to remove the solvent. The residue was refined by silica gel chromatography (NH silica) (hexane/ethyl acetate-based solvent), to obtain 47 mg of the subject compound.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:6][C:7]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[CH3:5].[OH-].[Na+].[Cl-].[NH4+:17]>O.[OH-].[NH4+].COC(C)(C)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([NH2:17])[CH:11]=[CH:12][CH:13]=1)=[O:8])[CH3:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(=O)c1cccn1N
Yield: 95.8 %

Procedure:
2 M of Sodium hypochlorite in Water (750 mL) (10-14% solution) was added dropwise to a solution of 1H-Pyrrole-2-carboxylic acid ethyl ester (50.0 g, 359 mmol), 2-Methoxy-2-methylpropane (1000 mL), Aliquot 336 (12 g, 31 mmol), 7 M of Sodium hydroxide in Water (1030 mL), 8 M of Ammonium hydroxide in Water (330 mL) and Ammonium chloride (120 g, 2200 mmol). The reaction was immediately worked up upon complete addition of sodium hypochlorite. The organic layer was separated and was washed with saturated sodium thiosulfate (3×500 mL). Organic extracts (3×500 mL) were dried over magnesium sulfate, filtered and reduced to afford 53.0 grams 1-Amino-1H-pyrrole-2-carboxylic acid ethyl ester as a brown oil without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[Br:14])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1Br
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3ccccc3Br)c2cn1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 33.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (198 mg, 1.03 mmol) (described in a previous experimental) and 2-bromoaniline (1.00 mL, 9.18 mmol) is stirred under N2 at 180° C. for 2.5 h, and the resulting product is chromatographed on alumina (1% EtOR/CHCl3) to give 7-amino-4-(2-bromoanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a pale yellow solid, 1H NMR (DMSO) δ 9.91 (1H, brs), 9.27 (1H, s), 8.20 (1H, s), 7.73 (1H, d, J=7.9 Hz), 7.50 (1H, m), 7.44 (1H, t, J=6.9 Hz), 7.25 (1H, m), 6.59 (2H, brs), 6.42 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br:11][C:12]1[C:17]2[N:18]([CH3:24])[C:19]([C@@H:21]([NH2:23])[CH3:22])=[N:20][C:16]=2[CH:15]=[CH:14][C:13]=1[F:25].CCN(C(C)C)C(C)C.O>CC(O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:23][C@H:21]([C:19]2[N:18]([CH3:24])[C:17]3[C:12]([Br:11])=[C:13]([F:25])[CH:14]=[CH:15][C:16]=3[N:20]=2)[CH3:22])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C

Procedure:
4-Amino-6-chloropyrimidine-5-carbonitrile (0.88 g, 5.71 mmol) was added to a solution of (S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamine (1.11 g, 4.08 mmol) and DIPEA (2.6 mL, 14.7 mmol) in IPA (30 mL) and the resultant mixture stirred at 85° C. for 16 h. The reaction mixture was poured into water and the precipitated solid removed by filtration. The solid was washed with water and dried to give the title compound as an off white solid (1.61 g, 100%). LCMS (Method C): RT 2.68 min [M+H]+ 390.1, 392.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)ccn1
Agent: O=C1CNCCN1
Product: Cc1cc(-n2nc(C(=O)N3CCNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
75 mg (0.23 mmol) of the compound of Example 30A is reacted analogously to the synthesis of the compound of Example 4 with 24 mg (0.24 mmol) of 2-oxopiperazine. 77 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.O>[C:2]([NH:5][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.3 %

Procedure:
2-Methylpropan-2-amine (5.8 g, 80 mmol) and K2CO3 (11 g, 80 mmol) were dissolved in a mixed solvents of THF and H2O (V:V=1:5, 30 ml). Benzenesulfonyl chloride (7.06 g, 40.0 mmol) was added drop wise at 0° C. to the above solution. After being stirred overnight, the resulting mixture was extracted with ethyl acetate (3×100 mL), washed with 1 N HCl (50 mL), sat. NaHCO3 (50 mL), sat. NaCl (50 mL), and dried over Na2SO4. After concentration, the residue was purified by silica gel chromatography eluting with a 0-10% gradient of EtOAc in petroleum ether to afford N-tert-butylbenzenesulfonamide (6.0 g, 90% yield) as white solid. 1H NMR (500 MHz, CDCl3): δ 7.93-7.91 (m, 2H), 7.54-7.47 (m, 3H), 5.06 (br, 1H), 1.22 (s, 9H)