Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:3]1=[O:25].C(=O)([O-])[O-:27].[Na+].[Na+].OO>C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH2:12])=[O:27])[C:5]=2[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:3]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C#N)cccc21
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(N)=O)cccc21
Temperature: 25 °C
Yield: 33 %

Procedure:
To a suspension of 1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile (0.25 g, 0.75 mmol) in ethanol (30 mL) was added saturated aqueous sodium carbonate (3 mL) and 30% w/w aqueous hydrogen peroxide (3 mL). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated in water to afford 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.09 g, 33%) as a colorless solid: mp>250° C. (water); 1H NMR (300 MHz, CDCl3) 7.59 (s, 1H), 7.43-7.36 (m, 1H), 7.24-7.13 (m, 3H), 6.28 (s, 1H), 5.98 (s, 1H), 5.15 (d, J=8.1 Hz, 1H), 4.57 (d, J=8.1 Hz, 1H), 4.16-3.99 (m, 4H), 3.13 (s, 3H); MS (ES+) m/z 352.9 (M+1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].CN(C)[CH:30]=[O:31]>C(OCC)(=O)C>[C:23]([Si:20]([CH3:22])([CH3:21])[O:31][CH2:30][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: COc1cc(C=CC(C)=O)ccc1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(C)=O)ccc1CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 4-(4-Hydroxy-3-methoxy-phenyl)but-3-ene-2-one (4.402 g, 22.93 mmol) in N,N-dimethylformamide (28.5 mL) were added imidazole (1.71 g, 25.22 mmol) and tert-butyldimethylsilyl chloride (3.8 g; 25.22 mmol). The reaction was allowed to stir for 4 h, then diluted with ethyl acetate (300 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL), and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure to give crude product. Column purification on silica (8:2 hexanes/ethyl acetate) afforded 4-{4-[(tert-butyl-dimethyl-silanyloxy)-methyl}-3-methoxy-phenyl}-but-3-ene-2-one (5.24 g, 73% yield) as a solid: 1H NMR (400 MHz, CDCl3): δ 7.32 (d, 2H), 6.92 (m, 2H), 6.78 (d, 1H), 6.53 (d, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 0.92 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:36][N:35]([CH2:34][C:33]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:31][N:32]=1)[CH3:37]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)Nc4ccc(F)cc4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3c2)n1
Yield: 50 %

Procedure:
Prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(4-fluorophenyl)carboxamide.2HCl (1.50 g, 3.15 mmol), N-amino-2-(dimethylamino) acetamide (1.2 g, 10.33 mmol) and sodium methoxide (1.8 mL of a 25% w/w in methanol) in anhydrous methanol (20.0 mL) with a reaction time of 1.5 days. Purification by flash chromatography on silica gel using 50% methanol in ethyl acetate afforded a solid which was dissolved in anhydrous methanol and treated with anhydrous hydrogen chloride gas for 10 min at 0° C. After stirring at ambient temperature for 5 min anhydrous ethyl acetate was added to precipitate the desired product which was collected on a sintered glass funnel, washed with methanol and ethyl acetate and dried under vacuum to give the title compound (267 mg, 50% yield) as a light yellow solid 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.5 (s, 1H), 8.5 (s, 1H), 8.2 (br d, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.84 (dd, 2H), 7.75-7.6 (m, 2H), 7.2 (t, 2H), 3.6 (bs, 2H), 2.2 (s, 6H), ES-MS (m/z) 456 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:21]Br)=[O:5])[CH3:2].[CH2:23]([O:25][C:26](=[O:36])[CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH2:21][N:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CBr)n(-c2ccccc2)c2ccccc12
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c2ccccc2n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 2-bromomethyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 503 (M+Na+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:19][C@@H:18]2[C@@H:13]([S:14][C:15]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:16]=3[N:17]2[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C@@H:12]([O:32][C:33](=[O:35])[CH3:34])[C@@H:11]1[O:36][C:37](=[O:39])[CH3:38])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:58]1CC[CH2:60][CH2:59]1.O.[C:64](OCC)(=[O:66])[CH3:65].CCCCCC>O1CCCC1>[C:33]([O:32][C@@H:12]1[C@@H:13]2[S:14][C:15]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:16]=3[N:17]([CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C@@H:18]2[O:19][C@H:10]([CH2:9][O:8][C:59](=[O:58])[CH3:60])[C@H:11]1[OH:36])(=[O:35])[CH3:34].[C:37]([O:36][C@@H:11]1[C@@H:10]([CH2:9][O:8][C:64](=[O:66])[CH3:65])[O:19][C@@H:18]2[C@@H:13]([S:14][C:15]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:16]=3[N:17]2[CH2:20][CH2:21][N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C@H:12]1[OH:32])(=[O:39])[CH3:38]
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]21
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCCCCC
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]21
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@H](O)[C@@H](COC(C)=O)O[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To the solution of 2.54 g of the compound (15) obtained in Example 15 in 6 ml of tetrahydrofuran, 6 ml of a 1M solution of tetrabutylammoniumfluoride-tetrahydrofuran was added dropwise. The mixture was stirred for one hour at room temperature. Water was added to the reaction solution, and the mixture was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography, and 580 mg (yield: 28.3 of the title compound (16) and 510 mg (yield 24.9%) of the title compound (17) were obtained from the fraction of ethyl acetate-hexane (4:1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].P([O-])([O-])([O-])=[O:13].[K+].[K+].[K+]>C(O)C>[OH:13][C@@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=P([O-])([O-])[O-]
Reactant: COC(=O)Cc1ccccc1
Agent: [K+]
Solvent: CCO
Product: COC(=O)[C@@H](O)c1ccccc1
Reaction time: 0.03 h

Procedure:
Experimental description: 90 mg methyl 2-phenyl acetate was dissolved in 500 μL ethanol and added to 240 mL potassium phosphate buffer pH 8.0. P450BM3 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 500 μL of a 5 mM NADPH solution was added to each vial and stirred for 2 minutes. 500 μL of a cofactor regeneration solution containing 300 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 4 hours, the reaction mixtures were joined together and extracted with chloroform (3×100 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the activated product ((S)-methyl 2-hydroxy-2-phenylacetate, 40.5 mg). 40 mg (0.24 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 41 μL DAST (0.29 mmol) was added. The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (5% ethyl acetate:95% hexane) afforded the fluorinated product ((R)-methyl 2-fluoro-2-phenylacetate) (30 mg, 75% yield, pale yellow oil) in 74% ee, as determined by chiral GC analysis. 1H-NMR (300 MHz, CDCl3): δ 3,75 (s, 3H, —OCH3), δ 5.77 (d, J=48 Hz, 1H, —CHF), δ 7.37-7.46 (m, 5H); 13C-NMR (75 MHz, CDCl3): δ2.8, 89.5 (d, J=184.5 Hz), 126.8, 126.9, 129.0, δ 129.9, δ 134.4 (d, J=34.5 Hz), δ 169.0. 19F-NMR (282 MHz, CDCl3): δ −180.29 (d, J=48.7 Hz). HRMS (EI+): exact mass calculated for C9H9FO2 requires m/z 168.0587, found 168.0594.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:23])OCC)[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1.[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([NH:18][C:19]([N:28]([CH2:27][CH:26]([O:30][CH3:31])[O:25][CH3:24])[CH3:29])=[O:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: CCOC(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1cc(Cl)c(Oc2cc(Cl)cc(Cl)c2)c(Cl)c1)OC

Procedure:
Ethyl [3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[3,5-dichloro-4-(3,5-dichlorophenoxy)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([O:30]C)=[O:29])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=[O:29])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccs3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylate (435 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 360 mg (86%) of the acid. HR—MS: m/z Calculated for C21H21NO6S2 448.0883; Found 448.0882.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][NH:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:4][N:3]=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[C:29]1([CH3:39])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][NH2:9])[O:4][N:3]=1
Reactant: Cc1noc(CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1noc(CCN)n1

Procedure:
A solution of 370 mg of [2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-trityl-amine and 190 mg of p-toluenesulfonic acid in 10 ml of ethanol was heated to 60° C. for 2 hours. The solvent was evaporated and the residue was triturated with diethylether/hexane to give 2-(3-methyl-1,2,4-oxadiazol-5-yl)ethylamine p-toluenesulfonate as white crystals of m.p. 122°-123° C.
Reaction SMILES: O(C(C)(C)C)[K].[CH2:7]([OH:10])[CH2:8][OH:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1>C(Cl)Cl>[N:14]1[CH:13]=[C:12]([O:9][CH2:8][CH2:7][OH:10])[CH:17]=[N:16][CH:15]=1
Reactant: Brc1cncnc1
Reactant: OCCO
Agent: CC(C)(C)O[K]
Solvent: ClCCl
Product: OCCOc1cncnc1
Yield: 6 %

Procedure:
KO-t-Bu (7.70 g, 68.6 mmol) was added to ethylene glycol (10.45 g, 168.4 mmol) under stirring. The mixture was gently heated in order to consume all KO-t-Bu. 5-Bromopyrimidine (8.45 g, 53.1 mmol) was added to the light brownish mixture. After 8 h of stirring at 130° C., CH2Cl2 (50 mL) was added to the brownish reaction mixture and two layers were formed. The CH2Cl2 layer was saved and the other layer was extracted with additional portions of CH2Cl2. The combined CH2Cl2 layers were concentrated in vacuo and the oily residue purified by column chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 0.45 g (6%) of the title product as an oil sufficiently pure for the next step. HRMS m/z calcd for C6H8N2O2(M)+140.0586, found 140.0589.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].N12CCCN=C1CCCCC2.[C@@H:16]1([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([OH:30])[C:28]=3[N:27]=[CH:26]2)[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]1[OH:18]>>[CH2:1]([N:31]1[CH:32]=[N:33][C:34]2[N:25]([C@@H:16]3[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]3[OH:18])[CH:26]=[N:27][C:28]=2[C:29]1=[O:30])[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1=O

Procedure:
reacting propargyl bromide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and inosine to produce 1-propargylinosine;
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([S:25][C:26]2[N:30]4[CH:31]=[C:32]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)[CH:33]=[CH:34][C:29]4=[N:28][N:27]=2)=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:40][N:38]1[CH:39]=[C:35]([C:32]2[CH:33]=[CH:34][C:29]3[N:30]([C:26]([S:25][C:21]4[CH:22]=[C:23]5[C:18](=[CH:19][CH:20]=4)[N:17]=[CH:16][C:15]([N:12]4[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]4)=[CH:24]5)=[N:27][N:28]=3)[CH:31]=2)[CH:36]=[N:37]1
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCC(O[Si](C)(C)C(C)(C)C)CC6)cc5c4)n3c2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCC(O)CC6)cc5c4)n3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (49.1) (48.5 mg, 0.085 mmol) in MeOH (2 mL) was added HCl solution in MeOH (1M) (5 mL, 5.00 mmol). The reaction mixture was stirred at rt for 1 h, quenched with saturated NaHCO3 solution and extracted with extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, concentrated, purified via biotage by flash chromatography on silica gel using a gradient of 0-10% MeOH/CH2Cl2 to give the title compound (38 mg, 0.083 mmol, 98% yield). [Method 1E]
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[CH:40]([NH2:43])([CH3:42])[CH3:41]>>[CH:40]([NH:43][C:32]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([N:13]3[CH:14]4[CH2:20][CH2:19][CH:18]3[CH2:17][O:16][CH2:15]4)[N:10]=2)=[CH:22][CH:23]=1)=[O:38])([CH3:42])[CH3:41]
Reactant: CC(C)N
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC(C)NC(=O)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Yield: 50 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and isopropylamine (11 mg, 0.18 mmol) gave the title compound as off-white solid (13.6 mg, 50% yield). MS (ESI) m/z 454.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C:19](=[O:37])[NH:20][C:21](=[O:36])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][OH:35])[CH:24]=2)[C:12]2[O:16][CH:15]=[CH:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.C(OCC)(=O)C>[CH3:45][S:46]([O:35][CH2:34][CH2:33][CH2:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:36])[NH:20][C:19](=[O:37])[C:18]=2[C:11]2[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:24]1)(=[O:48])=[O:47]
Reactant: O=C1NC(=O)C(c2cc(OCc3ccccc3)cc3ccoc23)=C1c1cn(CCCO)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCCn1cc(C2=C(c3cc(OCc4ccccc4)cc4ccoc34)C(=O)NC2=O)c2ccccc21
Yield: 100.1 %

Procedure:
Dissolve 3-(5-Benzyloxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (380 mg, 0.77 mmol) and triethylamine (0.43 ml, 3.1 mmol) in tetrahydrofuran (15 ml) and cool in an ice bath. Add methanesulfonyl chloride (0.066 ml, 0.85 mmol) dropwise, and stir for four hours. Dilute the reaction in ethyl acetate, wash with water and brine, dry with magnesium sulfate, and concentrate to give the title compound (440 mg, 100%). MS(ES+): 571.14.
Reaction SMILES: [NH2:1][C:2]([CH3:27])([CH3:26])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH3:26][C:2]([NH:1][C:35](=[O:37])[CH3:36])([CH3:27])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (6.5 g, 17.5 mmol), prepared in Part A of Example 45, in dichloromethane (200 mL) was cooled to 0° C.; triethylamine (4.87 mL, 35.0 mmol) and acetyl chloride (1.37 mL, 19.2 mmol) were sequentially added. The reaction was stirred at 0° C. for 30 minutes, allowed to warm to ambient temperature, and stirred for three hours. The reaction was washed with saturated aqueous sodium bicarbonate (2×) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide N-[1,1-dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]acetamide as a yellow powder.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][N:12]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)[C:13]([C:15]1[C:16]([Cl:22])=[N:17][CH:18]=[N:19][C:20]=1[Cl:21])=[O:14])(C(C)(C)C)(C)C>CO>[Cl:22][C:16]1[C:15]([C:13]([N:12]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:36])([CH3:37])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=2)[CH2:11][CH2:10][OH:9])=[O:14])=[C:20]([Cl:21])[N:19]=[CH:18][N:17]=1
Reactant: COC(=O)C(C)(C)COc1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2c(Cl)ncnc2Cl)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(N(CCO)C(=O)c2c(Cl)ncnc2Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A concentrated aqueous solution of hydrogen chloride (34-37.5%, 0.1 mL) was added at room temperature to a solution of methyl 3-(5-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)pyridin-2-yloxy)-2,2-dimethylpropanoate B-19 (139.4 mg, 0.25 mmol) in methanol (2.0 mL). The reaction mixture was stirred for 30 mins at room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, successively washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give crude intermediate methyl 3-(5-(4,6-dichloro-N-(2-hydroxyethyl)pyrimidine-5-carboxamido)pyridin-2-yloxy)-2,2-dimethylpropanoate (MS (ESI) [M+1]+ 444), which was then dissolved in acetonitrile (2.0 mL). Triethylamine (0.14 mL, 1.0 mmol) was then added at room temperature, and the reaction mixture was heated at 100° C. for 3 h then concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give methyl 3-(5-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-20. This material was used for the next step without purification. MS (ESI) [M+1]+ 407.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Yield: 92.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.2 g, 0.41 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.07 g, 0.41 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.2 g, 90%). The compound was characterized by the following spectroscopic data: