Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: CC(C)=CCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.05 %

Procedure:
To 61.2 g of p-hydroxybenzaldehyde and 208 g of potassium carbonate was added 300 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. Then, 66.0 ml of 1-chloro-3-methyl-2-butene was dropped into the mixture, and the mixture was stirred for 3 days. After the reaction, the reaction liquid was poured into ice water and extracted with ether, the ether layer was washed with a 10% solution of potassium carbonate, and the organic layer was shaken with a 5% solution of sodium hydroxide. The pH value of the aqueous layer was adjusted to about 2 by 6 N hydrochloric acid and the formed precipitate was extracted with ether. The ether layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in sequence, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was subjected to the column chromatography (330 g of 240-400 mesh silica gel; hexane/ethyl acetate=3/1; 0.4 kg/cm2). Fractions of 50 ml were recovered in sequence, and the 19th to 51st fractions were combined to obtain 12.31 g (yield=13.05%) of 4-hydroxy-3-(3-methyl-2-butenyl)benzaldehyde.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:16]([O:19][C:20](Cl)=[O:21])[CH:17]=[CH2:18]>O1CCCC1.O>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:20]([O:19][CH2:16][CH:17]=[CH2:18])=[O:21]
Reactant: O=C1CCCN1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Into a 500 mL four neck flask were added 2-pyrrolidone (17.02 g) [mw. 85.10, 200 mmol] and toluene (340 mL), and the mixture was dissolved. Powder sodium hydroxide (8.00 g) [mw. 40.00, 200 mmol] was added thereto, Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 4 hr. After cooling to 0° C., allyloxycarbonyl chloride (20.10 g) [mw. 120.53, 167 mmol] was added at not more than 30° C., and the mixture was stirred at 25° C. for 30 min. Water (85 mL) and tetrahydrofuran (85 mL) were added to allow for partitioning. The organic layer was washed with 5 w/w aqueous potassium hydrogen sulfate solution (85 mL), and further washed twice with water (85 mL). The organic layer was concentrated under reduced pressure, and the solvent was replaced with tetrahydrofuran. Pale-yellow oil, 19.28 g, yield 57.0%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.09 (quin, J=7.7 Hz, 2H), 2.54 (t, J=8.2 Hz, 2H), 3.80-3.86 (m, 2H), 4.70-4.77 (m, 2H), 5.25-5.38 (m, 1H), 5.38-5.45 (m, 1H), 5.88-6.04 (m, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 17.57, 32.78, 46.42, 66.87, 118.76, 131.57, 151.38, 173.98.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([NH:16][NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:28][C:18]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)=[N:17][N:16]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NNC(=O)CCc2cccc(F)c2)ccn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1
Yield: 73.4 %

Procedure:
A solution of tert-butyl[4-[[2-[3-(3-fluorophenyl)propanoyl]hydrazino]carbonyl]-2-pyridyl]carbamate (1.00 g, 2.48 mmol), p-toluenesulfonyl chloride (946 mg, 4.96 mmol) and triethylamine (1.72 mL, 12.4 mmol) in tetrahydrofuran (30 mL) was heated under reflux for 17 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100), and recrystallized from ethyl acetate to give the title compound (0.70 g, yield 73%) as colorless crystals.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[N:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:8][CH2:7][C@H:6]2[O:9][C@@H:1]([N:10]3[CH:17]=[N:16][C:14]([NH2:15])=[N:13][C:11]3=[O:12])[C@H:2]([OH:3])[C@@H:4]2[OH:5])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc(N)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 5-azacytidine (2.20 g, 9 mmol) in dry pyridine (45 mL) was added 4,4'-dimethoxytrityl chloride (3.15 g, 9.3 mmol) and the mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with chloroform. The combined organic extracts were dried (MgSO4) and chromatographed through a silica gel column (ethyl acetate--10% methanol/ethyl acetate) to give 2.89 g (59%) of a white product. NMR (CDCl3 +D2O); δ 3.35 (m, 2H), 3.70 (s, 6H), 4.26 (m, 3H), 5.80 (d, 1H), 6.80 (m, 4H), 7.31 (m, 9H), 8.45 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](C(S)C(O)=O)=[S:10])=[CH:4][CH:3]=1.[NH:16]([C:18]([O:20][CH3:21])=[O:19])[NH2:17]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:17][NH:16][C:18]([O:20][CH3:21])=[O:19])=[S:10])=[CH:6][CH:7]=1
Reactant: COC(=O)NN
Reactant: Cc1ccc(CC(=S)C(S)C(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(C)cc1
Yield: 81.8 %

Procedure:
A mixture of 37.0 g of 2-[2-(4-methylphenyl)-1-thioxoethyl]thioglycolic acid, 18.2 g of methyl hydrazinocarboxylate and 250 ml of dichloromethane was heated at reflux for one hour and then evaporated in vacuo. The residue was concentrated at high vacuum and 45° C. for one hour. The oily residue was chromatographed on a 75×800mm dry column of silica gel, eluting with dichloromethane. The desired fractions were pooled and the solid crystallized from toluene-hexane, giving 30 g of the desired compound as off-white needles, mp 104.5°-105° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 2.38 (s, CH3); 3.79 (s, 3H, OCH3); 4.07 (s, 2H, CH2CS); 7.23 (s, 4H, C6H4); 8.68 (bs, 1H, NH); 9.52 (bs, 1H, NH).
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=O)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([C:4]2[NH:12][C:11]3[C:10](=[S:19])[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=S)[nH]c(=O)c2[nH]c(C3CC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reaction time: 8 h
Yield: 54.6 %

Procedure:
In a 5 L 3-necked flask fitted with a mechanical stirrer and a condenser with a drying tube were placed 2.2 L of pyridine and 8-cyclopropyl-3-propyl-2-thio-xanthine (220 g, 0.88 mol). Phosphorus pentasulfide (236 g, 1.06 mol) was added and the mixture was heated under reflux for 5 hours and stored overnight at room temperature. The reaction mixture was cooled to 5-10° and 3 N aqueous sodium hydroxide (770 ml) was added over 1.5 hours with stirring. Stirring was continued for 30 minutes after removal of the cooling bath and the precipitated product was collected by suction filtration. The filter cake was washed successively with pyridine (300 ml) and four 300 ml portions of tetrahydrofuran. The solvents are evaporated in vacuo and the solid residue was stirred with water (750 ml), filtered and washed with water. The crude product was dissolved in 1.7 L of 1 N sodium hydroxide and stirred with 15 g of Darco G-60. The charcoal was filtered and the treatment was repeated with a fresh portion of charcoal. The solution was acidified to pH 1.5 with 6 N hydrochloric acid and the pale yellow precipitate was collected. The solid was dissolved again in 1.7 L of 1N sodium hydroxide and treated successively with two portions of charcoal as above. The solution was acidified and the precipitate was collected and washed with water. After drying to constant weight at 54° C. under vacuum, there was obtained 128 g (56%) of the title compound, mp over 245° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[C:15]=1[F:26].[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][OH:36])([OH:34])[CH2:30][CH2:29]1.[Cl-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:27][CH:28]3[CH2:33][CH2:32][C:31]([OH:34])([CH2:35][OH:36])[CH2:30][CH2:29]3)=[O:24])=[C:16]2[C:15]=1[F:26]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12
Reactant: NC1CCC(O)(CO)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(NC1CCC(O)(CO)CC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12

Procedure:
The title compound was prepared by the method similar to that mentioned in Example-6, using (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid and 4-amino-1-(hydroxymethyl)cyclohexanol (instead of ammonium chloride) to afford the crude compound. The crude compound was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 100% EtOAc as eluent) to afford 15 mg of the title compound.
Reaction SMILES: [Si]([O:8][CH:9]1[CH:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH3:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])=[O:17])[CH2:13][CH2:12][N:11](C(OCC)=O)[CH2:10]1)(C(C)(C)C)(C)C.[OH-].[Na+].Cl>CO.O1CCOCC1>[Cl:23][C:22]1[C:21]([Cl:24])=[C:20]([CH3:25])[NH:19][C:18]=1[C:16]([NH:15][CH:14]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[OH:8])=[O:17]
Reactant: CCOC(=O)N1CCC(NC(=O)c2[nH]c(C)c(Cl)c2Cl)C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)NC2CCNCC2O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
Ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 114, 0.805 g) was dissolved in a mixture of MeOH (10 mL) and 1,4-dioxane (15 mL), to which was added 1N NaOH (10 mL) and heated to reflux for twenty-four hours. An additional 5 mL of 1N NaOH was added, with 5 mL of 1,4-dioxane, and the reaction was heated for an additional forty-two hours, then cooled to 0° C. and acidified to ˜pH 9 with 2N HCl (6 mL). The cold mixture was filtered and washed with deionised water, yielding the title compound as a crude product. MS (ES) MH+: 292, 294 for C11H15Cl2N3O2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].Cl[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:9][CH2:8][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: ClCOCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: c1ccc(COCn2ccnc2)cc1
Reaction time: 1 h

Procedure:
To 58 g. of imidazole-sodium in 200 ml. of anhydrous tetrahydrofuran 100 g. of benzyl chloromethyl ether were added drop-wise with stirring at a temperature of 0° to 5° C. Cooling was discontinued after one hour. The mixture was left standing overnight and thereafter concentrated. The residue was treated with 2 N hydrochloric acid solution and with diethyl ether. The acidic aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was treated with activated carbon, dried and concentrated. The residue was subjected to distillation. Boiling point 147° C./3 mm.Hg.
Reaction SMILES: [CH:1]1([N:7]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH:1]1([N:7]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCN1CCOCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) using 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 4-(3-chloropropyl)morpholine
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[N:34]1[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc([N+](=O)[O-])cc23)CC1
Temperature: 60 °C
Reaction time: 13 h
Yield: 89 %

Procedure:
To a solution of 4-chloro-6-nitroquinazoline (prepared according to the literature: Alexander J. Bridges et al. J. Med. Chem. 1996, 39, 267-276, and references therein; 12 g, 57.5 mmol) and DIEA (10 mL, 57.5 mmol) in 230 mL IPA was added Boc-piperazine (10.7 g, 57.5 mmol). The reaction mixture was heated to 60° C. and stirred for 13 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica gel (1:1 to 1:4 DCM:EtOAc gradient) to furnish 4-(6-nitro-quinazolin-4-yl)-1-Boc-piperazine as a pale yellow oil (18.3 g, 89%). LCMS (APCI+) m/z 360 [M+H]+. HPLC Rt 3.06 min.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCOCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[C:13]4[N:12]([C:23](=[O:24])[NH:20][C:18](=[O:19])[C:17]=4[CH:16]=[N:15]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Yield: 59.9 %

Procedure:
To a stirred mixture of 10.0 g of 4,5-dihydro-7-(3-(trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 8) in 200 ml of dioxane at room temperature under nitrogen is added 20.0 g of 1,1'-carbonyldiimidazole. The mixture is then heated at reflux for 5 hours, and then is cooled and filtered. The filtrate is evaporated to dryness in vacuo and an excess of water is added to the residue. The white solid which forms is collected and is recrystallized from acetonitrile-ethanol to give 6.5 g of the desired product as a white solid, mp 260-262° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CN(C)[CH:15]=[O:16]>>[O:16]1[CH:15]=[CH:1][CH:2]=[C:10]1[CH2:9][CH2:8][CH2:7][CH2:3][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccco1
Temperature: 0 °C

Procedure:
2[1-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature in dry dimethylformamide overnight. The solution was poured into ice-water and the resulting white solid filtered, dried and recrystallised from chloroform/petroleum ether (b.p. 60°-80°) to give 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3(2H)-dione as white microcrystals (430 mg) m.p. 61°-63°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:23][C:24]2S[CH:26]=[CH:27][N:28]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH3:2].Br[C:30]1[CH:35]=CC=CN=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:23][C:24]2[CH:35]=[CH:30][CH:26]=[CH:27][N:28]=2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH3:2]
Reactant: Brc1ccccn1
Reactant: CCOc1cc(N(Cc2nccs2)c2ccc(C#N)cc2)ccc1OC(C)C
Product: CCOc1cc(N(Cc2ccccn2)c2ccc(C#N)cc2)ccc1OC(C)C

Procedure:
According to the procedure for Intermediate 2.1, 2-bromopyridine (100 mg, 0.633 mmol) afforded 177 mg of Intermediate 4.1.
Reaction SMILES: [N:1]1([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:30])C(=O)C1.O>CN(C=O)C>[Br:30][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
A solution of tert-butyl 3-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (1.86 g, 6.15 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (1.09 g, 6.15 mmol) in 15 mL DMF. The reaction was stirred at 0° C. for 1.5 hours then treated with 100 mL H2O. The suspension was extracted with 2×150 mL EtOAc. The combined organic layer was rinsed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated to give a viscous oil. This residue was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.50 g, 63.8%). 1H-NMR (CDCl3) δ 7.13 (d, J=9.0 Hz, 1H), 7.07 (brs, 1H), 6.55 (d, J=9.0 Hz, 1H), 4.35-4.33 (m, 1H), 3.58-3.18 (m, 6H), 2.71 (t, J=6.3 Hz, 2H), 2.11-2.04 (m, 2H), 1.91-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 325.1 and 327.1 (M+1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH:17]([NH2:20])=[CH:18][CH3:19]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: CC=CN
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
A stirred solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 3.0 g (0.04 mole) of propenylamine, and stirring was continued for 18 hr. The reaction mixture was diluted with 200 ml of ice water, and the solid which formed was collected by filtration, yielding 7.1 g of crude wet product. Recrystallization from benzene/ligroin yielded 3.95 g (65.6%) of white crystals, m.p. 98°-99° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][NH:13]1>CN1C(=O)CCC1>[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
An NMP solution of fluoro-4-nitrobenzene and (±)-trans-2,5-dimethylpiperazine was stirred at an oil bath temperature of 120° C. for 3 hours to obtain (±)-trans-2,5-dimethyl-1-(4-nitrophenyl)piperazine, which was further treated in a similar manner to Example 4 to obtain an objective compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[OH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:40]=[CH:39][C:38]([O:42][CH3:43])=[O:41])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: Oc1nc(-c2cccnc2)nc2ccc(I)cc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc2nc(-c3cccnc3)nc(O)c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 6-iodo-2-(pyridin-3-yl) quinazolin-4-ol (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (3.00 g, 8.6 mmol, 1.0 eq.), Pd(OAc)2 (48 mg, 0.21 mmol, 0.025 eq.) and PPh3 (113 mg, 0.43 mmol, 0.05 eq.) in DMF (8 mL) was added methyl acrylate (3.22 g, 25.8 mmol, 3.0 eq.) and DIPEA (1.22 g, 9.46 mmol, 1.1 eq.) under Ar atmosphere. The mixture was stirred at 110° C. overnight. After cooling, the mixture was filtered and the solid was washed with ethyl acetate three times to afford 1.30 g of xxxvi-a as green solid (yield 49%). LCMS m/z=308.0 (M+1) (Method B) (retention time=1.41 min).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CC(=O)Cl
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide in accordance with scheme 6 using 2-(dimethylamino)acetyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (dd, J=13.1, 4.0 Hz, 1H) 1.58 (m, 5H) 1.71 (m, 2H) 1.83 (m, 2H) 1.93 (m, 2H) 2.21 (s, 5H) 2.52 (d, J=1.8 Hz, 1H) 2.63-2.73 (m, 1H) 3.05 (t, J=12.1 Hz, 2H) 3.17-3.24 (m, 1H) 3.32 (s, 5H) 3.93 (s, 3H) 4.05 (t, J=14.2 Hz, 3H) 4.36 (d, J=12.6 Hz, 1H) 4.77 (q, J=8.3 Hz, 1H) 7.48 (dd, 1H) 7.50 (s, 1H) 7.97 (s, 1H) 8.17 (d, J=7.8 Hz, 1H) 8.26 (s, 1H) 8.29 (d, 1H). [M+H] calc'd for C30H40F2N8O4, 615. found 615.