Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[S:6]1(=[O:16])=[O:15]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: COc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (456 mg) was coupled to p-methoxyphenylboronic acid to provide 3-(3-chloropropyl)-1-(4-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (132 mg):
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:8][O:7][C:5]([CH2:4][O:3][C:10]1[N:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)=[O:6]
Reactant: N#Cc1ccc(Br)nc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise methyl 2-hydroxyacetate (0.7 mL, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (461 mg, 63%). MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [N:1]1([CH:6]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[N:1]1([CH:6]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]([OH:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)C(=O)C(Oc1ccccc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)C(O)C(Oc1ccccc1)n1ccnc1
Yield: 83 %

Procedure:
25.8 g (0.1 mol) of 1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-one are dissolved in 250 ml of methanol and 5.9 g (0.15 mol) of sodium borohydride are introduced in portions into this solution, at 5° to 10° C., while stirring and with reflux cooling. After stirring for 15 hours at room temperature, 20 ml of concentrated hydrochloric acid are added and the reaction mixture is stirred for a further 15 hours at room temperature and poured into 300 ml of saturated sodium bicarbonate solution. The mixture is extracted with twice 100 ml of methylene chloride, the organic phase is washed with twice 100 ml of water and dried over sodium sulphate and the solvent is distilled off under a water pump vacuum. The residue is ground with 30 ml of petroleum ether. 21.6 g (83% of theory) of 1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol are obtained as a mixture of isomers with a melting point of 99°-105° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>CO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:51])([F:50])[F:52])[CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NC2CCN(Cc3ccccc3)CC2)nc2ccccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)c1nc(NC2CCN(S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 50 °C
Reaction time: 16.5 h
Yield: 42.8 %

Procedure:
To a solution of N2-(1-benzyl-piperidin-4-yl)-N4,N4-dimethyl-quinazoline-2,4-diamine (500 mg, 1.38 mmol) in MeOH (5 mL) was added 20% Pd(OH)2 (100 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1.5 hr, at 50° C. for 8 hr, at ambient temperature for 16.5 hr, filtered through a pad of celite, and concentrated. To a solution of the residue in CH2Cl2 (5 mL) was added diisopropylethylamine (510 μL, 2.93 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (493 mg, 1.45 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give N2-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N4,N4-dimethyl-quinazoline-2,4-diamine (339 mg, 43%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CC(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 2,4-dinitrophenylacetic acid (1.2 gm) in methanol (60 mL), added Pd/C (80 mg, 10 wt %). H2 gas environment was maintained with pressure using hydrogen gas balloon and solution stirred for 6 hours at RT. The catalyst was removed by filtration, over celite. The filtrate was concentrated in vacuo to give 2,4-diaminophenylacetic acid without further purification, immediately refluxed with 16 ml of 1N HCl for 6 hrs. Reaction was monitored with TLC. The solution was neutralized with 1% sodium hydroxide, extracted with three portions of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate or magnesium sulfate, evaporated in vacuo to get the title compound D4: YD: 67.85%: mp: 193-195° C.; Rf: 0.358 (EA:Hx: 7.0:3.0). 1H NMR (DMSO-d6) 200 MHz, δ: 3.227 (s, 2H), 5.004 (s, 2H) —NH2, 6.094 (dd, J=2.2 & 6.2 Hz, 1H), 6.098 (d, J=2.0 Hz, 1H), 6.786 (d, J=8.4 Hz, 1H), 10.088 (s, 1H). MS (ESI): m/z 146.8 [M−H]−.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:30]4[C:19](=[CH:20][C:21]5[O:26][CH2:25][C:24](=[O:27])[N:23]([CH3:28])[C:22]=5[CH:29]=4)[O:18][CH2:17]3)[C:9]2=[O:31])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:28][N:23]1[C:22]2[CH:29]=[C:30]3[C:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[NH:8][C:9]4=[O:31])[CH2:17][O:18][C:19]3=[CH:20][C:21]=2[O:26][CH2:25][C:24]1=[O:27]
Reactant: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (73%) as a colorless solid: mp>250° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 10.62 (br s, 1H), 7.29-7.22 (m, 1H), 7.11 (d, J=7.1 Hz, 1H), 7.02-6.90 (m, 2H), 6.70 (s, 1H), 6.48 (s, 1H), 4.80 (d, J=9.2 Hz, 1H), 4.66 (d, J=9.2 Hz, 1H), 4.58 (s, 2H), 3.07 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.1, 163.3, 156.7, 146.2, 141.9, 132.3, 128.9, 124.0, 123.9, 122.9, 122.3, 109.9, 99.1, 80.3, 67.1, 57.7, 28.0; MS (ES+) m/z 322.9 (M+1).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:20][CH:21]=1)([O-:15])=[O:14]>CN(C=O)C.C(O)C.CO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][N:20]=2)[CH2:23][CH2:24]1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CO
Product: CCOc1c(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To 3,4-diethoxycyclobut-3-ene-1,2-dione (1.20 mL, 8.10 mmol) in anhydrous DMF (10.0 mL) at room temperature was added a solution of 1-(5-nitropyridin-2-yl)piperazine (B-8) (1.926 g, 9.26 mmol) in anhydrous DMF (14.0 mL). The reaction mixture was stirred at room temperature for 3 h, and then diluted with absolute ethanol (40 mL) and methanol (30 mL). The yellow precipitate formed was filtered and washed with methanol (25 mL). The alcoholic filtrate was discarded, and the solid residue was dissolved in methylene chloride. The solution obtained was concentrated to give 3-ethoxy-4-(4-(5-nitropyridin-2-yl)piperazin-1-yl)cyclobut-3-ene-1,2-dione (C-9) as a yellow solid (1.93 g, 72% yield). MS (M+1): m/e 333. Nota: The presence of 1 equivalent 2-fluoroaniline or 2,6-dichloroaniline in the reaction mixture does not affect the course of the reaction in those conditions.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][C:44]1=[O:49].CCN(CC)CC.O>CN1C(=O)CCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]2[S:21][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:34])=[O:33])[CH:9]=[C:8]4[C:6]3[N:7]=[C:2]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[C:44](=[O:49])[CH2:45]4)[CH:3]=[N:4][CH:5]=3)=[N:18][N:19]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: CN1CCNCC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 155 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (100 mg, 0.166 mmol) in NMP (1 mL) was added 1-methylpiperazin-2-one (28.4 mg, 0.249 mmol) and Et3N (69.2 μL, 0.497 mmol). The reaction was stirred at 155° C. for 18 h, then cooled to RT. H2O was added and the resulting suspension was filtered to give the crude material. MS (ESI, pos. ion) m/z: 681 (M+1).
Reaction SMILES: [BH4-].[Na+].O1C2C=CC(CN(CC3C=CC4OCOC=4C=3)[CH2:14][C:15]3[N:16]([CH2:27][CH2:28][CH2:29][CH3:30])[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][C:19]=3Br)=CC=2OC1.C[OH:42]>>[CH2:27]([N:16]1[C:15]([CH2:14][OH:42])=[CH:19][N:18]=[C:17]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CO
Reactant: CCCCn1c(-c2ccccc2)nc(Br)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Product: CCCCn1c(CO)cnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.135 g, 30 mmol) is added to a solution of aldehyde 138 (6.849 g, 30 mmol) in 100 ml of methanol cooled to 0° C. The resulting solution is stirred at 0° C. for 30 min, evaporated and the residue dissolved in 150 ml of ethyl acetate, washed with water and brine, dried over Na2SO4, concentrated and taken to dryness under high vacuum to give the product 139 as an oil. MS (+VE) m/z 231 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:3][CH:2]=1.[OH-].[K+].[CH3:20][C:21]([CH3:23])=[O:22]>>[OH:9][C:8]1([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[CH2:23][C:21](=[O:22])[CH:20]=[C:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1cccc(C(=O)C(=O)c2ccncc2)c1
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(C2(O)CC(=O)C=C2c2ccncc2)c1
Reaction time: 1 h

Procedure:
To a solution of 1-pyridine-4-yl-2-m-tolyl-ethane-1,2-dione (1.8 g, 8.0 mmole) in acetone (20 mL) was added crushed KOH (448 mg, 8.0 mmole) in one portion at r.t. The reaction mixture was stirred at that temperature for 1 hr before quenching the reaction with aqueous NH4Cl. Standard aqueous work up, followed by chromatographic purification (silica gel, hexane/ethyl acetate) gave the a mixture of the title compound and the regiosiomer, 4-hydroxy-4-pyridine-4-yl-3-m-tolyl-cyclopent-2-en-1-one. MS (m/z): Calcd. C17H15NO2(M+): 265, found (M+H)+: 265.9.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CO>[CH2:18]([N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=[C:5]([Br:4])[C:6]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c(Br)cc(-c2ccncn2)cn1Cc1ccccc1
Temperature: 70 °C

Procedure:
A solution of sodium methoxide (1.85 g) in 100 ml DMF and 30 ml MeOH is added to a stirred, suspension of 3-bromo-5-(4-pyrimidinyl)-2(1H)-pyridone in 100 ml DMF. Benzyl chloride (3.9 ml) is added to the reaction mixture, and the mixture is heated to 70° C. for 2 hours and allowed to cool to RT overnight. The reaction mixture is filtered and the solvent evaporated in vacuo. The residue is suspended in H2O, filtered and dried. The resultant solid is dissolved in hot isopropanol, filtered through charcoal and recrystallized, yielding 1-benzyl-3-bromo-5-(4-pyrimidinyl)-2-pyridone, M.P. 189°-191.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CO>[O:18]1[CH2:17][CH:16]1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: ClCC1CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (18.6 g, 100 mmol) and epichlorohydrine (10.2 ml, 12.0 g, 130 mmol) in methanol (50 ml) was stirred at room temperature for 24 hours and the solvent was evaporated. The residue was dissolved in 200 ml of ether and the solution was stirred with 10N aqueous NaOH (100 ml) at room temperature for 2 hours. Then the organic layer was separated, washed with brine until neutral, dried over MgSO4 and concentrated to afford the title compound (21.8 g) as a pale yellowish viscous oil, yield: 90.1%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:18]([C:22]1[CH:27]=[CH:26][C:25](O)=[C:24]([O:29][CH3:30])[CH:23]=1)([OH:21])[CH2:19][CH3:20])[CH3:17]>N1C=CC=CC=1>[CH2:16]([C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:24]([O:29][CH3:30])[CH:23]=1)([OH:21])[CH2:19][CH3:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(O)(CC)c1ccc(O)c(OC)c1
Solvent: c1ccncc1
Product: CCC(O)(CC)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was added to a solution of 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol (Example 176-(3); 1.0 g, 4.76 mmol) in pyridine (4 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (1.51 g, 93%). Trifluoroacetic acid (0.1 mL) was added to a mixture of trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (100 mg, 0.292 mmol) with o-cresol (68.2 mg, 585 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=4:1) to give the title compound (0.12 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22]C=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C=C[S:48]C=3CCC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[CH:25]=[CH:24][S:48][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3sccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2sccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.39, 7.12, 6.99, 5.45, 4.64, 2.90, 2.65, 2.51, 2.20, 1.99, 1.27, 1.20; 13C NMR (100 MHz, CDCl3) δ 151.51, 150.78, 140.47, 139.15, 137.82, 137.21, 135.35, 134.47, 132.93, 128.78, 127.51, 127.37, 123.01, 117.71, 46.74, 29.97, 27.62, 26.36, 25.53, 21.37, 12.32, 11.63; HRMS (FAB) calcd for C22H23Cl2N3S+H 432.1068, found 432.1073.
Reaction SMILES: CS(C)=O.[CH:5]([C:7]1[O:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].C([O-])(=O)C.[K+].I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][NH:25][C:24]2=[O:31]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:31]=[C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:10]3[O:11][C:7]([CH:5]=[O:6])=[CH:8][CH:9]=3)[CH:22]=2)[N:27]=[CH:26][NH:25]1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A 5:2 v/v solvate mixture of Dimethyl sulfoxide (DMSO) and H2O (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. Under an atmosphere of nitrogen, 5-formylfuran-2-ylboronic acid ((VIa); 26.8 g, 193 mmol) was added into this mixture and dissolved. [HP(t-Bu)3]BF4 (840 mg, 2.94 mmol) and palladium acetate (Pd(OAc)2, 680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature for 20 min. Then, potassium acetate (AcOK, 18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min. 6-Iodoquinazolin-4(3H)-one ((Va); 40 g, 147 mmol) was added. Then the reaction mixture was heated to 80±5° C. (internal temperature). Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5° C.) was added into the filtrate. This was slowly cooled to 0-15° C. (solid started to precipitate at 70° C. (internal temperature)) and was then filtered. The filter cake was washed with H2O (80 mL), then with MeCN (60 mL), and dried in vacuo at 60±5° C. for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol) with 99.7% HPLC purity in 97.6% HPLC yield. 1H NMR (300 MHz, d6-DMSO): δ 7.47 (d, J=3.8 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.77 (d, J =8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 110.5, 122.6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178.8; ESI-MS, Pos: [M+H]+m/z 241; IR (cm−1): 1713, 1671, 1604, 1462; m.p.: 267° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.Cl[CH2:21][C:22](Cl)=[O:23].[H-].[Na+]>C1COCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[NH:1][C:22](=[O:23])[CH2:21][O:12][C:3]=2[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2
Yield: 93.7 %

Procedure:
Using methyl 4-amino-3-hydroxybenzoate (2 g, 12 mmol), triethylamine (2.17 mL, 16 mmol) and chloroacetyl chloride (1.13 mL, 13 mmol) in THF (70 mL) followed by sodium hydride (1.0 g of a 60% suspension in oil, 24 mmol) to yield the title compound as a brown solid (2.33 g, 94%). δH (DMSO-d6) 3.81 (3H, s), 4.65 (2H, s), 6.99 (1H, d, J 8.3 Hz), 7.43 (1H, d, J 1.5 Hz). 7.59 (1H, dd, J 8.5, 1.9 Hz), 11.10 (1H, br s). LCMS (ES+) 208 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-tert-butylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H20N4, 317. Found, 317.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 68 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.