Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])(=O)=O)=CC=1.[Br:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:35]>CN(C)C=O>[Br:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:29][C:28]=1[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCCC2=O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1Br
Temperature: 50 °C

Procedure:
Cs2CO3 (850 mg) is added to a solution of 2-(2-oxopyrrolidin-1-yl)ethyl 4-methylbenzenesulfonate (390 mg) and 4-bromo-3,5-dimethylphenol (200 mg) in N,N-dimethylformamide (4 mL). The mixture is heated to 50° C. for 12 hours and partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. Yield: 210 mg; Mass spectrum (ESI+): m/z=312 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:14][C:12]1[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:25]=[CH2:24]
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1CC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 52 (0.200 g, 0.86 mmol) in DMF (3 mL), was added K2CO3 (0.18 g, 1.302 mmol) and stirred at 25° C. for 10 minutes, followed by slow addition of allyl bromide (0.15 g, 1.302 mmol). The reaction mixture was stirred at 25° C. for 1 hour. DMF was removed under vacuum, and the reaction mass was quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was taken for synthesis of compound of example 64 without purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5].[CH2:25]([Sn](CCCC)(CCCC)CCCC)C=C>>[CH2:23]([C:21]1[CH:20]=[CH:19][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=3[CH:18]=2)=[O:5])=[C:2]([Cl:1])[CH:22]=1)[CH:24]=[CH2:25]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: C=Cc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1
Product: C=CCc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that of 2-chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-vinyl-benzamide with allyltributyltin replacing tributyl(vinyl)tin. Data: LCMS (M/Z): 356 (M+H); 1H NMR (DMSO-d6) δ: 1.44 (s, 6 H) 3.44 (d, J=6.8 Hz, 2 H) 5.04-5.22 (m, 2 H) 5.87-6.06 (m, 1 H) 7.28 (d, J=9.0 Hz, 1 H) 7.35-7.41 (m, 2 H) 7.50 (s, 1 H) 7.68 (dd, J=8.3, 2.0 Hz, 1 H) 8.05 (d, J=1.8 Hz, 1 H) 9.09 (br. s., 1 H) 10.45 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)CCCC(NCc1cnc2ccccc2c1)c1c(OC)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(OC)c1C(CCCC(=O)O)NCc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
A yellow solution of methyl 5-(2,6-dimethoxyphenyl)-5-((quinolin-3-ylmethyl)amino)-pentanoate (1.320 g; 3.23 mmol; 1.0 equiv.) in MeOH (15 ml) was treated at rt with a solution of 1 M aq. NaOH (6.5 ml; 6.5 mmol; 2.0 equiv.). The resulting solution was further stirred at rt for 1 h45. Concentration to dryness under reduced pressure, and subsequent drying under HV afforded 5-(2,6-dimethoxyphenyl)-5-((quinolin-3-ylmethyl)amino)pentanoic acid as a beige solid. LC-MS (conditions B): tR=0.59 min.; [M+H]+: 395.36 g/mol.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[CH2:8][C:9]([NH:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])=[O:10].CO.O>C(O)(CC)(C)C>[OH:14][CH2:13][CH:12]1[NH:11][C:9](=[O:10])[CH2:8][O:16][CH2:15]1
Reactant: O=C(CCl)NC(CO)CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CO
Solvent: O
Product: O=C1COCC(CO)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Sodium tert-butoxide (6.70 g, 59.7 mmol) was dissolved in tert-amyl alcohol (40 mL). To this, a tert-amyl alcohol solution (90 mL) of 2-chloro-N-(2-hydroxy-1-hydroxymethylethyl)acetamide (4.00 g, 23.9 mmol) was added dropwise at room temperature over 30 minutes, and the mixture was stirred at room temperature for 2 hours. To this, methanol (25 mL) and water (1.5 mL) were successively added and the mixture was further stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=80/20) to give 5-(hydroxymethyl)morpholin-3-one (Compound EE) (2.00 g, yield: 64%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH2:21]([N:24]([CH2:37][CH2:38][CH3:39])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH2:22][CH3:23].N>ClCCl.C1CCCCC1.CO>[CH2:37]([N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]2[C:10]3[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=3[C:8](=[O:16])[NH:7][C:6]3[CH:17]=[CH:18][CH:19]=[N:20][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Reactant: Cc1ccc2c(c1)N(C(=O)Cl)c1ncccc1NC2=O
Agent: N
Solvent: C1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3cc(C)ccc3C(=O)Nc3cccnc32)CC1
Yield: 63 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-1-yl]ethanamine in a yield of 63% of theory. Colourless crystals, m.p. 195° C. (D.), RF =0.5 (Macherey-Nagel, Polygram® SIL G UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/15/2 v/v).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:26]=[CH:25][C:23](=S)[NH:22][C:20]1=[S:21].O>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:26]2[CH:25]=[CH:23][NH:22][C:20](=[S:21])[N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=c1cc[nH]c(=S)[nH]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: c1ccncc1
Solvent: O
Product: S=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)cc[nH]1

Procedure:
3-(3-(Piperidinomethyl)phenoxy)propylamine (11.0 g) and dithiouracil (5.8 g) were refluxed in pyridine (100 ml; dried over potassium hydroxide) for approximately 72 hours. The solution was cooled and evaporated under reduced pressure to afford a residue. This residue was treated with water, evaporated under reduced pressure, and azeotroped thoroughly with n-propanol in an effort to remove pyridine. To the resultant residue was added further n-propanol to give the title compound as a solid which was collected by filtration and dried (13.88 g).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:16]=1.BrCC=C>O1CCCC1.CCCCCC>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([S:23][CH:24]([CH2:3][CH:1]=[CH2:2])[C:25]([O:27][CH3:28])=[O:26])[N:18]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)CSc1nc(OC)cc(OC)n1
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(Sc1nc(OC)cc(OC)n1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.22 g (12.2 mmol) Diisopropylamine was dissolved in 10 ml tetrahydrofuran under nitrogen and treated with 7.8 ml (12.2 mmol) 1.6M n-butyllithium in hexane at a temperature between -78° and -50° C. The mixture was stirred for 20 minutes and then a solution of 3 g (12.2 mmol) methyl 2-(4,6-dimethoxy-2-pyrimidinylthio)acetate in 30 ml tetrahydrofuran was added to the reaction mixture and the mixture then stirred for 30 minutes. 1.45 g (12.2 mmol) 3-Bromopropene was added, dropwise, to the solution. The reaction mixture was slowly allowed to reach room temperature, with stirring, and then stirred for 20 hours. The mixture was added to 100 ml ice/water and extracted with ethyl acetate. The ethyl acetate phase, after drying over magnesium sulphate, was evaporated and then purified by medium pressure chromatography using hexane/ethyl acetate as eluent.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:6]=1[OH:13].C(N(CC)CC)C.[CH2:21]=[O:22].Cl>C(#N)C.C(OCC)C>[OH:4][C:5]1[C:6]([OH:13])=[C:7]([CH2:11][CH3:12])[CH:8]=[CH:9][C:10]=1[CH:21]=[O:22]
Reactant: C=O
Reactant: CCc1cccc(O)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccc(C=O)c(O)c1O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Magnesium chloride (1.71 g, 18 mmol) was added at room temperature to a solution of 10 (1 g, 7.2 mmol) in acetonitrile (10 mL), followed by triethylamine (6.3 mL, 45 mmol). Paraformaldehyde (1.47 g, 49 mmol) was then added portionwise to the stirred suspension and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature then poured into a vigorously stirred mixture of 50 mL of 5% HCl and 50 mL of diethyl ether. The organic phase was separated, and the aqueous layer re-extracted with 50 mL of ether. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 6:1) to give 0.9 g of 11:
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[C:1]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCCCCC2)c1
Reaction time: 1 h
Yield: 126.3 %

Procedure:
To a stirred solution of 66.16D (0.350 g, 0.9 mmol) in THF (9 mL, 0.9 mmol) at 0° C. was added LAH in THF (2 mL, 2 mmol, 1.0M). The reaction was stirred for 1 hour. 1N NaOH(aq) was then added to quench the reaction. The reaction was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-20% EtOAc in hexanes) to yield 66.16E as a colorless oil (0.387 g, 120% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(=O)C(C)C)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and isobutyryl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:10][CH2:9]1
Reactant: OC(c1ccccc1)(c1ccccn1)C1CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C(O)(c2ccccc2)c2ccccn2)CC1

Procedure:
2.5 g (10-2 mole) of 4-[(2-pyridinyl)(phenyl)hydroxymethyl]piperidine, 2.5 g (10-2 mole) of 1-(1-bromo-2-ethyl)-1,3-dihydro-2(2H)-benzimidazolone, 1.2 g of Na2CO3, one crystal of NaI and 75 ml of methyl isobutyl ketone are introduced into a round flask.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.CCOCC>[OH:5][CH2:4][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(O)c2)c1CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of methyl 2-methyl-6-[(3-hydroxy-phenoxy)-methyl]-benzoate (220 mg, 0.76 mmol, example 5) in THF (2 mL) is added lithium aluminum hydride solution (1.5 mL, 1 M in THF). The resulting solution is stirred for 10 min then warmed to room temperature and stirred for 40 min. This solution is then cooled to 0° C. and water (75 mL) added, dropwise, followed by sodium hydroxide solution (75 mL, SN) and water (75 mL). The resulting suspension is diluted with ether, filtered through celite and the solid washed thoroughly with methanol (until the solid is free of product by TLC analysis). The combined filtrates are concentrated under vacuum to give the title compound as a white solid. MS (EI) 244 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:31]1([C:34]2([F:38])[CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH:31]1([C:34]2([F:38])[CH2:37][N:36]([C:2]3[CH:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:5]=[C:4]([S:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=4)[N:3]=3)[CH2:35]2)[CH2:33][CH2:32]1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Nc3ccccn3)cc(N3CC(F)(C4CC4)C3)n2)cc1
Temperature: 140 °C
Yield: 3.9 %

Procedure:
N-(4-(4-chloro-6-(pyridin-2-ylamino)pyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (2b, 620 mg, 1.4 mmol) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (598 mg, 3.94 mmol, 2.8 eq.) were dissolved in 1,4-dioxane and transferred to a microwave vial. DiPEA (437 mg, 3.38 mmol, 2.4 eq.) was added. The mixture was flushed with N2 for 10 minutes while stirring and heated at 140° C. for 30 minutes in the microwave. HPLC-MS analysis showed 27-40% product in the mixture. The mixture was concentrated and purified by preparative HPLC and lyophilized, yielding 28 mg (3.8%) of a light-yellow solid with a purity of 98+% (HPLC method B: Rf=5.855 minutes).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:30][CH3:31])[C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:30]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:6]=1)[C:25](=[O:29])[CH2:26][O:27][CH3:28])[CH3:31]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COC

Procedure:
(2′-{[Ethyl-(2-methoxy-acetyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.135 g, 0.31 mmol) in THF (2 mL) was treated with 1N aqueous LiOH (2 mL) for 2 hours at room temperature. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 440.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:41])=[C:14]([C:32]([O:34]CCCN(C)C)=[O:33])[CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:10][C:11]1[NH:12][C:13]2[CH2:41][O:34][C:32](=[O:33])[C:14]=2[CH:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18]
Reactant: CC1=C(C(=O)OCCCN(C)C)C(c2ccccc2)C(C(=O)OCCCN(C)C)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCCCN(C)C)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
1.31 grams of 80 percent pyridinium bromide perbromide (3.28 millimoles) was added to a cooled to -20° C. solution of 1.30 grams (2.84 millimoles) of bis(3-dimethylaminopropyl) 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate and 0.4 milliliter of pyridine in 20 milliliters of chloroform. The resulting mixture was stirred at -20° C. for 1/2 hour and then heated at reflux for 2 hours. The mixture was cooled to room temperature and allowed to stir overnight. The crude product was chromatographed on silica gel with 1 percent methanol in chloroform saturated with ammonia as eluant to obtain 161 milligrams of an oil which crystallized when mixed with CDCl3 for NMR analysis. The product was concentrated in vacuo and recrystallized from ethyl acetate-hexane to obtain crystals of m.p. 112°-115° C. after drying 70° C. overnight. The product was a hydrate having elemental analyses as follows:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:50]([CH3:49])(=[O:52])=[O:51])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of methanesulfonyl chloride (32 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, washed with pentane and dried to afford the title compound as a solid (80 mg).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([N+:20]([O-])=O)=[CH:7][CH:8]=2)[N:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([NH2:20])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1-n1c(C)nc2cc([N+](=O)[O-])ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-n1c(C)nc2cc(N)ccc2c1=O

Procedure:
To a mixture of 2.0 g of iron powder (reduced) and 1.0 g 2-methyl-3-o-tolyl-7-nitro-4-quinazolone (0.0036 mole) in a test tube (8"×1") was added 2 ml of 1 N ammonium chloride and 8 ml ethanol. The mixture was warmed gently in a water bath until the initial vigorous reaction had subsided. The test tube was then heated in the water bath until the solvents had evaporated (about 1 hr). The residue was extracted with four 10 ml portions of benzene, and the extracts were suction-filtered. The filtrate was heated with stirring, and n-hexane was added to cloudiness. The suspension was placed in the refrigerator overnight, and the white crystals were removed by suction-filtration. The yield was 0.9 g (100%), mp 211°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([F:25])=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:25])=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: Nc1cc(Cl)c(Cl)cc1F
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Yield: 78 %

Procedure:
3,4-Dichloro-6-fluoroaniline (1 equivalent) was reacted with 4-chloro-7-fluoro-6-nitroquinazoline (3.5 equivalents), in iso-propylalcohol. After filtration, 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline was obtained in 78% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][CH:5]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)cc1
Yield: 93.8 %

Procedure:
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate*, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered and the filtrate concentrated to give an oil as residue. The oil crystallized when triturated with cold petroleum ether (30°-60° C.). The solid was collected by filtration and recrystallized from petroleum ether (60°-110° C.) to yield 42.9 g (94%) of title compound as a white solid, mp 56.5°-59° C.