Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH3:21][NH:22][CH3:23]>C(N(CC)CC)C>[CH3:21][N:22]([CH3:23])[CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1
Reactant: CNC
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Solvent: CCN(CC)CC
Product: CN(C)CC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy) phenyl]-4-trifluoromethylimidazole in triethylamine (15 ml) is added 1.1 equivalents of a dimethylamine. This solution is refluxed until reaction is complete as indicated by TLC. The solvent is removed under reduced pressure and the residue recrystallized to yield 2-[4-(3-dimethylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([OH:44])=[C:39]([C:41](=[O:43])[CH3:42])[CH:40]=1.O>O1CCCC1>[Br:1][CH2:42][C:41]([C:39]1[CH:40]=[C:35]([Cl:34])[CH:36]=[CH:37][C:38]=1[OH:44])=[O:43]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
Phenyltrimethylammonium tribromide (0.44 g, 1.17 mmol) was added to a solution of 5′-chloro-2′-hydroxyacetophenone (0.20 g, 1.17 mmol) in tetrahydrofuran (6 mL) and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (220.7 mg, 75.6%) as an yellow oil.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CC(=O)OCC>[OH:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a stirred solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (21 mg, 0.06 mmol) in anhydrous THF (1 mL) was added 1M tetrabutyl ammonium fluoride (0.3 mL, 0.3 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with EA (10 mL), washed with saturated NaHCO3 and brine, and dried over MgSO4. The product was purified by chromatography (EA/hexanes) to afford 8 mg (81%) of (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C21H19N3O2S: 377.1; found 378.1 [M+H]+, tR=3.67 min. 1H NMR (400 MHz, CDCl3) δ 8.28-8.07 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 5.41-5.18 (m, 1H), 4.74 (dd, J=12.2, 6.0 Hz, 1H), 3.48 (ddd, J=17.1, 8.7, 4.6 Hz, 1H), 3.30-3.06 (m, 1H), 2.72-2.40 (m, 1H), 2.04 (ddd, J=13.6, 8.7, 6.5 Hz, 1H), 1.64 (s, 2H), 1.44 (d, J=6.1 Hz, 5H). 13C NMR (101 MHz, CDCl3) δ 167.61, 166.22, 162.23, 147.58, 142.93, 134.04, 133.83, 129.81, 128.30, 127.45, 127.09, 123.37, 116.14, 114.45, 104.34, 77.23, 76.71, 73.09, 36.24, 31.69, 22.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C[C:25]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([O:37][CH2:38][CH2:39][NH2:40])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].CCN(CC)CC.Cl>CN(C=O)C>[N+:34]([C:33]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]([OH:29])=[O:28])([O-:36])=[O:35]
Reactant: Cc1c(C(=O)O)ccc(OCCN)c1[N+](=O)[O-]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2[N+](=O)[O-])ccc1NC(=O)Nc1ccccc1C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy)benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The crude solid was recrystallized from CHCl3—EtOH to give 60 mg (3% for 2 steps) 3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 257 as a yellow crystalline solid. mp 112-115° C.; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37-3.66 (m, 7 H), 3.84 (s, 3 H), 4.27-4.30 (m, 1 H), 6.74-8.56 (series of m, total 12 H); MS (FAB) m/z 523 (M++1); Anal. Calcd. for C26H26N4O8.3/2H2O: C, 56.83; H, 5.32; N, 10.20. Found: C, 56.66; H, 4.90; N, 9.33.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>CN(C=O)C>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:32]
Reactant: CCNCC
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline (0.1 g, 0.24 mmol) in DMF was treated with N,N-diethylamine (excess) and KI (catalytic). The reaction was heated to 60° C. in a sealed tube and stirred overnight. The reaction was quenched with water and extracted with CH2Cl2. The organic was dried and the solvent removed. The crude was purified by silica gel column to afford the desired product. MS ES+ m/e 452 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Hydroxy-cyclopropanecarboxylic acid methyl ester (5.07 g, 43.71 mmol) was dissolved in methylene chloride (75 mL) and 3,4-dihydro-2H-pyran (3.86 g, 45.90 mmol) was added followed by pyridinium-p-toluene-sulfonic acid (1.10 g, 4.37 mmol). The reaction stirred at 25° C. for 3 h. The reaction was concentrated in vacuo to give a clear oil. The oil was dissolved in diethyl ether (75 mL), washed with saturated aqueous brine solution (25 mL), dried over sodium sulfate and concentrated in vacuo to an oil. The oil was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; 100% ethyl acetate) to afford 1-(tetrahydro-pyran-2-yloxy)-cyclopropanecarboxylic acid methyl ester (7.49 g, 86%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 1.14-1.42 (4H, m), 1.88-3.46 (6H, m), 3.46-3.54 (1H, m), 3.70-3.72 (3H, m), 3.82-3.90 (1H, m), 4.81-4.96 (1H, m).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([CH2:7][C:8]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH2:10][CH2:9]1)([OH:6])CO.I([O-])(=O)(=O)=O.[Na+]>CO>[F:21][C:2]([F:1])([F:20])[C:3](=[O:6])[CH2:7][C:8]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH2:9][CH2:10]1
Reactant: COc1ccc(F)cc1C1(CC(O)(CO)C(F)(F)F)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: COc1ccc(F)cc1C1(CC(=O)C(F)(F)F)CC1
Reaction time: 7 h
Yield: 71.7 %

Procedure:
To a solution of 310 mg (1.01 mmol) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]propane-1,2-diol in 15 mL of MeOH was added 1.5 g (7.01 mmol) of sodium periodate. After 7 hours, the mixture was concentrated and the residue diluted with hexanes and filtered through diatomaceous earth. The crude residue was chromatographed on silica gel using hexanes to load the sample and then eluting with EtOAc-hexanes (0:100, then 0.25:99.75, then 0.5:99.5, then 1:99) to afford 200 mg of the title compound as a clear oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[Cl:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][N:29]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[CH:8][C:9]=3[F:16])=[O:13])[CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 102.3 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (272 mg) described in Preparation Example 23 and 1-(3,5-dichloropyridin-2-yl)piperazine (244 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (508 mg) was obtained.
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.CC1(C)OCC(COC2C(C)=CN=[C:45]([CH2:50][OH:51])C=2C)CO1.O.CC1(C)OCC(COC2C(C)=CN=C(CO)C=2C)C[O:57]1>C1(C)C=CC=CC=1>[NH:29]1[C:28]2[CH:30]=[C:31]3[O:51][CH2:50][CH2:45][O:57][C:32]3=[CH:33][C:27]=2[N:26]=[C:25]1[SH:23]
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: Sc1nc2cc3c(cc2[nH]1)OCCO3

Procedure:
The same procedure as in the steps (5f) to (5h) was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol, which was obtained by subjecting (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol monohydrate obtained in the same manner as in Example 96(5) to azeotropic distillation with toluene, and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol, to obtain the title compound (395 mg, total 61.7% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][CH:4]=1.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C(O)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[C:14]([C:13]#[N:17])[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#CCC#N
Reactant: COc1ccc(C=CC=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=CC=C(C#N)C#N)cc1
Yield: 90.7 %

Procedure:
To 0.52 g (3.2 mmol) of the aldehyde from step (a) and 0.26 g (4 mmol) malononitrile in 30 ml ethanol was added 2 drops piperidine and the reaction mixture was refluxed for 40 minutes, cooled, filtered and washed with ethanol to yield 0.61 g (90% yield) of an orange solid, m.p. 160° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][OH:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]([NH:38][C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][O:29][C:43](=[O:44])[C@@H:39]([NH:38][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:40]([CH3:42])[CH3:41])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10-1 (0.5 g, 1.19 mmol), Boc-L-valine (0.27 g, 1.28 mmol), DMAP (36 mg) and EDC(0.27 g) were combined in 10 mL of DCM and stirred at room temperature for 18 h. The mixture was concentrated and purified by flash LC(eluent: 0 to 40% EtOAc in hexane with 0.1% of triethylamine) to afford 42-1 as a colorless oil: LC-MS 525.2 (MH-Boc), tR=10.38 (Method 2). EC50: 928 nM.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH2:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16]>>[OH:16][CH2:15][C:14]([NH:13][S:8]([C:6]1[CH:5]=[N:4][C:3]([Cl:12])=[C:2]([Br:1])[CH:7]=1)(=[O:10])=[O:9])([CH2:17][OH:18])[CH3:19]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NS(=O)(=O)c1cnc(Cl)c(Br)c1
Yield: 83.4 %

Procedure:
Prepared by general procedure III from 3-bromo-2-chloropyridine-5-sulphonylchloride (580 mg, 2 mmol) and 2-amino-2-methyl-1,3-propanediol (231 mg, 2 mmol) to give 5-Bromo-6-chloro-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (600 mg, 83%) as a yellow solid. MS (ISN) 357[(M−H)−], 359.0[(M+2−H)−], 361.0[(M+4−H)−].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]([O:9]N2C(=O)CCC2=O)=O)[CH2:2]1.Cl.Cl.[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][CH:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][C@H:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:36][CH2:37][N:38]([C:7]([O:6][C@H:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:9])[CH2:39][CH2:40]4)[C@H:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CCOC2)CC1

Procedure:
A solution of 1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (U.S. Pat. No. 6,344,465) (55 mg, 0.24 mmol), amine dihydrochloride II (100 mg, 0.199 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (3 mL) was stirred overnight at rt. The solvent was removed at reduced pressure and the remaining material was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane solution provided the crude product which was purified by chromatography on silica gel eluting with 5% methanol/dichloromethane. Title compound in example 692 was obtained as a white hygroscopic powder (70 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.37 (m, 2H), 7.30-7.20 (m, 4H), 7.16 (m, 2H), 5.25 (m, 1H), 4.61 (m, 1H), 3.85 (m, 4H), 3.73 (m, 2H), 3.22 (m, 4H), 2.58 (br s, 3H), 2.36 (m, 2H), 2.17 (m, 3H), 2.05-1.70 (m, 13H). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal., 543.3331 (M+H)Obs..
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[CH:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.I[C:37]1[N:41]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[N:40]=[CH:39][CH:38]=1.C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][C:37]2[N:41]([S:42]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)(=[O:43])=[O:44])[N:40]=[CH:39][CH:38]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Reactant: C#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccnn4S(=O)(=O)c4ccc(C)cc4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of N-(5-chloro-7-ethynyl-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.140 g, 0.28 mmol ), 5-iodo-1-[(4-methylphenyl)sulfonyl)-1H-pyrazole (0.147 g, 0.42 mmol) and diisopropylamine (0.078 ml, 0.56 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this mixture was added copper (I) iodide (0.016 g, 0.084 mmol) and bis(triphenylphospine)palladium (II) chloride (0.039 g, 0.056 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was filtered and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a yellow solid (0.103 g, 51%). Mass Spectrum: M+H+ 717 and M+H− 715.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:7][C:8]=1[CH:14]=[O:15]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(CC(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(F)(F)F)cc1C=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a stirred solution of Compound 45 (760 mg, 4.00 mmol) in dry CH2Cl2 (15 ml) was added TiCl4 (1.67 g, 8.80 mmol) via a syringe with ice-cooling. After 15 min, to this was added a solution of dichloromethyl methyl ether (920 mg, 8.00 mmol) in dry CH2Cl2 (5 ml) at same temperature. The reaction mixture was stirred at 0° C. for 15 min, and then for 1.5 h at room temperature. The mixture was diluted with water (20 ml) with ice-cooling and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with sat. NaHCO3 aq. and brine, dried MgSO4), and concentrated in vacuo to give crude product as a yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate (40:1-20:1) to give Compound 46 (500 mg, 57%) as a colorless solid(needle).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCc1ccccn1
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccn1
Yield: 35.5 %

Procedure:
Using an analogous procedure to that described in Example 38, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 24), was reacted with 2-(chloromethyl)pyridine hydrochloride (310 mg, 1.9 mmol) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((2-pyridyl)methoxy)quinazoline (146 mg, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:55]1[C:59](=[O:60])[C:58]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:57]2[C:56]1=[O:65].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@@H:9]1[CH2:33][O:34][N:55]1[C:56](=[O:65])[C:57]2=[CH:64][CH:63]=[CH:62][CH:61]=[C:58]2[C:59]1=[O:60])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrrolidine-2-methanol (2: 1.37 g: 2.88 mMol.) in tetrahydrofuran (8.6 ml) under ice cooling are added triphenylphosphin (892 mg: 3.40 mMol.), N-hydroxyphthalimide (705 mg: 4.32 mMol.) and azodicarboxylic acid diethyl ester (0.59 ml: 3.74 mMol.), and the mixture is stirred under ice cooling for 90 minutes. The reaction mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3: 1.73 g). Yield: 97%.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:15])=[N:11][NH:12][C:13]=1[NH2:14].[C:17]([C:19](=[C:25](OCC)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]>C(O)C>[NH2:18][C:17]1[N:12]2[N:11]=[C:10]([CH3:15])[C:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:16])=[C:13]2[N:14]=[C:25]([CH3:26])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1N
Yield: 20.4 %

Procedure:
Concentrated dihydrochloric acid (0.1 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (2.5 g, 11.61 mmol) and ethyl 2-cyano-3-ethoxy-2-butenoate (2.13 g, 11.61 mmol) in ethanol (30 mL), followed by heating under reflux for 18 hours. The reaction mixture was evaporated as it was. Then, water was added and a 5N aqueous solution of sodium hydroxide was added under ice-cooling, to neutralize. Further, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (835 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:11][C:4]1[S:3][C:2]([NH:1][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(C)sc1N
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CCO
Product: COC(=O)c1cc(C)sc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-amino-5-methyl-thiophene-3-carboxylate and 2,5-difluoronitrobenzene, m.p. 149°-151° C. (EtOH).