Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Product: COc1cc(-c2cc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[Br:37]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([Br:37])=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(2-thienylmethyl)benzene (11.08 g) obtained in Example 158-(1) was dissolved in chloroform (100 ml), and added dropwise thereto at 0° C. was a solution of bromine (3.71 g) in chloroform (13 ml). The mixture was stirred at 0° C. for 1.5 hours, and then, at room temperature for 1 hour, and the mixture was poured into a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-67:33) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 446/448 (m+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39]Br)=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39][N:8]2[CH:9]=[CH:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:6]([O:5][C:4]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]2=[O:16])=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Br)c3)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (3B, 0.050 g, 0.136 mmol) and potassium carbonate (0.019 g, 0.136 mmol) suspended in dimethylformamide (1 mL) was added N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (0.046 g, 0.136 mmol) as a solution in dimethylformamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 12 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 10.23 (s, 1H), 8.0 (d, J=8.6 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.6 Hz, J=2.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.44-7.42 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.10 (m, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.02 (s, 2H). HRMS (M+1)=613.913.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[N:5][N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cn1nnnc1CCl
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3nnnn3C)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 5-chloromethyl-1-methyl-1H-tetrazole [57235-84-4] and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=443.4 (MH+).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH3:29][O:30][C:31](=[O:38])[C@H:32]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH2:33]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:38])[CH:32]([NH:33][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]([CH3:35])[CH2:36][CH3:37]
Reactant: O=C(O)c1cccnc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
To a solution of nicotinic acid (2.0 g, 16.5 mmol) in DCM (20 mL), was added N-methylmorpholine (6.9 mL, 49.5 mmol), EDCI.HCl (6.3 g, 33.0 mmol) and isoleucine methyl ester (3.0 g, 16.5 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain product as yellow solid (2.9 g, 72%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[CH:52][CH:51]=2)=CC=1)([O-])=O>>[N:56]1([C:53]2[CH:52]=[CH:51][C:50]([NH:49][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]6[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:55][CH:54]=2)[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared in the previous step, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.34 (s, 1H), 7.28 (m, 2H), 7.25 (s, 1H), 6.88 (m, 2H), 6.34 (s, 1H), 4.27 (m, 4H), 4.05 (s, 3H), 3.86 (m, 4H), 3.59 (tt, 1H), 3.16 (td, 2H), 3.11 (m, 4H), 2.57 (m, 2H), 2.65-2.34 (br, 8H), 2.30 (s, 3H), 2.21-2.08 (m, 4H), 2.03-1.95 (m, 2H). LC/MS (ESI): calcd mass 603.4, found 604.4 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:16]COC.Cl.O.[C:22](OCC)(=[O:24])C>CC(C)=O>[OH:16][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:13][CH2:14][CH3:15])[C:11]([CH:22]=[O:24])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CCOC(C)=O
Reactant: CCCc1cccc2ccc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cccc2c(C=O)cc(OC)c(O)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
206 g of 2-methoxy-1-methoxymethoxy-8-propylnaphthalene was dissolved in 1160 ml of acetone and cooled to 0° C. Diluted hydrochloric acid (concentrated hydrochloric acid 84 ml/water 206 ml) was added to the solution in 15 minutes, which was returned to room temperature at which the reaction was effected at 20° C. for 5 hours, followed by addition of water and extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution to neutrality, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. 173 g of the resultant brown oily substance was dissolved in 1350 g of dichloromethane without purification and cooled down to 0° C. 176.3 ml of titanium tetrachloride was dropped in the solution at 5° C. or below, to which 114.3 ml of dichloromethyl methyl ether was added at 5° C. or below at which the reaction was carried out for 10 minutes. The reaction solution was slowly added to iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order and dried with anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resultant crystals were washed with a 30% isopropyl ether/hexane solution to obtain 103 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH2:26][OH:27])[CH:25]=1>>[F:28][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:25][C:24]=1[CH2:26][OH:27]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(CO)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(CO)c1
Yield: 62.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 525 mg of (5-amino-2-fluorophenyl)-methanol in place of the 2,4-difluoroaniline. 218 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[NH2:30]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:19]2[CH:20]=[CH:21][C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:23][C:18]=2[O:17][CH3:16])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (978 mg, 5.33 mmol) was dissolved in Tetrahydrofuran (30 mL), then Potassium carbonate (1.52 g, 11.0 mmol) was added. 2-Methoxy-4-morpholin-4-yl-phenylamine (1.030 g, 4.95 mmol) was added, and the reaction was stirred under an atmosphere of Nitrogen, overnight. The reaction was partitioned between 30 mL water, 30 mL dichloromethane and separated. The aq. layer was extracted once with 30 mL dichloromethane, the combined organics washed once with 50 mL brine, then dried over sodium sulfate. The contents were concentrated onto silica gel, and chromatographed on an ISCO cartridge (120 g SiO2, 0-40% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (1.40 g, 80%). m.p.=156-160° C.; LCMS (m/e)=355 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.30 (d, 1H, J=8.8 Hz), 8.13 (s, 1H), 7.87 (s, 1H), 6.57 (d, 1H, J=8.8 Hz), 6.52 (s, 1H), 3.93 (s, 3H), 3.88 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1>O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[CH:1]2
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: NNc1ccc(Cl)cc1
Solvent: O
Product: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 2,4-dichloroacetophenone (378 mg, 2.0 mmol), p-chloro-phenylhydrazine (358 mg, 2.0 mmol and polyphosphoric acid (PPA) (0.5 mL) is heated at 100° C. for 8 h, cooled to room temperature, diluted with water, stirred briefly, allowed to stand at room temperature for 16 h and filtered. The filtercake is washed with water and air-dried to afford the title compound, 320 mg (54% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1([C:7]2[C:16]([OH:17])=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2cccnc2nc1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 5.5 h
Yield: 68.4 %

Procedure:
2-Phenyl-[1,8]naphthyridin-3-ol (23 mg), 4-chloro-6,7-dimethoxyquinoline (69 mg), and 4-dimethylaminopyridine (38 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 5.5 hr. The reaction solution was cooled to room temperature. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)C.C(N(CC)CC)C.[C:52]1(=O)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:52]1([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[C:32](=[O:33])[N:24]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:25]4=[O:40])[CH2:35][CH2:36]2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C1CCCC1
Reactant: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCNCC4)c3C2=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN(C5CCCC5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A 50-mL round bottom flask was charged with Compound 167 (10.0 mg, 0.016 mmol) and dichloroethane (2.3 mL). Triethylamine (2.5 μL, 0.018 mmol) was added followed by cyclopentanone (7.1 μL, 0.06 mmol) and sodium triacetoxyborohydride (4.7 mg, 0.022 mmol). The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL). The organic layer was dried using Na2SO4, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a on a Gilson HPLC with a reversed phase Kromasil column (10u, 100 Å C18, column length 250×50 mm, gradient 75:25-0:100 H2O:MeCN) to give 5.1 mg of Compound 193 as a yellow solid. 1H NMR (300 MHz, CDCl3) 7.53-7.64 (m, 3H), 7.44 (d, J=7.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.91-7.06 (m, 3H), 6.79 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 5.13-5.19 (m, 1H), 4.51-4.64 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73-3.83 (m, 2H), 3.42-3.64 (m, 2H), 2.78-3.22 (m, 6H), 2.48-2.61 (m, 1H), 1.88-2.31 (m, 4H), 1.47-1.69 (m, 4H), and 1.27-1.33 (m, 4H); MS (ES+) 653 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9][OH:10].C[O-].[Na+].[C:21](OCC)(=[O:23])C>CO>[N+:12]([C:5]1[CH:4]=[C:3]([N+:15]([O-:17])=[O:16])[C:2]([O:23][CH3:21])=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([O-:14])=[O:13]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCCO)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To 20.0 g (0.076 moles) of 2-(5'-chloro-2',4'-dinitrophenoxy) ethanol in 200 ml methanol is added 10.8 g (0.20 moles) sodium methoxide, with stirring. The mixture is heated to reflux. TLC (ethyl acetate) after 6 hours shows the reaction is complete. The hot mixture is poured into 1 liter ice. The pale yellow precipitate is collected by vacuum filtration, washed with water and dried in a vacuum oven at 50° C. Yield is 16.3 g (82.9%), m.p. 137°-140°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[C:26]2[CH3:33].Cl>C(O)(C)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:32])=[C:26]4[CH3:33])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (7 g, 23 mmol), (prepared as described for the starting material in Example 1), and 5-amino-2,3-dimethylindole (4.5 g, 28 mmol) in isopropanol (90 ml) containing 6.2 N hydrogen chloride in isopropanol (380 μl) was heated at relux for 3 hours and stirred overnight at ambient temperature. The mixture was triturated with ether and the solid was filtered, washed with ether and dried under vacuum to give 7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline (10.5 g, quant.).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>COCCO>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (prepared in a manner similar to that described by W. J. Link, R. F. Borne and F. L. Setliff, J. Heterocyclic Chem. 4, 641–3, 1967) (131 mg 1 mmol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (248 mg, 1 mol) and diisopropylethylamine (129 mg, 1 mmol) were heated to reflux in 2-methoxyethanol for 2 days under nitrogen. The reaction mixture was concentrated, partitioned between ethyl acetate and water, the organic layer washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give the crude product purified by chromatography on silica. M.S. (M+1): 344.3
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:43]([NH2:45])[CH3:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN1C(=O)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([NH:9][C:7](=[O:8])[C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:45][CH:43]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:44])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(N)c1cccc2ccccc12
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The resin-bound 4-chloromethyl-N-dodecyl-benzamide (described in step b, 0.0426 mmol) was swelled in NMP (0.25 mL) for 15 min at rt. DIEA (33 mg, 0.256 mmol), tetrabutyl-ammonium iodide (94.4 mg, 0.256 mmol) and 1-naphthalen-1-yl-ethylamine (44 mg, 0.256 mmol) dissolved in NMP (0.75 mL) were added and the reaction mixture was shaken 14 h at 80° C. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}-methyl)benzamide which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([NH2:26])=[N:28][CH:29]=[C:30]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1cc(Br)cnc1N
Product: Cc1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cnc1N

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromo-3-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (140 mg, 30%). MS (ISP) 462.2 [(M+H)+]; mp 233-234° C.