Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[C:19]1([C@H:25]2[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:27]2[CH2:28][CH2:29][C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[C@H:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cccc([C@H]2CCNC[C@H]2c2ccccc2)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(C(F)(F)F)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=546.1 (M+H+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-phenyl-4-(3-trifluoromethylphenyl)piperidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40]Br)[C:25]=1[CH2:42][CH2:43][CH3:44])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][CH2:40][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:25]=1[CH2:42][CH2:43][CH3:44])[CH3:17]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Yield: 21.9 %

Procedure:
A mixture of 0.850 g of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.811 g of 4-[4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.0 g of anhydrous potassium carbonate in 65 ml of anhydrous acetone was stirred at reflux for 4 days. Additional 1.0 g portions of potassium carbonate were added after 21 and 30 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a brown oil. Purification by high pressure liquid chromatography using 20% ethyl acetate-hexane gave 0.516 g (22% yield) of 4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[Si:20]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: OCC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-phenyl-1,2-ethanediol (1.38 g, 10 mmole), immidazole (817 mg, 12 mmole), and tert-butylchlorodimethylsilane (1.81 g, 12 mmole) in DMF 15 (ml) was stirred at 0° C. for 1.5 hrs and then at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:4) as eluent. 2-(tert-butyidimethylsilyl)oxy-1-phenylethanol was obtained as an oil (2.6 g, 100% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([NH:16]C(=O)OC(C)(C)C)([CH3:15])[CH3:14])=[N:10][C:9]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][S:31]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[C:25]=2[F:42])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:44]>>[NH2:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:44])[N:7]=2)=[C:9]([C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[N:10]=1)([CH3:15])[CH3:14]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(N)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Yield: 45 %

Procedure:
Following a procedure analogous to the procedure described in Example 312 using 1,1-dimethylethyl {1-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate (100 mg, 0.156 mmol) and ammonium hydroxide (2 mL, 51.4 mmol) at 90° C. for 3 hours, the title compound was obtained as a solid (37 mg 45% yield). MS (ESI): 521.2 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Manganese (IV) oxide (4 eq) was added to a 0.18M solution of (4-bromo-2-nitrophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid in 78% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:6]#[N:7])[NH:8][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(N)C#N
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)NC(=O)COC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
A solution of aminocyanacetic acid ethyl ester (1.00 g, 7.80 mmol) in dichloromethane (15.00 ml) was cooled to 0° C. and treated with pyridine (0.62 g, 7.80 mmol). Methoxy-acetyl chloride (0.85 g, 7.80 mmol) was added dropwise during 15 min. The mixture was stirred for 5 min at 0° C., then warmed to room temperature and stirred for 10 min. The volatiles were evaporated, and the residue was redissolved in dichloromethane and washed twice with water. The organic layer was dried with sodium sulphate and evaporated. The residue was triturated in diisopropyl ether to yield cyano-(2-methoxy-acetylamino)-acetic acid ethyl ester (1.04 g, 66%), MS (ISP): m/e=201.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH2:23][CH:24]([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(C)c1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(CC(C)C)c3c(F)cccc23)c(C)c1
Yield: 99.8 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.300 g, 1.20 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and 1-iodo-2-methylpropane (0.23 mL, 2.00 mmol) to give the title compound (0.374 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[N:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:28][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[N:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1cccnn1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cccnn1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridazin-3-yl-methylamine (example 4.11).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCN1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 44.8 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-tridecylpiperidine (0.596 g, 2.0 mmol) of according to procedure used for Example 2 to give 0.240 g of the title compound as a white solid (mp-70-72° C., Et2O).
Reaction SMILES: [CH2:1]([Sn:5]([C:14]#[CH:15])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[N:16]([CH2:19][CH2:20][CH2:21][OH:22])=[N+:17]=[N-:18]>C1(C)C=CC=CC=1>[CH2:10]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]1[N:18]=[N:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: [N-]=[N+]=NCCCO
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCO)nn1
Temperature: 110 °C
Yield: 77 %

Procedure:
A solution of tributylstannylethyne (1.47 g, 4.67 mmol) and 3-azidopropan-1-ol (450 mg, 4.4 mmol) in PhMe (15 mL) was heated at 80° C. under nitrogen for 3 days. Another 0.5 eq. of Tributylstannylethyne was added, and the resulting mixture was heated at 110° C. for 5 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO system: acetone/heptane=0-30%) to give the desired product as a colorless oil, 1.42 g, 77% yield. 1H NMR (CDCl3, 400 MHz): δ=7.48 (s, 1H), 4.57 (d, J=6.6 Hz, 2H), 3.63-3.67 (m, 2H), 2.11-2.17 (m, 2H), 1.95 (br s, 1H), 1.54-1.58 (m, 6H), 1.33-1.37 (m, 6H), 1.10-1.14 (m, 6H), 0.89 (t, J=7.3 Hz, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[C:19]3[C:18]4[C:22](=[CH:23][CH:24]=[C:16]([F:15])[CH:17]=4)[NH:21][C:20]3=[O:25])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: O=C1Cc2cc(F)ccc2N1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(F)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 5-fluoro-2-oxindole to give 0.3 g of 3-(2,2-Dimethylchroman-6-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20].[NH2:21][CH2:22][CH2:23][SH:24].C(N(CC)CC)C>C(#N)C>[NH2:21][CH2:22][CH2:23][S:24][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:20]
Reactant: NCCS
Reactant: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCc2c(SCCN)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 49.8 %

Procedure:
100 mg of compound (8) obtained in Example 3(1), 56 mg of 2-amino-ethanethiol and 109 mg of triethylamine were added to 2 ml of acetonitrile, and the solution was heated at reflux for 2 hours. After air-cooling, the solvent was removed by distillation. To the residue, ethanol was added, and the deposited solids were filtered off and washed with ether to obtain 60 mg of the subject compound (184).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[C:1]1([C:7]#[C:8][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3ccccc3)c21

Procedure:
Using general Method D above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.16 mmol) (Starting Material 1) using DPPFPdCl2 (6.5 mg) (Aldrich) and CuI (1.5 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h, to yield (Z)-1,3-dihydro-4-(phenylethynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 37%)
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]([NH:12][C:13]([NH:15][CH3:16])=[O:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:23]1SC=C(C2C=CC=CC=2)C=1C(OCC)=O.CN.C(N)C>>[CH2:16]([NH:15][C:13](=[O:14])[NH:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:23]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1NC(=O)NC
Agent: CCN
Agent: CN
Product: CCNC(=O)Nc1scc(-c2ccccc2)c1C(=O)OCC

Procedure:
In exactly the same manner ethyl 4-phenyl-2-(N'-methylureido)thiophene-3-carboxylate. m.p. 109°-12° C. and ethyl 2-(N'-ethylureido)-4-phenyl-thiophene-3-carboxylate M.p. 129°-33° C. were prepared from ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (Gewald et. al., Chem. Ber. 99, 94 (1966) and methylamine and ethylamine respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](O)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Cl:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: COc1cnc(SC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: COc1cnc(SC)nc1Cl

Procedure:
5-Methoxy-2-methylsulfanyl-pyrimidin-4-ol (250 mg) is dissolved in acetonitrile (7 ml) and thereto are added phosphorus oxychloride (0.7 ml) and N,N-diethyl aniline (460 μl) and the mixture is heated under reflux for 5.5 hours. The reaction solution is evaporated azeotropically with toluene three times, and to the residue are added aqueous citric acid solution and chloroform, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (260 mg). MS (m/z): 191/193 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:26][S:27]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])=[O:28]
Reactant: OCCOc1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1OCc1ccccc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 2-(2-benzyloxyphenoxy)ethanol (3.07 g, 12.6 mmol) and triethylamine (2.63 ml, 18.8 mmol) in chloroform (30 ml) was added methanesulfonyl chloride (1.12 ml, 14.4 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and the precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried in vacuo to give 2-(2-benzyloxyphenoxy)ethyl methanesulfonate (3.77 g, yield 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:38][C:39](=[O:42])[NH:40][CH3:41])([CH3:37])([CH3:36])[CH3:35].O>O1CCCC1>[C:34]([O:38][C:39](=[O:42])[N:40]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1)[CH3:41])([CH3:37])([CH3:36])[CH3:35]
Reactant: CNC(=O)OC(C)(C)C
Reactant: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccccc3F)nc(-n3ccc4cnccc43)c2c1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
6-Bromo-2-(2-fluoro-phenyl)-4-pyrrolo[3,2-c]pyridin-1-yl-quinazoline from step E (0.1 g, 0.23 mmol) was dissolved in tetrahydrofuran (5 ml) in a 50 ml round bottomed flask. Cesium carbonate (0.11 g, 0.35 mmol), Xanphos (0.007 g, 0.002 mmol) and methyl-carbamic acid tert-butyl ester (0.045 g, 0.35 mmol) was then added. The mixture was degassed for 5 mins and tris (dibenzylidineacetone)dipalladium(0) (0.005 g, 0.005 mmol) was added. The resulting solution was then magnetically stirred and the heated to 80° C. for 3 hrs. Water was added and compound extracted into ethyl acetate, dried over sodium sulfate and concentrated in rotary evaporator to yield desired title compound (0.066 g, 58%). MS (ES) 470.1 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Product: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)OCC

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidinophenyl) -1-butyl}-aminocarbonylmethyl]-benzoate, using allyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:22](=[O:23])[CH2:21][CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)CCC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)CCC2CCCC2)c[nH]1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Ethylpyrrole-2-carboxylate (1.8593 g, 13.36 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.5756 g, 26.82 mmol) and 3-cyclopentylpropionyl chloride (4.1 mL, 26.59 mmol) in dichloroethane (20 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 4 h. 18.18 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. The crude product was recrystallized from Hexanes/Ethyl acetate. The crude was dissolved in a minimal amount of hot EtOAc, then allowed to slowly cool to room temperature. When no product crystallized, a small amount of hexanes was pipetted down the sides of the flask. Pure crystals of desired product (2.3068 g, 65.6%) were obtained after sitting overnight. 1H (CDCl3, 400 MHz): δ 10.04 (1H, broad s), 7.55 (1H, s), 7.29 (1H, s), 4.34 (2H, q, J=7.1 Hz), 2.77 (2H, t, J=7.6 Hz), 1.85-1.67 (5H, m), 1.64-1.46 (4H, m), 1.36 (3H, t, J=7.1 Hz), 1.78-1.06 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 196.38, 161.09, 127.03, 126.14, 124.05, 114.76, 60.91, 39.82, 39.06, 32.53, 30.82, 25.11, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 60.91, 39.06, 32.53, 30.82, 25.11; CH carbons: 126.14, 114.76, 39.82 ppm. HPLC: 10.800 min.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[C:10]3[N:14]=[CH:13][NH:12][C:11]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[CH:5][CH:6]=1.[O-]CC.[Na+].[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C(O)C>[NH2:18][C:16]1[N:15]=[C:11]2[C:10]([N:14]=[CH:13][N:12]2[CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([O:8][CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:17]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Nc1nc(OCc2ccccc2)c2nc[nH]c2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)OCn1cnc2c(OCc3ccccc3)nc(N)nc21
Reaction time: 0.17 h

Procedure:
To 0.24 g (1 mmol) of O6 -benzylguanine under argon was added 1 mL of a 1M solution of sodium ethoxide in ethanol. The homogeneous solution was stirred for 10 minutes. The ethanol was then removed under vacuum. The remaining solid was dissolved in 2 mL of dry DMF. Chloromethyl pivalate (0.145 ml, 1 mmol) was added dropwise to the stirred solution. The mixture was allowed to react for 30 minutes at room temperature. The DMF was removed under vacuum. The residue was triturated with a small volume of 10% ethanol in CHCl3 and the soluble material was loaded on a 2.5×17 cm silica gel column (Davisil grade 633, 200-425 mesh, 60 Å). The product was eluted with 10% ethanol in CHCl3. Yield, 257 mg (72%); mp 161°-162° C.; 1H NMR δ1.09 (s, 9 H, (CH3)3), 5.48 (s, 2 H, CH2N<), 5.96 (s, 2 H, BzlCH2), 6.64 (s, 2 H, NH2), 7.34 (cm, 1 H, p-ArH), 7.39 (cm, 2 H, 2 m-ArH), 7.50 (cm, 2 H, 2 o-ArH), 7.92 (s, 1 H, 8-H); 13C NMR δ26.51 ((CH3)3), 38.20 (C(CH3)3), 65.13 (CH2N), 66.94 (BzlCH2), 113.11 (C-5), 128.05 (p-Ar), 128.38 (2 m-Ar), 128.47 (2 o-Ar), 136.50 (ipso-Ar), 139.96 (C-8), 154.30 (C-4), 160.11 (C-2), 160.18 (C-6), 176.96 (CO2); MS (EI) Calcd. m/z for C18H21N5O3 : 355.1644. Found: 355.1660 (5 ppm error). Anal. Calcd. for C18H21N5O3 : C, 60.83; H, 5.96; N, 19.71. Found: C, 61.11; H, 6.07; N, 19.64.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([O:9][CH2:13][CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1cccc(Br)c1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 10.1 grams (0.045 mole) of 3-bromocinnamic acid and 40 drops of concentrated sulfuric acid in 75 mL of ethanol was heated at reflux for about 19 hours. After this time the reaction mixture was concentrated under reduced pressure to a residual oil. The oil was dissolved in methylene chloride, and the solution was washed with 50 mL of water and then with 50 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 11.4 grams of ethyl 3-(3-bromophenyl)-2-propenoate. The NMR spectrum was consistent with the proposed structure.