Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5]1(=[O:20])=[O:19].[N:21]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:19]=[S:5]1(=[O:20])[N:4]([CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][CH2:27][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:23]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CCN2c3ccccc3N(c3ccccc3)S2(=O)=O)CC1
Temperature: 90 °C

Procedure:
A mixture of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure VI, 112 mg, 0.317 mmol), tert-butyl 1-homopiperazinecarboxylate (381 mg, 1.90 mmol, 6 equiv.), sodium carbonate (202 mg, 1.90 mmol, 6 equiv.) and ethanol (4 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solvent was removed, and the residue was dissolved in ethyl acetate (15 mL). The resulting solution was washed with an aqueous potassium carbonate solution, water, dried (anhydrous sodium sulfate), and concentrated. The crude liquid was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 10-60% ethyl acetate/hexane) to give tert-butyl 4-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]-1,4-diazepane-1-carboxylate as a viscous, colorless liquid. Yield: 121 mg (81%). MS (ESI) m/z 473.0 ([M+H]+). HPLC purity 100.0% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:11]=3[CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([NH:23][C:22]4[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=4[F:20])=[O:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1-c1cc2cc(C(=O)O)ccc2s1
Reactant: Cc1ccc(F)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(F)c(NC(=O)c2ccc3sc(-c4cccnc4N)cc3c2)c1
Temperature: 60 °C

Procedure:
The reaction mixture of 2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid (54 mg, 0.2 mmol, 1 eq), 2-fluoro-5-methylaniline (0.048 mL, 2.1 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (2 mL) and anhydrous DMF (0.5 mL) was stirred and heated at 60° C. for 1 hour. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and finally dried with anhydrous sodium sulfate. The upper, clear solution-layer was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex 1:4 to 1:1) to yield 2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophene-5-carboxamide as a white solid in amount of 39.8 mg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].C([Li])CCC.Br[CH:46]([OH:48])[CH3:47]>C1COCC1>[OH:48][CH2:46][CH2:47][CH2:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Reactant: CC(O)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCCO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
834 mg of trans-2-[3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran dissolved in 8 ml of dry THF was cooled to -78° C. and to it was added 2 ml of n-butyllithium (1.6 N solution in THF) in nitrogen atmosphere. After 15 min. 140 mg of bromoethanol dissolved in 2 ml of THF was added to the reaction mixture. The yellow solution was warmed to room temperature and was quenched with a saturated NH4Cl solution. The title compound was obtained after workup and chromatography on silica gel: MS, m/z 600 M+ ; NMR (CDCl3, 200MHz) δ1.0(t, OCH2CH2CH3), 1.82 (q,OCH2CH2CH3), 1.0-2.4(m, SO2CH2CH2CH2OH, H-4), 2.5(m,H-3), 3.58 (t,SO2CH2CH2CH2OH), 3.72(m, CH2OH), 3.86, 3.92(2s,3 OCH3), 4.18 (t,OCH2CH2CH3), 5.18(s, OCH2Ar), 5.08-5.22 (m,H-2,H-5), 6.62(s,C5ArH), 7.28-7.54(m,ArH).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1>>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9](=[O:11])[C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:34][CH:33]=2)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccn3)cc2)C1
Yield: 45 %

Procedure:
Following the general method as outlined in Example 4 (Method B), starting from 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4-(2-pyridinyl)benzoic acid, the title compound was obtained, after flash-chromatography (eluent cyclohexane/ethyl acetate 8:2), as a mixture of two isomers in 45% yield (95% purity by HPLC).
Reaction SMILES: [N:1]1([CH:6]2[CH:11]3[CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10]3)[CH:5]=[N:4][N:3]=[N:2]1>Cl.O1CCOCC1>[N:1]1([CH:6]2[CH:7]3[CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2n1cnnn1
Agent: Cl
Solvent: C1COCCO1
Product: c1nnnn1C1C2CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound from Step A above (2.6 g, 12.2 mmol) was dissolved in 4 M HCl in dioxane (200 mL) and stirred at RT overnight. The product was concentrated under reduced pressure and dried under high vacuum to give 6-(1H-tetrazol-1-yl)-3-azabicyclo[3.1.0]hexane. ESI-MS calculated for C6H9N5: Exact Mass: 151.09. Found 152.05.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccn2)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
2-[(4-Nitrophenoxy)methyl]pyridine (2.30 g, 10 mmol) was dissolved in ethanol (160 mL) and water (40 mL). NH4Cl (5.30 g) was added to the above mixture and heated to 70-80° C. To this reaction mixture was added iron powder (5.50 g) in portion wise manner under a vigorous stirring and the stifling was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the filter bed with MeOH. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried and concentrated to provide 2-[(4-aminophenoxy)methyl]pyridine as brown solid (1.735 g) in 86% yield. 1H NMR (CDCl3): δ 8.56 (m, 1H), 7.67 (m, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.18 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 5.12 (s, 2H), 3.43 (br s, 2H); LCMS (m/z): 201 (MH+).
Reaction SMILES: [CH:1]12[CH2:16][CH:12]([CH2:13][NH:14][CH2:15]1)[C:11]1[C:10]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:9]3[C:4]([NH:5][C:6](=O)[CH:7]=[CH:8]3)=[CH:3][C:2]2=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]3[CH:1]4[CH2:16][CH:12]([C:11]=3[C:10]=2[C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:13][NH:14][CH2:15]4)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1c2c(cc3[nH]c(=O)ccc13)C1CNCC2C1)C(F)(F)F
Product: O=C(c1c2c(cc3nc(Cl)ccc13)C1CNCC2C1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1-(5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone (156 mg, 0.49 mmol) was treated with POCl3 (5 mL) and warmed to 100° C. with stirring for 3 hours. After concentration in vacuo, the residue was diluted with CH2Cl2 (15 mL) and carefully treated with saturated NaHCO3 solution (10 mL) with stirring. Once CO2 evolution slowed the mixture was separated and the aqueous layer extracted CH2Cl2 (3 times). The organic layer was washed with H2O and saturated NaCl solution, filtered through cotton and concentrated to a brown oil (217 mg, 93%). (TLC ethyl acetate, Rf 0.3) 1H NMR (400 MHz, 2HCCl3) δ 8.03 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 4.43 (m, 1H), 4.01 (m, 1H), 3.62 (m, 1H), 3.29 (m, 2H), 3.23 (m, 1H), 2.45 (m, 1H), 2.10 (d, J=11.6 Hz, 1H). APCI MS m/e 341.1 [(M+1)+].
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:21](OCC)=[O:22])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:4])[CH3:3].[OH-].[K+].[NH2:30][CH2:31][C:32]1[C:33]([F:49])=[C:34]([O:39][C:40]2[CH:41]=[C:42]([CH:45]=[C:46]([Cl:48])[CH:47]=2)[C:43]#[N:44])[C:35]([Cl:38])=[CH:36][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(O)C.CN(C=O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:21]([C:10]2[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:12]=[C:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:27])[CH3:26])[N:9]=2)=[O:22])=[C:33]([F:49])[C:34]=1[O:39][C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[C:46]([Cl:48])[CH:47]=1
Reactant: CCOC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)cn1COCC[Si](C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n1
Yield: 0.1 %

Procedure:
A solution of ethyl 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxylate (0.201 g, 0.49 mmol) in 6N KOH (0.10 mL, 0.6 mmol) and ethanol (1.5 mL) was stirred at RT for 30 mins and evaporated to dryness. The residue was stirred with 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.10 g, 0.32 mmol), HATU (0.203 g, 0.53 mmol) and DIEA (0.085 mL, 0.49 mmol) in DMF (3 mL) at RT overnight. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-50% EtOAc/hex) to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamide (0.13 mg, 58%) as a brown oil and as a mixture of the expected two isomers. This material was stirred in TBAF (2 mL of a 1N solution in THF, 0.2 mmol) for 1 h. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The residue was stirred with TFA (0.4 mL) in EtOH (0.02 mL) and CH2Cl2 (0.8 mL) for 8 h and the solution was evaporated and purified by silica gel chromatography (0-100% EtOAc/hexs, then 0-5% MeOH (2M NH3)/CH2Cl2) to provide the title compound (0.0163 g, 20%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, J=1.51 Hz, 1H), 7.35-7.43 (m, 2 H), 7.28 (t, J=2.06 Hz, 1H), 7.22-7.26 (m, 1H), 7.15 (br. s., 1H), 4.64 (s, 2H), 4.57 (s, 2H). ES-LCMS: m/z 435.1, 437.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:2]>ClCCl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOc1cc(CO)ccc1-c1ccc(F)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of (2-ethoxy-4′-fluoro-biphenyl-4-yl)-methanol (0.42 g, 1.71 mmol, 1.0 equiv) in dichloromethane (20 mL) was added activated MnO2 (2.97 g, 34.11 mmol, 20.0 equiv). The reaction mixture was stirred vigorously for 3 h at ambient temperature and then filtered through Hyflo Super Cel. The organic phase was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (4:1) providing 0.33 g (79%) of the title compound. MS (EI): 244.1 [M]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[O:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #32 (353 mg, 0.488 mmol, 1 eq.) in dichloromethane (10 mL, 0.04 M), amine #67 (271 mg, ≦0.588 mmol, 1.3 eq.), HATU (223 mg, 0.586 mmol, 1.2 eq.) and diisopropylethylamine (238 μL, 1.71 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane), affording #68 (404 mg, 88% over two steps) as a solid. LC-MS: m/z 940.7 [M+H+], 962.7 [M+Na+], retention time=1.04 minutes; HPLC (Protocol C): retention time=9.022 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.25 (br d, J=8 Hz) and 8.48 (br d, J=8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.31-7.36 (m, 2H), 7.14-7.24 (m, 5H), 4.43-4.69 (m, 3H), 4.17-4.26 (m, 3H), 3.91-3.99 (br m, 1H), 3.63 and 3.65 (2 s, total 3H), 3.19 and 3.24 (2 s, total 3H), 3.14 and 3.15 (2 s, total 3H), 2.90 and 2.99 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.6 Hz), total 3H].
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH:12]([CH3:14])[CH3:13].[CH3:15][CH2:16][O:17]CC.O>C(O)(=O)C.Br>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:16](=[O:17])[CH3:15])[CH:7]=[CH:8][C:3]=1[OH:2])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOCC
Reactant: COc1cccc(OC)c1CC(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(O)c(CC(C)C)c1O

Procedure:
1,3-Dimethoxy-2-(iso-butyl)benzene (11.3 g) was dissolved in acetic acid (250 ml) and 48% hydrobromic acid (150 ml). The resultant solution was heated to reflux for 2 days, cooled, and ether and water added. The ether layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated to dryness. The concentrate was chromatographed by HPLC (column eluted with a gradient of 1 to 10% ethyl acetate in hexane) to yield 3.87 g of the title product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:33])[N:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>>[NH:38]1[C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][C:10]3[C:9](=[O:26])[N:8]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:7]([CH3:33])=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:16]=2)=[N:25][N:40]=[N:39]1
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
Process 3: To the toluene (3 mL) solution of 4′-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (335 mg, 0.77 mmol), trimethylsilylazide (2.64 g, 22.9 mmol) and dibutyltin oxide (96 mg, 0.386 mmol) were added, and stirred at 80° C. for 24 hrs under argon atmosphere. The reaction solvent was distilled off and the resulting residues were separated and purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the target compound (224 mg, 61%) as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:49][C:50](=[O:60])[CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:52]Br)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:52][CH:51]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([OH:60])=[O:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CBr)c1ccccc1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOCOCC
Solvent: COC(C)(C)C
Product: O=C(O)C(COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 35.8 g (110 mmol) of fine-powder cesium carbonate in 400 ml of diethoxymethane is cooled to 0° C. At 0° C., 38.6 g (150 mmol) of 2-phenyl-3-bromopropionic acid-ethyl ester is added in drops and dissolved in 30 ml of diethoxymethane over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for four hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:8]3[C:13]4[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:8]3[C:13]4[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2sc3c(c2c1)C(N1CCN(C)CC1)=Nc1ccc(F)cc1N3
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccc(O)cc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-2-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-2-hydroxyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OC)=CC=2F)C2C(=CC=CC=2)[N:28]=1.[H-].[Na+].CI>C1COCC1.CO>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)c(F)c1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Reaction time: 2 h

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-methyl-amine: A solution of (2-chloromethyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine hydrochloride (291 mg, 0.82 mmol) in THF (4 mL) was treated with NaH (130 mg, 3.12 mmol), followed by MeI (0.26 mL, 4.2 mmol). The reaction was stirred for 2 h, diluted with MeOH and concentrated. Purification by MPLC (SiO2, EtOAc/hexanes, 0-100%) gave the desired compound. 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.55-7.65 (m, 1H), 7.02-7.17 (m, 3H), 6.68-6.79 (m, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 3.58 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1cccc(Br)c1)OCC
Yield: 95.2 %

Procedure:
To a solution of 3-bromophenol (1.68 g, 9.77 mmol) in N,N′-dimethylformamide (32 mL), sodium hydride (purity 50%) (516 mg, 10.7 mmol) was added under ice-cold conditions, and bromoacetaldehyde diethylacetal (1.76 mL, 11.7 mmol) was added at 0° C., and the resultant mixture was stirred at 120° C. overnight. The reaction solution was added with water at room temperature and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane). 1-Bromo-3-(2,2-diethoxyethoxy)benzene (2.69 g. yield >100%) was obtained as a yellow oil.