Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([F:10])[C:3]=1[O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Br:22]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:8][C:6]1[CH:5]=[C:4]([F:10])[C:3]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)[Si](Oc1c(F)cc(CO)cc1F)(C(C)C)C(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
7.40 g (23.4 mmol) of 1,3-difluoro-5-hydroxymethyl-2-triisopropylsilanyloxybenzene are dissolved in 90 ml of dry dichloromethane by stirring at 0° C. under argon. 10.1 g (30.4 mmol) of tetrabromomethane and 7.97 g (30.4 mmol) of triphenylphosphine are successively added to this solution, and the mixture is then stirred under reflux under argon for 12 h. The reaction mixture is washed with water, the organic phase is separated off, dried over magnesium sulfate and filtered, and the solvent is distilled out in vacuo. The oily residue is taken up in diethyl ether and stirred at RT, then filtered, and the filtrate is concentrated. Chromatography of the residue on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1) results in 7.42 g (15.6 mmol, 84% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C>[F:9][C:8]([F:10])([F:11])[CH:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Solvent: CC(=O)O
Product: OC1CCC(C(F)(F)F)CC1
Yield: 86.9 %

Procedure:
4-Hydroxybenzotrifluoride (5 g, 30.8 mmol) was placed in a hydrogen reaction vessel, dissolved in acetic acid (15 ml), and Pt−2O (500 mg) was added. The hydrogen reaction vessel was pressurized with hydrogen (50 psi), and reacted for 16 h. After the reaction finished, the reaction mixture was filtered through Celite, and to the filtrate was added 1N-NaOH, extracted with diethylether, dried over MgSO4, and concentrated in vacuo at rt to give the title compound (4.5 g, 87%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:33]2[CH:32]=[N:31][CH:30]=[C:29]([F:28])[CH:34]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 195.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.89 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.04 Hz, 3H) 3.15 (m, J=6.60 Hz, 2H) 3.32-3.41 (m, 2H) 3.47 (m, J=5.90 Hz, 2H) 4.61 (t, J=1.00 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.86-8.00 (m, 3H) 8.07 (d, J=2.35 Hz, 1H) 8.54-8.67 (m, 2H) 8.75 (d, J=2.35 Hz, 1H) 10.34 (s, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:19]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:20]([Cl:28])[CH:21]3[N:26]=[CH:25][N:24]([CH3:27])[CH:22]3[N:23]=2)(=[O:16])=[O:15])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl>C1COCC1>[Cl:28][C:20]1[CH:21]2[N:26]=[CH:25][N:24]([CH3:27])[CH:22]2[N:23]=[C:18]([NH:17][S:14]([C:11]2([CH2:10][CH2:9][OH:8])[CH2:13][CH2:12]2)(=[O:16])=[O:15])[C:19]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=1[F:37]
Reactant: CN1C=NC2C(Cl)=C(Nc3ccc(I)cc3F)C(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)=NC21
Agent: Cl
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=C(Nc3ccc(I)cc3F)C(NS(=O)(=O)C3(CCO)CC3)=NC21
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(7-chloro-6-(2-fluoro-4-iodophenylamino)-3-methyl-3a,7a-dihydro-3H-imidazo[4,5-b]pyridin-5-yl)cyclopropane-1-sulfonamide (40 mg, 0.060 mmol) in THF (2 ml) is added HCl (0.20 ml, 1.2 N in H2O, 0.24 mmol). After stirring for 1 h, the reaction is quenched with saturated aqueous NaHCO3 solution (3 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is dried over Na2SO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([O-:13])=[O:12].[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4)(=[O:13])=[O:12]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccc2ccccc2c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc5ccccc5c4)ccc31)C1CCC(C2)N1
Yield: 24 %

Procedure:
Intermediate 24 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(2-napthyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (113 mg, 24%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.58 (d, J=0.9 Hz, 1H), 8.26 (s, 1H), 7.93-8.04 (m, 1H), 7.81-7.88 (m, 2H), 7.71 (d, J=9.9 Hz, 1H), 7.52-7.63 (m, 2H), 7.42-7.51 (m, 1H), 7.29 (d, J=8.7 Hz, 1H), 5.26 (br s, 1H), 4.71 (br s, 1H), 3.59 (s, 3H), 3.39 (br s, 1H), 2.49 (d, J=16.2 Hz, 1H), 2.20-2.48 (m, 2H), 1.88-1.99 (m, 1H), 1.59-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([S:10][CH3:11])[NH:6][CH2:7][CH2:8]Br)([O-:3])=[O:2].O1CCCC1>>[CH3:11][S:10][C:5]1[NH:6][CH2:7][CH2:8][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCBr
Solvent: C1CCOC1
Product: CSC1=C([N+](=O)[O-])CCN1
Yield: 26 %

Procedure:
(ii) A solution of 1-nitro-2-methylthio-2-(2-bromoethylamino) ethylene (3g, 0.012 mol) and solium hydride (50% in oil, 0.62 g, 0.013 mol) in dry tetrahydrofuran (100 mol) was refluxed for 7 hours. The reaction mixture was cooled, and the solvent was removed in vacuo. The residue was extracted with boiling ethyl acetate (2×50 ml), and the extracts were decolourized with charcoal. Concentration of the extracts in vacuo, followed by cooling, resulted in the crystallisation of 2-methylthio-3-nitro-4,5-dihydropyrrole (0.5 g, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH2:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C:17]1([C:21](O)=[O:22])[CH2:20][O:19][CH2:18]1)=[O:15].NC1(C(O)=O)COC1.C(OC(=O)C(F)(F)F)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:11][C:21]([C:17]1([NH:16][C:14](=[O:15])[C:13]([F:25])([F:12])[F:24])[CH2:18][O:19][CH2:20]1)=[O:22])[CH2:6][CH2:5]2
Reactant: N[C@H]1CCc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)COC1)C(F)(F)F
Agent: CCOC(=O)C(F)(F)F
Agent: NC1(C(=O)O)COC1
Product: O=C(NC1(C(=O)N[C@H]2CCc3cc(Br)ccc32)COC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (S)-5-bromo-indan-1-ylamine has been coupled with 3-(2,2,2-trifluoro-acetylamino)-oxetane-3-carboxylic acid (prepared from 3-amino-oxetane-3-carboxylic acid and trifluoro-acetic acid ethyl ester in analogy to the procedure described for the preparation of intermediate A-1 [A]) to give 3-(2,2,2-trifluoro-acetylamino)-oxetane-3-carboxylic acid ((S)-5-bromo-indan-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as dark brown viscous oil. MS: 453.3 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]=[O:29].[CH:31]([Mg]Br)=[CH2:32]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:30])[CH:28]([OH:29])[CH:31]=[CH2:32]
Reactant: C=C[Mg]Br
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC=C(C)C=O)C(=O)OC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-2-methylbut-2-enaldehyde (0.90 g) in tetrahydrofuran (40 mL) was added vinylmagnesium bromide (4.5 mL of a 1M solution in tetrahydrofuran). After stirring for 0.5 hours, the reaction was diluted with ethyl acetate nd washed successively with aqueous ammonium chloride and brine. Drying over magnesium sulfate was followed by filtration and solvent removal to leave a residual oil, 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-3-hydroxy-4-methylhexa-1,4-diene, which was carried on without further purification.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:11]2[C:12]([CH3:26])=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=2[O:9][C:8]1([CH3:28])[CH3:27])(=O)=O.[NH:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32]>>[CH2:19]([O:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]2[O:9][C:8]([CH3:28])([CH3:27])[CH:7]([CH2:6][N:29]3[CH2:35][CH2:34][CH2:33][C@H:30]3[CH2:31][OH:32])[C:11]=2[C:12]=1[CH3:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(COS(C)(=O)=O)C(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(CN1CCC[C@H]1CO)C(C)(C)O2
Yield: 66.3 %

Procedure:
The title compound (1 g, 66%) was prepared as a pale yellow solid from (3RS)-5-benzyloxy-2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-3-ylmethyl methanesulfonate (1.49 g) and L-prolinol (1.5 g) by an analogous procedure to that described in preparation 1, mp 99°-101° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:8][C:7]1[C:2]2=[N:1][C:9]([CH3:10])=[C:12]([CH2:17][CH2:16][OH:15])[C:13](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1ncccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1nc2c(O)cccn2c(=O)c1CCO

Procedure:
According to the U.S. Pat. No. 5,688,799 (hereinafter referred to as the '799 patent), the compound of formula I is prepared by the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid in xylene solvent at reflux temperature for overnight using a water separator to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is converted into its hydrochloride salt, followed by reaction with thionyl chloride in dimethylformamide to produce 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:27]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][O:22][CH3:27])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)cc3N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium hydride (55–65% dispersion in mineral oil, 27 mg, 0.67 mmol) was added to a solution of (4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (200 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL) at r.t., then after 1 h iodomethane (89 mg, 0.63 mmol) was added and the reaction mixture was stirred 2 h at 50° C. After cooling another portion of sodium hydride (27 mg, 0.67 mmol) was added, then after the addition of a second equivalent of iodomethane (89 mg, 0.63 mmol) the reaction mixture was stirred 2 h at 50° C. After cooling the reaction mixture was poured onto ice and extracted with ether (30 mL), the organic layer was washed with half-saturated brine, dried (MgSO4), and concentrated. Chromatography on SiO2 (Hexane/EtOAc 3:1) yielded the title compound (109 mg, 52%). Light yellow oil, ISP-MS: m/e=333.3 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[C:6]2=[N:11][CH:12]=[CH:13][N:5]2[N:4]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:13]1[N:5]2[C:6]([C:7]([S:9][CH3:10])=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(SC)c2nccn2n1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(SC)c2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (5.27 g, 24.82 mmol) and 1-bromopyrrolidine-2,5-dione (6.19 g, 34.8 mmol) in DMF (15 mL) was stirred at RT for 2 hours. The reaction was diluted with water, and the product extracted with dichloromethane (3×50 mL). The organic layer was washed with brine, dried and concentrated. The crude product mixture was purified via ISCO (0-50% of ethyl acetate/dichloromethane in 10 minutes, 80 g silica column) to give the pure product 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (4.61 g, 15.83 mmol, 63.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11](OCC)[O:12]CC)=[CH:8][C:9]=1[CH3:10])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCOC(OCC)c1cc(C)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1sc(C=O)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 5-diethoxymethyl-3-methyl-thiophene-2-carboxylic acid methyl ester (4.41 g, 17.1 mmol) in dioxane (20 ml) was cooled to 0° C. (ice bath). 88% formic acid (40 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 30 min. The mixture was concentrated under reduced pressure to afford the desired product which was not further purified (3.2 g, 100% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a7) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1>CC(O)=O.O.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][C:5]2[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=2)=[CH:14][CH:13]=1)=[O:17])=[O:29]
Reactant: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Sc2ncc(Br)cn2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccccc1C(=O)NC(=O)Nc1ccc(Sc2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Iron powder (1.77 g, 31.63 mmol) was added in portions to a mixture of 6n (3 g, 6.32 mmol) in AcOH (90 mL) at 80° C. The reaction mixture was refluxed for 30 min and then cooled to room temperature and diluted with water. The precipitated solid was collected by filtration. The solid was dissolved in an excess of ethyl acetate and filtered. The filtrate was dried and concentrated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-hexane 2:3) to give 7d, yield 62%. 1H NMR (400 MHz, DMSO-d6): δ 11.92 (br, s, 1H), 10.73 (br, s, 1H), 8.75 (s, 2H), 7.68 (m, 2H), 7.57 (m, 2H), 7.25 (m, 1H), 6.79 (m, 1H), 6.59 (m 2H); EI-MS m/z 443 [M]+, 445 [M+2]+; HRMS calculated for C18H12BrN5O2SNa [M+Na]+: 465.9943, found: 465.9938. Anal. (C18H14BrN5O2S) C, H, N.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC=CC=1>CCOCC>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccccc1)NN1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 8 h

Procedure:
A stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole and 3.53 g of phenylisocyanate in 100 ml. of dry benzene is refluxed for 6 hours and then allowed to stand at ambient temperature overnight. Ether is added slowly to promote crystallization. The solid product is filtered, washed with ether and dried. The solid is recrystallized twice from a dimethylformamide water mixture to give crystals m.p. 168°-171° C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-phenylurea.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)[CH:28]=[CH:29][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)[CH:28]=[CH:29][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 64 from methyl 4'-[[2-n-propyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of ethyl 2-cyanoacetate (4.52 g, 40 mmol), 1-(bromomethyl)-2,3-dichlorobenzene (4.8 g, 20 mmol) and potassium carbonate (11.04 g, 80 mmol) in THF (80 mL) was under reflux for 30 h. After cooled to room temperature, the solvent was removed in vacuo and the resulting mixture was acidified with 2 N hydrochloric acid. The resulting solution was extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure. The residue was crystallized with MeOH to give the titled product (1.0 g, 18%) as a white solid. The mother liquor was concentrated in vacuo and the residue was purified by a silica gel chromatography eluted with PE/EA=20/1 to give the titled product (1.53 g, 33%) as a colorless oil; LC/MS: MS (ES+) m/e 272 (MH+); 1H NMR (300 MHz, CDCl3) δ ppm 1.31 (t, J=7.2 Hz, 3H), 3.24 (dd, J=9.6, 13.8 Hz, 1H), 3.56 (dd, J=6.3, 13.8 Hz, 1H), 3.90-3.96 (dd, J=6.3, 9.6 Hz, 1H), 4.28 (dq, J=0.9, 7.2 Hz, 2H), 7.18-7.29 (m, 2H), 7.44 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[O:27][C:19]3=[C:20]([O:25][CH3:26])[N:21]=[CH:22][C:23]([Br:24])=[C:18]3[CH:17]=2)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>[OH-].[Na+]>[Br:24][C:23]1[CH:22]=[N:21][C:20]([O:25][CH3:26])=[C:19]2[O:27][C:16]([C:11]3([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:17][C:18]=12
Reactant: COc1ncc(Br)c2cc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(Br)c2cc(C3(OC)CCNCC3)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
4-(4-Bromo-7-methoxyfuro[2,3-c]pyridin-2-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (1.5 g), dichloromethane (50 ml) and trifluoroacetic acid (5 ml ) were combined and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 1N sodium hydroxide solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined extracts were then dried over magnesium sulphate and evaporated in vacuo to give the title compound (1.2 g) as a pale yellow oil.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:57]=[CH:58][CH:59]=1)[C:24]([NH:26][C:27]1[S:28][C:29]2[CH2:56][CH2:55][CH2:54][CH2:53][C:30]=2[C:31]=1[C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)=[O:33])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:57]=[CH:58][CH:59]=1)[C:24]([NH:26][C:27]1[S:28][C:29]2[CH2:56][CH2:55][CH2:54][CH2:53][C:30]=2[C:31]=1[C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[CH:37][CH:36]=1)=[O:33])=[O:25]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCO)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a mixture of 830 mg of methyl 4-[2-(4-{[(2-{[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 10 mL of THF was added 1.5 mL of tetrabutylammonium fluoride (TBAF) (1.0 M THF solution) under ice cooling, followed by stirring for 4 hours at room temperature and then overnight at 50° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% methanol/chloroform), thereby obtaining 540 mg of methyl 4-[2-(4-{[(2-{[3-(2-hydroxyethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.