Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5][OH:6].B(F)(F)F.[N+](=[CH:17][C:18](=[O:43])[CH:19]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[N-].CCN(CC)CC>C(Cl)Cl>[Cl:42][C:37]1[CH:36]=[C:35]([CH:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]([OH:34])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)[C:18](=[O:43])[CH2:17][O:6][CH2:5][C:4]2[CH:7]=[C:8]([CH3:10])[CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: Cc1cc(C)cc(CO)c1
Reactant: [N-]=[N+]=CC(=O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(COCC(=O)C(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Dissolve 3,5-dimethyl benzyl alcohol (1.32 g, 9.71 mmoles) in 4.0 ml of dry CH2Cl2 and add BF3 etherate (0.44 ml, 3.56 mmoles). Add a dry CH2Cl2 solution (2.0 ml.) of the product of Step 5 (0.7 g, 1.62 mmoles) dropwise at room temperature, under N2, over a period of 4.5 h. Stir the mixture at room temperature for another 30 min, then quench the reaction with water (6.0 ml) followed, after 10 min of stirring, by Et3N (2.0 ml). Stir for 15 min, then dilute with 90 ml of CH2Cl2. Wash the organic layer with water and dry it over anhydrous Na2SO4. Purify the reaction mixture by flash chromatography (SiO2), eluting the column first with 30% EtOAc/hexanes, then, after elution of the excess of 3,5-dimethyl benzyl alcohol, change the eluent to 40% EtOAc/Hexanes. Yield: 0.435 g. HRMS (FAB, M+H+): m/e calc'd for [C31H36NO3Cl2 ]+ : 540.2072; found 540.2075.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]([CH2:21][CH2:22][O:23][CH3:24])(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCOC)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a 150 mL flask was added diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate (1.59 g, 3.59 mmol) dissolved in acetone (16 mL) and ethanol (16 mL), followed by addition of 1N aqueous sodium hydroxide solution (3.6 mL). The reaction mixture was then heated at 55° C. for 3 h. The reaction mixture was concentrated in vacuo to remove solvents, the residue redissolved in dimethoxyethane (32 mL), and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (50 mL) and water (50 mL), and stirred for 15 minutes until almost all color was extracted into the organic layer. The layers were separated, the aqueous layer was extracted with additional ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, to afford ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 86%). No further purification of this material was required. LC-MS ret. time 3.18 min, m/z 342.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.35 (t, 3H), 1.77-1.92 (m, 1H), 1.94-2.10 (m, 1H), 3.05-3.2 (m, 2H), 3.35-3.50 (m, 3H), 4.09-4.25 (m, 2H), 7.60 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]1.[H-].[Na+].CS([C:23]1[N:24]([CH3:34])[C:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([O:16][C:23]2[N:24]([CH3:34])[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[CH3:15])=[N:10]1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Reactant: Cc1ccc(F)c(-n2nnc(C(C)O)n2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C)n2)c1

Procedure:
The title compound is prepared from 1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:20]=1[CH3:30])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:30])[C:21]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1CCC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydro-indol-2-one was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:14]1([C:17](=[N:25][O:26][CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1>C(OCC)C>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([CH2:27][O:26][N:25]=[C:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:29][CH:30]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(CON=C(c2ccc(Cl)cc2)C2CC2)cc1
Solvent: CCOCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(CON=C(c2ccc(Cl)cc2)C2CC2)cc1
Reaction time: 3 h

Procedure:
36.6 g of 2,6-difluorobenzoylisocyanate in 50 ml of dry diethyl ether were added to a solution of 59.0 g 4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)aniline in 700 ml of dry diethylether with external cooling at 0°-10° C. After stirring for 3 hours at 0°-10° C. the formed precipitate was sucked off, washed with diethyl ether, and dried. The product obtained in a yield of 76.0 g was chromatographed over silica, chloroform being used as an eluent. The desired product was isolated in a yield of 60,7 g having a purity of at least 95% (PMR). The product obtained had a melting range of 145°-175° C. and comprised the syn- and anti-form in approximately equal amounts. In another experiment the desired product was obtained as a mixture of the syn- and anti-form in a ratio of 85:15; melting point 187°-191° C.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[CH:20]=[C:21]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1cc(C)cc(-n2cnc3ccc(O)nc32)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 3,5-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[CH3:2].[OH:29][CH2:30][CH2:31][NH2:32]>>[CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][C:9]2[C:14]3[N:15]=[C:16]([NH:32][CH2:31][CH2:30][OH:29])[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(Nc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Reactant: NCCO
Product: CCOc1ccc(Nc2ncnc3c(N4CCS(=O)CC4)nc(NCCO)nc23)cc1

Procedure:
This compound was prepared analogous to Example 3 from 8-(4-ethoxy-anilino)-2-chloro-4-(1-oxido-thiomorpholino) pyrimido[5,4-d]pyrimidine (melting point: 237°-240° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(O)cc3)C2)CO1
Reactant: CCCCCCCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A solution of (5R,7R)-7-(4-hydroxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one (75 mg, 0.32 mmol), octanol (55.6 μL, 0.35 mmol) and resin bound triphenylphosphine (343 mg, 2 mmol/g, 0.70 mmol) in THF (4.0 mL) was cooled to about 0° C. and di-tert-butyl azodicarboxylate (80.5 mg, 0.35 mmol) was added dropwise. The reaction was allowed to warm up to room temperature for about 3 hours, then the resin was filtered off and washed with DCM (10 mL). The filtrates were combined and concentrated. The crude product was purified on silica gel using a gradient of 30% to 60% EtOAc in heptane. Pure fractions were combined and concentrated to yield 67.0 mg (61%) of (5R,7R)-7-(4-octyloxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one as a white solid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[CH:8]1[S:4][CH2:1][CH2:2][S:3]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C2SCCS2)c1
Yield: 97.2 %

Procedure:
9.9 g of ethane 1,2-dithiol are added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene and the mixture is refluxed for 5 hours under a water separator. After the mixture has been cooled, the solvent is removed, the residue is stirred with petroleum ether and the product is filtered off and dried. 25.5 g of 4-chloro-3-(1,3-dithiolan-2-yl)-nitrobenzene (mp. 130-131° C.) are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]1.I[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[CH3:15][Si:16]([CH2:19][N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]1)([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)CI
Reactant: C1=CNc2ccccc2C=C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CN1C=CC=Cc2ccccc21
Temperature: 50 °C
Yield: 89 %

Procedure:
60% sodium hydride in mineral oil (39 mg, 0.96 mmol, 1.3 equiv) was added to a stirred solution of benzazepine 25 (180 mg, 0.74 mmol, 1.0 equiv) in tetrahydrofuran (9.3 mL) at 25° C. The resulting brown suspension was stirred at 25° C. for 1 h. (Iodomethyl)trimethylsilane (0.55 mL, 3.7 mmol, 5.0 equiv) was added via syringe at 25° C. The reaction vessel was sealed under argon and heated to 50° C. via oil bath for 30 m. The reaction mixture was cooled to 25° C. and approximately 50% of the solvent volume was removed by sweeping with nitrogen. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 31 (151 mg, 62% yield) as an off-white amorphous solid. Rf=0.41 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H, ArH), 6.48 (s, 1H, ArH), 5.89 (s, 2H, OCH2O), 3.56 (m, 2H, CH2), 3.02 (br s, 2H, NCH2Si), 2.91 (m, 2H, CH2), 2.59 (m, 2H, CH2), 2.49 (m, 2H, CH2), 0.13 (s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3) δ 200.86, 169.37, 146.18, 145.19, 132.71, 127.17, 110.46, 109.47, 108.06, 100.92, 57.78, 46.78, 36.22, 33.37, 28.08, −1.26; IR (neat film) 2953 (w, br), 1647 (w), 1556 (s), 1488 (m), 1445 (m), 1353 (w), 1248 (m), 1039 (m), 843 (m) cm−1; HRMS (EI) m/z: Calcd for C18H23NO3Si (MH+) 330.1525, observed 330.1525.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(C)(=O)=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (833 mg, 1.86 mmol) in anhydrous CH2Cl2 (27 ml) was added methanesulfonyl chloride (0.95 ml, 12.2 mmol) and Triethylamine (2.34 ml, 16.3 mmol). The reaction stirred at room temperature for 2 hours, was diluted with dichlormethane and washed with sat. NaHCO3, and brine, dried and filtered to give a yellow oil. Purification by silica gel chromatography (Isco) gave the product as an off white solid, (662 mg, 68% ). Calcd for C27H34FNO4S (M+H) 525.62, Found 526.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH:9]([Mg]Br)=[CH2:10]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:9]=[CH2:10])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: C=C[Mg]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ncc(Br)cn1
Yield: 86.5 %

Procedure:
To a solution of 5-bromo-2-iodopyrimidine (14.2 g, 50 mmol) and Pd(PPh3)4 (865 mg, 0.75 mmol) in THF (200 mL) at room temperature under nitrogen was added dropwise vinylmagnesium bromide (100 mL, 100 mmol, 1 M in THF). The reaction mixture was heated to reflux for 2 hours. The formed mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford an oil which was purified by preparative column chromatography to afford 5-bromo-2-vinylpyrimidine (8 g, yield: 86%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:43][CH2:42][C:41]4[CH:44]=[CH:45][CH:46]=[C:39]([CH3:38])[CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: Cc1cccc(CN)c1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C)c4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-methyl benzylamine, m.p. 165-166° C. MS [(+)ESI, m/z]: 556 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.72; H, 5.96; N, 7.54.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH3:11][O:12][C:13](=[O:16])C=C.C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:16]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CC(=O)OC
Agent: Oc1ccc(O)cc1
Product: COC(=O)C12C=CC(CC1)C2
Temperature: 180 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 256.5 ml 1.9 mol), methylacrylate (Aldrich 405 ml, 4.5 mol), and hydroquinone (3.2 g, 0.03 mol) were put in a 2 L autoclave. After heating to 180° C., reaction was carried out for 5 hours while stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 50° C. to obtain the product (yield: 85%). The mole ratio (mol %) of exo-isomers to endo-isomers of the product was 41.1:58.9.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:23]([CH3:24])[O:22][C@@H:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:11]([OH:25])[C@@H:10]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29]C(OCC)(OCC)C)[CH3:28]>CN(C=O)C>[C:27]([O:25][C@@H:11]1[C@H:10]([OH:26])[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:23]([CH3:24])[O:22][C@H:12]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](O)[C@H]2O)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CN(C)C=O
Product: COc1ccc(O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](O)[C@H]2OC(C)=O)cc1
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
4-Methoxyphenyl 4-O-benzyl-α-L-rhamnopyranoside (4.06 g, 11.28 mmol) and 1,1,1-triethoxyethane (2.20 g, 2.47 mL, 13.53 mmol) are dissolved in 75 mL of DMF and stirred for 50 min at 50° C. DMF was removed in vacuo. The residue was dissolved in AcOH/H2O (4:1, v/v) and stirred for 10 min at room temperature. The acetic acid is removed in vacuo and the crude product was purified by column chromatography (3:1 hexane/EtOAc) yielding 4.51 g (98%, 2 steps) of 12 as a colorless oil: [α]D: −69.4 (c=1.25, CHCl3). IR (thin film, CHCl3): 3005, 2933, 1739, 1503, 1374, 1126, 1041 cm−1. 1H NMR (CDCl3, 300 MHz) δ 1.34 (d, J=6.0 Hz, 3H), 2.19 (s, 3H), 2.41 (b, 1H), 3.44 (t, J=9.3 Hz, 1H), 3.76 (s, 3H), 3.92 (m, 1H), 4.31 (d, J=9.0 Hz, 2H), 4.74 (d, J=12.6 Hz, 2H), 4.87 (d, J=12.6 Hz, 2H), 5.29 (m, 1H), 5.36 (s, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.33 (m, 5H). 13C NMR (CDCl3, 75 MHz) 18.1, 21.2, 55.7, 68.1, 70.0, 72.6, 75.3, 81.6, 96.3, 114.5, 117.6, 127.8, 127.8, 128.4, 138.0, 149.9, 154.9, 170.6. MALDI-HRMS: m/z [M+Na]+ calcd 425.1571, obsd 425.1565.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccs2)c1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a mixture of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromopyridine (0.42 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.034 mmol), sodium carbonate (2.0 M, 2 mL) in toluene (10 mL) was added 2-thienylboronic acid (0.38 g, 3.0 mmol). The reaction mixture was stirred and heated at 80° C. for 16 h. Solvent was evaporated. The residue was chromatographed (silica gel; hexane/EtOAC, 10:1 to 2:1) to afford an oil (0.24 g, 57%): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.26-2.90 (m, 2H), 3.86-3.94 (m, 2H), 4.20 (m, 1H), 4.39 (m, 1H), 4.55 (m, 1H), 7.12 (m, 1H), 7.36 (s, 1H), 7.44 (s, 1H), 8.26 (s, 1H), 8.50 (s, 1H); MS (CI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(C)CC2)c(S(N)(=O)=O)c1

Procedure:
141 Grams of 4-chloro-3-sulfamoylbenzoic acid-ethylester (0.5 mole) were stirred for 1 hour at 110° C. with 250 ml of N-methylpiperazine. The crystalline precipitate obtained after the reaction solution had been poured into 2.0 l of water suction-filtered, was washed with water, dried on the steam bath and recrystallized twice from a mixture of diisopropylether and acetic ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[CH3:30][O:31]C(Cl)Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[S:11][C:12]3[C:13](=[CH:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:30](=[O:31])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc2sc3ccc(C(C)(C)C)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 12 g of bis-(4-t-butylphenyl)-sulfide, 100 mL of dry CH2Cl2 and 21 g of SnCl4 cooled in an ice bath for a period of 30 min., a solution of 9.27 g of α,α-dichloromethyl methyl ether in 50 mL of CH2CH2 was added dropwise. After addition was complete, a deep red mixture was obtained which was allowed to warm slowly to room temperature, stirred for 2 hours and then slowly poured into water. Extraction with CHCl3, followed by washing of the extracts successively with H2O, 5% NaHCO3, H2O and saturated NaCl solution, drying over (MgSO4), and evaporation of solvent gave a red oil which was chromatographed on silica gel. Elution by means of hexane-ethyl acetate (95/5) removed 4.6 g (37% of 2,7-di-t-butylthioxanthene after which there was obtained 4.65 g (37%) of the ketone which was recrystallized from hexane --CH2Cl2 as yellow crystals, m.p. 176°-178°, 'NMR (CDCl3) δ 1.35 (s, 18H, CH3), 7.5 (m, 4H, aryl), 8.75 (d, 2H, CHCCO). Anal. calculated for C21H24OS: C, 77.73; H, 7.46; S, 9.88. Found C, 77.83; H, 7.58; S, 9.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1COCC1.C([N-]C(C)C)(C)C.[Li+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccccc1OC
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.9 %

Procedure:
A 500 mL round-bottom flask is charged with methyl 2-(2-methoxyphenyl)acetate (8.496 g, 47 mmol, 1 eq) and THF (200 mL). The homogeneous mixture is cooled to 0° C. in an ice bath. Lithium diisopropyl amide (23.5 mL of a 2.0 M solution in heptane/THF) is added, maintaining a temperature less than 3° C. The reaction is stirred 45 minutes at this reduced temperature. Benzyl bromide (5.6 mL, 47 mmol, 1 eq) is added dropwise. The reaction is allowed to gradually warm to room temperature and is stirred for 18 hours. The reaction is quenched with 1N HCl and extracted 3 times with equal portions of EtOAc. The combined extracts are washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The residue is purified over silica to afford 4.433 g (35%) of the desired compound. ESI+ MS 293 (M+Na).