Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.BrC1C=C2C(CCC(=O)C2)=CC=1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:26]([NH:29][CH:2]1[CH2:11][C:10]2[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1)[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: N#Cc1ccc2c(c1)CC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1CCc2ccc(Br)cc2C1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCNC1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [prepared from commercially available 7-bromo-2-tetralone following a similar procedure as described in WO2004/071389A2](500 mg, 2.9 mmol) in 20 mL of anhydrous DCM was added 3 drops of HOAc, allylamine (330 mg, 5.8 mmol) and NaBH(OAc)3 (2.46 g, 12 mmol), and the mixture was stirred at RT under nitrogen for 48 hours. DCM was added and the mixture was washed with saturated NaCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 7-(Allylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH2:11]([C:13]1[NH:17][N:16]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:31])([F:30])[F:29])[CH:14]=1)[CH3:12].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:17]1[C:13]([CH2:11][CH3:12])=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[N:16]1)=[O:10]
Reactant: CCc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Reactant: CN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and methyl isocyanate (0.29 g, 5.0 mmol) were added to a solution of 5-ethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.81 g, 6.0 mmol) in ethyl acetate (15 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a yellow solid of N-methyl-5-ethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (1.42 g, yield: 79.3%). mp: 97-100° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.30 (t, J=7.5 Hz, 3H), 2.95 (d, J=5.0 Hz, 3H), 3.12 (q, J=7.5H, 2H), 5.93 (s, 1H), 6.75-7.00 (m, 1H), 7.45 (d, J=9.2 Hz, 1H), 8.41 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.[CH3:19][O:20][N:21]=[C:22]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:23]([O-])=[O:24].[Na+].N1CCC1=O>O1CCOCC1>[C:11]([O:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:23](=[O:24])[C:22](=[N:21][O:20][CH3:19])[C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:17](=[O:18])[N:4]2[C:5]=1[C:14]([OH:16])=[O:15])(=[O:13])[NH2:12]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CON=C(C(=O)[O-])c1cccs1
Agent: O=C1CCN1
Agent: [Na+]
Solvent: C1COCCO1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccs1
Yield: 50.4 %

Procedure:
Following the procedure of Example 2, the title compound (888 mg., 50%) was prepared from (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid (1.09g., 4 mmole) and sodium 2-methoxyimino-2-(thien-2-yl)acetate (syn -isomer) (923mg., 4.8 mmole). Its properties are: m.p. 157° to 163° , [α]D20° + 57.3° (c 1.0 in dioxan), RPAC 0.8* Solvent system A*,λmax. (pH6 buffer) 262.5 nm (ε 15,550), and inflexion at 235 nm (ε 10,350), τ (DMSO-d6) 0.20 (d, J 8 Hz, NH), 2.29 (dd, J 2 and 5 Hz, thienyl C5 -H), 2.7 to 2.9 (m, thienyl C3 -H and C4 -H), 3.40 (s, CONH2), 4.13 (dd, J 5 and 8 Hz, C7 -H), 4.75 (d, J 5 Hz, C6 -H), 5.01 and 5.34 (AB-q, J 13 Hz, C3 -CH2), 6.08 (s, NOCH3), and 6.42 (collapsed AB-q, C2 -H2), νmax. (Nujol) 3700 to 2100 (CO2H), 3480, 3440, 3365, and 3255 (NH and NH2), 1760 (azetidin-2-one), 1722 (CO2H), 1709 (OCONH2) and 1652 and 1530 cm-1 (amide).
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=[CH:15][C:16]=2[F:18])[CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:29]1[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=1.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[Si:5]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:29]3[C:30]([F:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:14]=[CH:15][C:16]=2[F:18])[CH2:11][CH2:10]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: CC1(C)OB(c2ccc(F)c3c2CC[C@@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3cccnc3F)ccc(F)c21

Procedure:
The title compound is prepared from (S)-tert-butyl(7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)dimethylsilane and 3-bromo-2-fluoropyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.31 min.; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16](CO)[N:17]=1)[CH2:10][CH2:11][CH3:12].C(O)C>O1CCOCC1>[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16]([Br:1])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCc1nc(Br)c(CO)[nH]1

Procedure:
3.56 Grams (20 mmol) of the N-bromosuccinimide was added to a solution consisting of 3.68 g (20.0 mmol) of the 2-butyl-4,5-bis(hydroxymethyl) imidazole, 40 ml of ethanol and 15 ml of dioxane maintained at a temperature of 45° to 50° C. with stirring. The mixture was further reacted at the same temperature for 30 minutes with stirring, and then the solvent was distilled off under reduced pressure. The obtained reaction product was washed with water and was recrystallized from acetonitrile to obtain a pale yellowish scale-like crystalline 2-butyl-4-bromo-5-(hydroxymethyl) imidazole in an amount of 2.36 g (yield, 51%).
Reaction SMILES: Cl.FC(F)(F)O[C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.[C:15](O)(=O)[CH3:16]>>[NH:11]1[C:8]2[C:7](=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:16]=[CH:15]1
Reactant: CC(=O)O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: c1ccc2[nH]ccc2c1

Procedure:
Ketone 2 (3.65 gr, 17 mmol) and 4-trifluoromethoxy phenylhydrazine hydrochloride (4.66 gr, 20.4 mmol) were stirred at reflux in acetic acid (0.25M) for 1 h under nitrogen atmosphere. The reaction was cooled to room temperature the acetic acid was removed under reduced pressure and the residue was diluted with ether and washed with water (1×) and brine (1×). The ether layer was dried with magnesium sulfate, filter and evaporated to afford 3 as a yellow oil after column chromatography (hexanes/ethyl acetate, 4:1); 1H-NMR (CDCl3, 500 MHz) δ 7.79 (br s, 1H), 7.25 (d, 1H), 7.17 (s, 1H), 7.14 (t, 1H), 7.03 (dd, 1H), 6.58 (dd, 1H), 6.50 (dd, 1H), 6.44 (t, 1H), 4.95 (br s, 1H), 2.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH:10]=2)[NH:5][C:4](=[O:30])[CH:3]=1.[OH:31]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)=[O:31])[CH:10]=2)[NH:5][C:4](=[O:30])[CH:3]=1
Reactant: OO
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccc(-c4ccccc4)cc3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(4-biphenylyl-mercapto)-butoxy]-carbostyril (m.p. 174°-176° C.) and hydrogen peroxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25]1[NH:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=2[N:10]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
4,5-Difluoro-benzene-1,2-diamine (1.00 g, 6.9 mmol) and 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (1.69 g, 6.9 mmol) were heated at 120° C. with stirring, under argon for 4 h. A further portion of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) was added and heating was continued for a further 2 h. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (2×) and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-30% ethyl acetate-pentane) to give a yellow solid which was triturated with diethyl ether to afford the title compound as a pale brown solid (0.38 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.[Li]CCCC.[F:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:38](=[O:39])[C:37]([F:44])([F:43])[F:36])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a mixture of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1 g, 9 mmol) in THF (25 mL) at −78° C. was added Tetramethylethylenediamine (0.93 mL, 0.0062 mol) followed by 2.5 M of n-BuLi (2.5 mL, 0.0062 mol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then ethyl trifluoroacetate (0.74 mL, 0.0062 mol) was added, continue stirred for 2 hours at −78° C. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was purified by ISCO with 0-100% EtOAc/hexane to give pure 1-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)-2,2,2-trifluoroethanone as a white solid (2.5 g, 70% yield). LC/MS (ESI+): m/z 421 (M+H)
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)[CH:17]=2)[CH2:10][C@H:9]1[C:28]([N:30]1[CH2:34][CH2:33][S:32][CH2:31]1)=[O:29])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:26]1[C:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[C:15]([NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:28]([N:30]3[CH2:34][CH2:33][S:32][CH2:31]3)=[O:29])[NH:8][CH2:12]2)=[O:27])=[N:23][N:24]=[N:25]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Example 30B (292.8 mg, 0.6 mmol) dissolved in methanol (10 mL) was added a solution of 4N HCl in dioxane (1.5 mL, 4 M, 6 mmol) via syringe at room temperature. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 388 (M+H)+, 386 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.97 (m, 1 H) 2.86 (m, 2 H) 3.16 (m, 2 H) 3.39 (m, 1 H) 3.61 (s, 2 H) 3.69 (m, 1 H) 3.76 (s, 2H) 3.97 (m, 1 H) 4.53 (m, 2 H) 7.69 (m, 1 H) 8.07 (m, 1 H) 8.20 (m, 1 H) 8.57 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:26]=[O:27])=[CH:9][N:8]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCn1ccc2cc(Br)cnc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)OCn1cc(C=O)c2cc(Br)cnc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (4.09 g, 13.14 mmol) was dissolved in N,N-dimethylformamide (4 ml), and phosphorus oxy-chloride (1.33 ml) was added. The reaction mixture was stirred for 18 hours at 50° C. The reaction was quenched with saturated, aqueous sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography (0-100% (ethyl acetate in hexanes) to give 3.65 g (82%) of 2,2-dimethyl-propionic acid 5-bromo-3-formyl-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 338.0+340.0 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:27])[CH:3]=1.CC(P(C(C)(C)C)C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[Zn][CH2:49][C@@H:50]([CH3:55])[C:51]([O:53][CH3:54])=[O:52]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:26][C:18]1[CH:17]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[N:4]([CH3:27])[CH:3]=[C:2]4[CH2:49][C@@H:50]([CH3:55])[C:51]([O:53][CH3:54])=[O:52])[N:15]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H](C)C[Zn]Br
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)cn(C)c34)no2)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Cc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C

Procedure:
To a suspension of 3-bromo-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D59) (100 mg), tris(1,1-dimethylethyl)phosphane (13 mg), Pd2(dba)3 (41 mg) and Cs2CO3 (30 mg) in THF (5 mL) stirred under nitrogen at room temperature was added a solution of bromo[(2S)-2-methyl-3-(methyloxy)-3-oxopropyl]zinc (1.0 M in THF, 2 mL) in one portion. The reaction mixture was stirred at 60° C. for 1.5 h. The mixture was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water, aqueous HCl (2 M) and brine, dried over sodium sulphate and evaporated to afford methyl (2R)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-methylpropanoate (D60) (120 mg). MS (ES): C25H26ClN3O4 requires 467; found 468.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC(C)=O>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
To a solution of 4-(4-aminophenyl)butyric acid (1 g, 5.6 mmol) in dry acetone (30 ml) was added dropwise a solution of benzenesulphonyl chloride (0.99 g) and pyridine (1.1 g) in dry acetone (10 ml). The mixture was heated at reflux for 3 hours, then concentrated in vacuo. The resulting oil was dissolved in dichloromethane (100 ml) and the solution was washed with 2N aqueous HCl (2×100 ml), followed by water (2×100 ml). The dichloromethane solution was extracted with 10% aqueous NaOH (2×50 ml), followed by water (2×50 ml), and these extracts were combined and stirred with dichloromethane (100 ml) while conc. HCl was added to adjust the pH of the mixture to 5. The layers were separated and the organic solution was dried (MgSO04) and concentrated in vacuo. The resulting solid was recrystallised from isopropanol to give 4-[4-(phenyl-sulphonamido)phenyl]butyric acid. (1.03 g, 58%) mp. 128°-130 ° C.
Reaction SMILES: [S:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:26]([S:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)(=[O:3])=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(S(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)OC)cc1
Temperature: 70 °C

Procedure:
Methyl 4-sulfinobenzoate (4), (12.7 g, 63.43 mMole) and 1-bromododecane (17.4 g, 69.77 mMole) were dissolved in dimethylformamide (100 mL). Potassium carbonate (10.5 g, 76.12 mMole) was added and the mixture heated to 70° C. for 3 hours with good stirring. At the end of this period of time the mixture was cooled and carefully poured into ice cold 2N-HCl (500 mL). The crude methyl 4-dodecylsulfonylbenzoate, a white solid, was filtered off, washed well with water and used as such in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])=[CH:3][CH:2]=1.[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](Cl)=O)=[CH:16]1.N1C=CC(N2C3C=CC=CC=3N=C2/C=C/C2C=CC=CC=2)=CC=1>>[O:15]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:16]1
Reactant: Nc1ccccc1Nc1ccncc1
Reactant: O=C(Cl)/C=C/c1ccoc1
Agent: C(=C/c1nc2ccccc2n1-c1ccncc1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccncc1)\c1ccoc1

Procedure:
The titled compound was prepared from N-(4-pyridyl)-o-phenylenediamine and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(4-pyridyl)-2-styryl-1H-benzimidazole (Example 3). MW: 287.32; mp: 171.5-172.5° C.; 1H-NMR (DMSO) δ: 8.88 (2H, dd, J=4.6, 1.7 Hz), 8.07 (1H, br.s), 7.81 (1H, d, J=15.8 Hz), 7.74-7.65 (4H, m), 7.35-7.25 (3H, m), 6.89 (1H, br.s), 6.73 (1H, d, J=15.8 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[Cl:10][C:4]1[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][S:13][C:12](=[NH:11])[NH2:14]
Reactant: NC(N)=S
Reactant: Clc1cccc(CBr)c1Cl
Solvent: CCO
Product: N=C(N)SCc1cccc(Cl)c1Cl

Procedure:
2,3-Dichlorotoluene (8.05 g., 0.05 mol.) dissolved in 150 ml. of carbon tetrachloride containing N-bromosuccinimide (8.9 g., 0.05 mol.) was heated to reflux and irradiated with a 275-watt sunlamp for two hours. The mixture was cooled, filtered and evaporated to give α-bromo-2,3-dichlorotoluene. The α-bromo-2,3-dichlorotoluene (2.4 g., 0.01 mol.) and thiourea (0.38 g., 0.005 mol.) were dissolved in 25 ml. of ethanol and refluxed for about sixteen hours. The mixture was cooled, concentrated, treated with ether, filtered and the filter cake recrystallized from water to give carbamimidothioic acid 2,3-dichlorobenzyl ester, m.p. 238°-243° C. (dec.).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@@H:6]2[CH2:13][N:14]([C:16](OC(C)(C)C)=O)[CH2:15][C@H:5]2[CH2:4][NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:14]1[CH2:15][C@@H:5]2[C@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:2][NH:3][CH2:4]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)c3ccccc3[C@@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C[C@H]2CNCc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 71A (2.62 g, 8.66 mmol) in tetrahydrofuran (87 mL) was added lithium aluminum hydride in tetrahydrofuran (13.00 mL, 26.0 mmol) in small portions, and the mixture was stirred at room temperature for 24 hours. Water was added carefully and the product was extracted once with dichloromethane, dried over Na2SO4 and concentrated to afford the title compound. 1H NMR (500 MHz, pyridine-d5) δ ppm 7.31 (d, J=7.4, 1H), 7.20-7.17 (m, 2H), 7.13 (d, J=7.7, 1H), 4.58 (dd, J=14.5, 48.4, 2H), 4.01-3.90 (m, 2H), 3.71-3.57 (m, 2H), 3.40 (t, J=10.4, 1H), 3.19-3.05 (m, 2H), 2.71 (s, 3H), 2.66-2.52 (m, 1H); MS (ESI+) m/z 203.0 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(C2CCC(O)CC2)cc1
Reactant: BrCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OC1CCC(c2ccc(OCCCCCCCCCCCBr)cc2)CC1
Yield: 85 %

Procedure:
A mixture of 2.40 g (0.012 mol) of 4-(4-Hydroxy-cyclohexyl)-phenol obtained in Step 1, 11.76 (0.037 mol) of 1,11-Dibromoundecane, 5.17 g (0.037 mol) of K2CO3 and 40 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered off and the butanone is distilled off under reduced pressure. The crude product is purified by recrystallisation from ethanol to give a pure product as a white solid (4.34 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([N:17]([C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29](Cl)=[C:28]([Cl:35])[N:27]=1)COCC[Si](C)(C)C)(=[O:16])=[O:15]>>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:28]([Cl:35])[N:27]=1)(=[O:15])=[O:16]
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: COCCN
Product: COCCNc1nc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)nc1Cl

Procedure:
Prepared by the method of Example 67 using 2-methoxyethylamine (3 mL) and 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (0.24 g). Yield 0.08 g.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]3[CH:20]=[CH:21][CH:22]=[C:11]3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32].O>O1CCOCC1>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]3[C:20]([C:31](=[O:32])[C:30]([Cl:35])([Cl:34])[Cl:29])=[CH:21][CH:22]=[C:11]3[CH2:10]2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C

Procedure:
10-(1,1′-Biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (1.822 g; 0.005 mol) was dissolved in 50 mL of 1,4-dioxane to which was then added 0.946 g (0.0052 mol) of trichloroacetyl chloride. The reaction solution was heated under reflux with stirring over night, cooled to room temperature and then poured into 250 mL of water. Recrystallization of the crude material from ethanol provided a solid, m.p. 197-198° C.