Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].C1O[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[O:13]C1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]2[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CCCCC12OCCO2
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To Grignard reagent prepared from 3,5-difluorobromobenzene 100 g (518 mmol) and magnesium in dried THF 300 ml at room temperature, a THF (300 ml) solution of cyclohexanedione monoethyleneketal 74.6 g (517 mmol) was added dropwise at room temperature, and the mixture was stirred for 3 hours at room temperature. The reactant was added to one liter of 2N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid 5 g and toluene 800 ml were added. The mixture was refluxed with heating while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 500 ml. The catalyst was filtered off, the solvent was distilled off under reduced pressure, formic acid 40 g and toluene 300 ml were added to the residue, and the mixture was refluxed for 3 hours. After cooling, water 500 ml was added to the reactant, and the organic layer was fractionated, washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3,5-difluorophenyl)cyclohexanone 29.4 g (140 mmol). The yield was 27.0% from 3,5-difluorobromobenzene.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([N:15]([CH2:20][CH:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:22][CH2:23][O:24]C2CCCCO2)[CH2:16][CH2:17][O:18][CH3:19])=[O:14])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]>C(OCC)C.CO>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([N:15]([CH2:20][CH:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:22][CH2:23][OH:24])[CH2:16][CH2:17][O:18][CH3:19])=[O:14])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: COCCN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COCCN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1

Procedure:
A saturated solution of hydrochloric acid in diethylether is added to a solution of 2.2 g of the product obtained in step 3 in 30 ml of methanol, until the obtention of a pH value of 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2O)=[CH:4][C:3]=1[O:20][CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:8]=[C:9]2[Cl:24])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 7-Bromo-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (7-Bromo-1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:16]1[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1Cl
Yield: 59.7 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.043 g (60%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.C(Cl)(=O)[C:10](Cl)=[O:11]>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]=[C:10]=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccoc1
Solvent: ClCCl
Product: O=C=NC(=O)c1ccoc1
Temperature: 25 °C

Procedure:
3-Furancarboxamide (167 mg) was suspended in dichloromethane (10 ml), followed by addition of oxalyl chloride (0.20 ml) under ice-cooling, and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was refluxed for 10 hours and the solvent was distilled off to give crude 3-furoyl isocyanate. In the same manner as in Example 8, the above product was reacted with fumagillol (213 mg) with stirring at room temperature for 30 minutes. Purification by silica gel column chromatography (eluent: n-hexane-ethyl acetate=2:1) gave colorless, powdery O-[N-(3-furoyl) carbamoyl]fumagillol (120 mg) (38% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10])[CH3:2].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:9]=1[CH3:10])[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[N:11]=2)[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOc1ccc(N)nc1C
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2nc(C)cc(=O)n2c1C
Temperature: 95 °C

Procedure:
A mixture of 5-ethoxy-6-methyl-pyridin-2-amine (22.0 g) and ethyl acetoacetate (22.4 ml) was stirred at ambient temperature while polyphosphoric acid (47 ml) was added slowly. After the addition the mixture was warmed gradually on a steam bath, with caution, until an exotherm occurred with considerable frothing. After the reaction had subsided the mixture was heated for 75 minutes at 95° C., then cooled and added to ice/water. When all the polyphosphoric acid had dissolved the mixture was basified with 5M sodium hydroxide solution and the mixture extracted with dichloromethane to give 7-ethoxy-2,6-dimethylpyrido[1,2-a]pyrimidin-4-one m.p. 112°-114° C. The pyrimidine (12.3 g) was added to stirred paraffin oil (190 ml) at 340° C. over 10 minutes. The mixture was heated at 340° C. for a further 40 minutes then cooled to ambient temperature and diluted with petroleum ether, b.p. 60°-80° C. (180 ml). The mixture was filtered and the solid obtained was washed with ether. The solid was recrystallised from IMS to give 6-ethoxy-2,7-dimethyl-1,8-naphthyridin-4-ol, m.p. 281°-4° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:52]=[CH:51][C:13]([C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C@@H:27]([CH2:40][S:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[C:22]([N+:48]([O-:50])=[O:49])[CH:21]=2)(=[O:19])=[O:18])=[O:15])=[CH:12][CH:11]=1.Cl>O1CCOCC1>[NH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([N:2]3[CH2:3][CH2:4][C:5]4([CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:1]3)=[CH:52][CH:51]=2)(=[O:19])=[O:18])=[CH:21][C:22]=1[N+:48]([O-:50])=[O:49])[CH2:40][S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)C3)cc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)C3)cc2)cc1[N+](=O)[O-]

Procedure:
A solution of Example 120D (24 mg, 0.03 mmol) and 4N HCl (0.5 mL) in dioxane at room temperature was stirred for 4 hours, partially concentrated, and treated with diethyl ether. The precipitate was filtered, washed with diethyl ether, and was dried under vacuum to provide the desired product. MS (ESI(+)) m/e 652 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.52 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.74 (d, 2H), 7.70 (s, 2H), 7.24-7.07 (m, 6H), 6.51 (d, 2H), 4.10 (m, 1H), 3.57 (s, 4H), 3.35 (m, 4H), 3.18 (s, 2H), 2.74 (m, 2H), 1.86 (t, 2H), 1.76 (m, 2H), 1.65 (m, 4H), 1.55 (t, 4H).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([CH3:14])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[CH3:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:11])([F:12])[F:13])[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(N)cc1C(F)(F)F
Agent: CC(C)CCON=O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C(F)(F)F
Temperature: 23 °C
Yield: 92.8 %

Procedure:
To a solution of 2-amino-5-methyl-4-trifluoromethyl-benzonitrile from step 4 (23.34 g, 117 mmol) in dry THF (350 mL) was added isoamyl nitrite (34.3 mL, 257 mmol) and the mixture was refluxed for 20 h. Additional isoamyl nitrite (16.6 mL, 129 mmol) was added and the mixture was refluxed for further 20 h. The mixture was cooled to 23° C. and diluted with TBME, the organic layer was washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (25.82 g), which was purified by bulb to bulb distillation to give a yellow liquid (20.11 g), which was finally purified by distillation to give the title compound as a yellow liquid (17.10 g, 79%; by 38-42° C. at 0.8 mbar). MS (EI) 185.1 [M].
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[C:10]2[C:9]([N:26]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:21])[CH2:27]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Reactant: C[C@H]1CNCCN1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CCN1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a mixture of pyrrolopyrimidine from step B (76 mg, 0.2 mmol) and (S)-2-methylpiperazine (21 mg, 0.2 mmol) in isopropanol (2 ml) was added triethylamine (0.11 ml, 0.8 mmol). The mixture was heated at 80° C. for 5 mins via microwave and concentrated under vacuum to give crude (S)-5-bromo-4-(3-methylpiperazin-1-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 0.15 mmol, 75%) which was used directly for the next step. MS (ES+) [M+H]+=437.
Reaction SMILES: [C:1]([C@:3]1([OH:25])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C@H:11]1O[C@@H:10]31)#[CH:2].[ClH:26]>C(O)(=O)C>[C:1]([C@:3]1([OH:25])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C:11]([Cl:26])=[CH:10]3)#[CH:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Reactant: Cl
Solvent: CC(=O)O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
460 mg. of 17α-ethinyl-6α,7α-epoxy-11β-fluoro-17β-hydroxy-4-androsten-3-one is introduced at room temperature into 25 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. After 20 hours, the solution is poured into ice/water. The thus-precipitated product is vacuum-filtered and worked up as indicated in Example 17. After chromatography of the crude product on silica gel with acetone/hexane, 215 mg. of 17α-ethinyl-6-chloro-11β-fluoro-17β-hydroxy-4,6-androstadien-3-one is obtained as a foamy product. UV: ε282 = 20,600 (methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][S:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>CN(C=O)C.O>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[C:11](=[O:13])[CH2:10][S:9][C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a stirred suspension of 7-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (1.02 g, 4.85 mmol) and potassium carbonate (4.69 g, 34.0 mmol) in a pressure flask in DMF (30 mL) under argon was added 2-chloro-N,N-dimethylethanamine hydrochloride (3.49 g, 24.26 mmol). The flask was immediately sealed and heated with stirring to 90° C. overnight. The mixture was then cooled to room temperature, diluted with water and extracted (2× ethyl acetate). The combined organics were then washed with a 1:1 mixture of brine and water (3×) then brine (1×). The organic phase was dried, filtered, concentrated, and then chromatographed in 5% (2M NH3 in MeOH) in dichloromethane, giving the desired product (755 mg, 55.3%). 1H NMR (DMSO-d6) δ 8.30 (d, J=2.7 Hz, 1H), 8.13 (dd, J=9.3, 2.7 Hz, 1H), 7.59 (d, J=9.3 Hz, 1H), 4.11 (t, J=6.9 Hz, 2H), 3.62 (s, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.17 (s, 6H); MS-EI: (m/z, %) 281 (M+, 55), 251 (65), 58 (100).
Reaction SMILES: [CH3:1]C1CCCO1.[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].S(OC)(OC)(=O)=O>>[F:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH3:1])=[C:10]([NH:17][C:18]2[C:19]([O:24][CH3:25])=[N:20][N:21]([CH3:23])[CH:22]=2)[N:9]=1
Reactant: CC1CCCO1
Reactant: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Temperature: 5 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C11H13FN7O 278.2 (M+H)+.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([SH:15])[NH:14][C:10]=2[CH:9]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>N1C=CC=CC=1>[SH:15][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([NH:7][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH:17]=[CH:16][C:11]=2[N:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc2nc(S)[nH]c2c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
N,N-dimethylacetamide (250 ml) was added to 36.6 g of 5-amino-2-mercaptobenzimidazole and 17.1 ml of pyridine, and 34.4 g of phenyl chloroformate was added dropwise at room temperature. The mixture was stirred at room temperature for 1.5 hours, and 1.5 liters of ice water was added. As a result, crystals precipitated. The resulting crystals were collected by filtration and recrystallized from acetonitrile to give 47.7 g of 2-mercapto-5-phenoxycarbonylaminobenzimidazole.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[NH:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)#[N:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.CO>CN(C=O)C>[CH2:14]([C:13]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:1]#[N:2])=[CH:6][CH:7]=2)[C:26](=[O:25])[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][N:18]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound is prepared by stirring one equivalent of N-[(2'-cyanobiphen-4-yl)-methyl]valeramidine with diethyl ethoxymethylenemalonate (Aldrich) in a suitable solvent such as methanol or DMF. After the initial adduct is formed, one equivalent of base such as sodium methoxide is added then the material is stirred for an additional period of time, possibly with heating. Standard workup procedures appropriate to the chosen reaction solvent should be followed.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([N:16]([CH2:18][C:19](O)=[O:20])[CH3:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[C:12]([O:11][C:9]([N:16]([CH2:18][C:19]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])=[O:20])[CH3:17])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1ccccc1N
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC(=O)Nc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A solution of phenylenediamine (100 g, 0.924 mole) and Boc-sarcosine (175 g, 0.924 mole) in DMF (1750 mL) was cooled to -10° C. under argon, and a solution of DCC (190.8 g, 0.924 mole) in CH2Cl2 (1750 mL) was added in a slow stream over 1 hr. The temperature rose to 0° C. during the addition. The reaction was stirred overnight while the temperature was allowed to rise to RT. The white precipitate was removed by filtration, and the filtrate was diluted with H2O (3.5 L) and saturated brine (1 L). The CH2Cl2 layer was separated and the aqueous phase was extracted with EtOAc (2×1 L). The combined organic layers were washed with H2O (1 L) and brine (0.5 L), then were concentrated to a yellow residue (341 g). This was triturated with EtOAc to afford the title compound (179.4 g, 70%): mp 134-136° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:9][CH2:8][N:7](C(OCC)=O)[CH2:6]1)[CH3:2]>O>[CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2]
Reactant: CCNCC1(O)CCN(C(=O)OCC)C1
Solvent: O
Product: CCNCC1(O)CCNC1

Procedure:
7.7 g (35.6 mmol) of ethyl 3-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylate are heated under reflux overnight with 22 g of Ba(OH)2. 8H2O in 220 ml of water. The mixture is filtered off with suction from BaCO3 and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:33])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([S:23]CC3C=CC(OC)=CC=3)[CH2:20][NH:19]2)=[O:17])[CH3:15])=[CH:7][CH:6]=1)[CH3:2].[C:35]1([CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([SH:23])[CH2:20][N:19]2[S:44]([CH2:43][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:46])=[O:45])=[O:17])[CH3:15])=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=S(=O)(Cl)CCCc1ccccc1
Reactant: CCOC(=O)c1ccc(NC(=O)CN(C)C(=O)[C@@H]2C[C@@H](SCc3ccc(OC)cc3)CN2)cc1
Product: CCOC(=O)c1ccc(NC(=O)CN(C)C(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)CCCc2ccccc2)cc1

Procedure:
Analogously, (2S,4R)-4-(2-[[4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetylamino)-benzoic acid ethyl ester was treated with 3-Phenyl-propane-1-sulfonyl chloride folowed by deprotection according to 8.1. to give (2S,4R)-4-[2-[[4-Mercapto-1-(3-phenyl-propane-1-sulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetylamino]-benzoic acid ethyl ester as colorless foam MS: 548 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:17]=[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=2)[CH:21]=[CH:20][NH:19]1>>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][N:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[C:18]1=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)OC(C)(C)C)c3)c(=O)c2c1

Procedure:
The title compound was prepared from tert-butyl[3-(bromomethyl)phenyl]carbamate (0.42 g, 1.48 mmol) and methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.20 g, 0.98 mmol) following the procedure outlined in Example 3, step 1 (0.31 g, 77%). LC-MS: (FA) ES+ 409.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][CH2:33][CH2:34]O)[CH3:31].Cl>>[ClH:1].[CH2:16]([O:17][CH2:18][CH2:20][O:24][C:23]([C:18]1([C:20]([O:22][CH2:34][CH2:33][O:32][CH2:30][CH3:31])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH3:15]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CCOCCO
Agent: Cl
Product: CCOCCOC(=O)C1(C(=O)OCCOCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-ethoxyethanol according to the procedure of Example 1 as an oily off-white gummy solid; 1H NMR (300 MHz, CDCl3): δ 1.10-1.20 (t overlaps with d, J=6.9 Hz, 9H), 1.31-1.41 (brm, 2H), 2.75-2.90 (brm, 1H), 3.10-3.30 (brm, 2H), 3.50 (brq, J=6.9 Hz, 4H), 3.62-3.71 (brm, 4H), 4.37-4.47 (brm, 4H), 5.30-5.70 (brm, 2H), 6.70-6.90 (brm, 4H), 7.19-7.50 (brm, 3H), 8.50-8.85 (brs, 1H), 9.90-10.30 (brs, 1H); MS (ES) m/z (relative intensity): 566 (M+ -HCl, (60).