Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38].[Na+].[Cl-]>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)CN)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Boc-Phe-OH (9.16 g, 34.54 mmol) was dissolved in 100 ml of dimethylformamide (DMF), cooled to 0° C. and N-methylmorpholine (NMM) (3.83 ml) added. The solution was cooled to -15° C. and isobutyl chloroformate (IBCF) (3.96 ml, 30 mmol) was added slowly under stirring while maintaining the temperature at -15°±1° C. After stirring at this temperature for 15 minutes, a precooled solution of II (9.4 g, 21.59 mmol) and NMM (2.4 ml) in DMF (40 ml) was added and stirring continued for two hours at ice-bath temperature. A saturated solution of KHCO3 was added to bring the pH to 8.0 and stirred for an additional 30 minutes. The reaction mixture was poured into a cold 90% saturated NaCl solution (1000 ml) and the precipitate obtained was filtered, washed with satd. NaCl, H2O and dried. The peptide was crystallized from ethyl acetate to give 10 g of III (yield: 81.5%). Rf2 0.83 Anal. Calcd. for C30H40N4O7 : C 63.35, H 7.09, N 9.85%. Found: C 62.96, H 7.37, N 9.86%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[CH:14])[CH:11]=2)[S:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.I[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:15]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[C:14][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH:11]=2)[S:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(CC)(CC)CCS2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(CC)(CC)CCS3)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of 0.338 g (1.47 mmol) of (4,4-diethylthiochroman-6-yl)acetylene, 24 mg (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol) of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (Compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 16 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([Li])CCC.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:17]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSc1ccc(Br)cc1
Reactant: [Li]CCCC
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(CP(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 55 h

Procedure:
A cooled solution of 4-bromothioanisole (10.2 g; 0.05 mol) and anhydrous tetrahydrofuran (50 ml) under nitrogen was treated dropwise with 2.5 M n-Butyllithium (19.92 ml; 0.05 mol) in tetrahydrofuran. The cooled mixture was then treated dropwise with a solution of chlorodiphenylphospine (10.0 g; 0.045 mol) and anhydrous tetrahydrofuran (10 ml). The resulting mixture was allowed to warm to room temperature and left to stir for 55 hours. The reaction was quenched with water (500 ml) and extracted with diethyl ether. The combined extracts were dried with magnesium sulphate, filtered and evaporated to dryness to give a yellow solid. Recrystallisation from butanol afforded bisphenyl-4-thioanisylphosphine (XI) as a white solid (3.26 g; 23%).
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1([CH3:13])[CH2:12][CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH3:6][C:7]1([CH3:13])[C-:8]=[CH:9][CH:10]=[CH:11][CH2:12]1.[Li+:5]
Reactant: [Li]CCCC
Reactant: CC1(C)C=CC=CC1
Product: CC1(C)[C-]=CC=CC1
Product: [Li+]
Reaction time: 8 h

Procedure:
35 mmol of butyllithium (1.6 M solution in hexanes, 22 ml) were added slowly to a solution of 5,5-dimethyl-1,3-cyclohexadiene (35 mmol, 3.85 g) in THP (10 ml) and stirred overnight to give a solution of lithium 6,6-dimethylcyclohexadienide. (5,5-dimethyl-1,3-cyclohexadiene was prepared as described previously by P. T. DiMauro and P. T. Wolczanmki, Organometallics 1987, 6, 1947-1954.) Chlorodimethyl(9-fluorenyl)silane was prepared in situ as follows: 30.5 mmol of phenyllithium (1.8 M solution in cyclohexano-ether (70:30), 17 ml) were added slowly to a solution of fluorene in other (70 ml) at room temperature. After stirring overnight, solvents were removed in vacuo and the residue was washed with pentane. The resulting yellow solids were mixed with 60 ml of pentane, cooled to −78° C., and 60 mmol of dichlorodizethylsilane (7.3 ml) were added by syringe. After slowly warming the reaction flask to room temperature over the course of several hours, solvents and residual dichlorodimethylsilane were removed in vacuo. The product was dissolved in 60 ml of other without removing the LiCl and the lithium 6,6-dimethylcyclohexadienide solution described above was added slowly at −30° C. via cannula. After stirring overnight at room temperature, the reaction was quenched with 20 ml of a saturated NH4Cl solution. The aqueous layer was extracted with ether (2×20 ml) and the combined organic fractions were washed with water (2×20 ml), dried over MgSO4 filtered, and evaporated to an orange oil (9.20 g). The oil was chromatographed on silica gal using a 9:1 hexane-methylene chloride solvent mixture. Following a short run of an unidentified light oily product, 3.60 g of the title product were isolated as a colorless oil. Mass spectrum (m/e RA): 330(0.3), 223(100), 195(69), 165(23), 59(9.0). 1H-NMR (CDCl3) δ, ppm: 7.9 (d, 2H), 7.5 (d, 2H), 7.3 (m, 4H), 5.4 (m, 4H), 4.05 (s, 1H), 2.4 (m, 1H), 1.06 (s, 3H), 1.03 (s, 3H), 0.0 (s, 6H).
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][C@@H:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Yield: 99 %

Procedure:
Following method 2, tert-butyl(3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding tert-butyl(3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].CC([O-])=O.[Na+]>CN(C=O)C.CS(C)=O>[C:24]1([CH3:23])[CH:31]=[CH:30][CH:29]=[C:26]([CH:27]=[CH:28][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=2)[CH:25]=1
Reactant: CC(O)c1cccc(Nc2nccc(-c3ccc(Br)s3)n2)c1
Reactant: C=Cc1cccc(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cccc(C=Cc2ccc(-c3ccnc(Nc4cccc(C(C)O)c4)n3)s2)c1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
1-{3-[4-(5-Bromothiophen-2-yl)pyrimidin-2-ylamino]-phenyl}-ethanol (20 mg, 0.056 mmol), 3-methylstyrene (22 uL, 0.168 mmol), FibreCat 1001 (12 mg, 0.0056 mmol), and NaOAc (9.2 mg, 0.112 mmol) were combined in degassed DMF (0.5 mL) in an 8-mL glass vial. The reaction was heated at 100° C. for 18 hours. The mixture was diluted with DMSO, filtered and purified by preparative LCMS to afford 1-(3-{4-[5-(2-m-tolyl-vinyl)-thiophen-2-yl]-pyrimidin-2-ylamino}-phenyl)-ethanol (1.0 mg, 4.3%). 1H NMR (500 MHz, DMSO-d6) δ1.35 (d, J=6 Hz, 3H), 2.27 (s, 3H), 4.68 (q, J=6 Hz, 1H), 5.12 (br s, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.98 (d, J=16.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 7.18-7.26 (m, 3H), 7.32 (d, J=8 Hz, 1H), 7.38 (Br s, 1H), 7.41 (d, J=16 Hz, 1H), 7.50 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 7.87 (d, J=4 Hz, 1H), 7.92 (br s, 1H), 8.34 (s, 1H), 8.40 (d, J=5 Hz, 1H), 9.57 (s, 1H). MS: m/z 414 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].Cl.[CH3:12]O>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:12])=[O:9]
Reactant: CO
Reactant: COCCCCCC(=O)O
Agent: Cl
Product: COCCCCCC(=O)OC
Reaction time: 8 h

Procedure:
6-Methoxy-caproic acid (6.17 g) was dissolved in dry methanol (90 ml) containing hydrogen chloride (catalytic amount) and held overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to give methyl 6-methoxy-caproate. Yield; 5.68 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[C:5](=[O:21])[NH:4][C:3]1=[O:22].O1CCOCC1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[C:5](=[O:21])[NH:4][CH:3]1[OH:22]
Reactant: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)c2cc3[nH]c(-c4ccncc4)nc3cc2C(=O)NC1O

Procedure:
5 g. (17 mmole) of the compound obtained in Example 8 were suspended in 250 ml. dioxan, 250 ml. methanol and 25 ml. water. While cooling with water, sodium borohydride was added thereto in 0.5 g. portions. After each addition, the course of the reaction is monitored chromatographically. When the substance had just gone into solution (conversion 70% of theory), the reaction is discontinued. The product is precipitated by the addition of 1 litre of water and evaporated to give 3.8 g. (76% of theory) of the title compound; m.p. 260 -268° C.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)([CH3:14])[CH3:13].[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:24])[CH:22]=[CH2:23])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Production in a way similar to: D. A. Evans, K. T. Chapman, J. Bisha J. Am. Chem. Soc. 1988, 110, 1238; A Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185. 6.88 ml of a 1.6M solution of n-BuLi in hexane (11.0 mmol) is slowly added to a solution of 1.299 g (10.0 mmol) of (S)-4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF at -78° C. The solution is stirred for 30 minutes at -78° C.; 1.22 ml (15.0 mmol) of acrylic acid chloride is added drop by drop; it is allowed to reach room temperature and hydrolyzed with 50 ml of saturated NH4Cl solution. It is extracted three times with 50 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (10:1), 1.63 g (8.9 mmol, 89%) of 20 is obtained.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[O:15])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[O:15])[CH2:9]1
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 93.5 %

Procedure:
(S)-N-(1-Benzylpyrrolidin-3-yl)-1-adamantanecarboxamide (10.5 g, described in Example 13) was dissolved in ethanol (100 ml), and 10% palladium-carbon (5 g) was added thereto. The mixture was stirred at room temperature, and to the reaction mixture was added hydrazine monohydrate (1.5 ml). The mixture was stirred under heating for 1 hour. The reaction mixture was cooled to room temperature, and 10% palladium-carbon was filtered off with celite. The filtrate was concentrated, and IPE (isopropyl ether) was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(pyrrolidin-3-yl)-1-adamantanecarboxamide (7.2 g), melting point 186-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (7.5 ml) and triethylamine (1 ml), and a solution of triphosgene (99 mg) in chloroform was then added to the solution. The mixture was heated under reflux for 5 min. Next, n-propylamine (21 mg) was added to the reaction solution, and the mixture was heated under reflux for additional 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was supported on diatomaceous earth, followed by extraction with chloroform. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (8/1). Thus, the title compound was quantitatively obtained.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH3:15][C:16]1([CH3:35])[CH2:21][CH2:20][C:19](=[O:22])/[C:18](=[CH:23]/[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])/[CH2:17]1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:15])([CH3:35])[CH2:17]/[C:18]/2=[CH:23]\[O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1=O)(C(C)C)C(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
To EXAMPLE 2 (26 g, as a solution in toluene) was added to anhydrous tetrahydrofuran (65 mL). The resulting mixture was cooled to −5 to 0° C. A separate flask was charged with anhydrous tetrahydrofuran (65 mL) and a 1 M solution of (4-chlorophenyl)magnesium bromide (172 mL, 2.05 equiv). The reagent mixture was cooled to −5 to 0° C. The mixture of EXAMPLE 2 in toluene was slowly added to the Grignard reagent, maintaining a reaction temperature below 5° C. The reaction was monitored by HPLC and was determined to be complete in about one hour. The reaction mixture was quenched slowly with methanol (91 mL), maintaining an internal temperature below 5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].Cl>O1CCOCC1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:3][CH:4]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-aminobenzenesulfonamide (1.00 g) and pyridine (1.41 mL) were added to 1,4-dioxane (30 mL). Acryloyl chloride (0.49 mL) was added dropwise and the solution was stirred for 3 hours at room temperature. 1M HCl was added, and the solution extracted with ethyl acetate. The extracts were dried using brine and anhydrous sodium sulfate and the solvent was removed to afford crude product of sufficient purity for subsequent use.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.Cl.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(Cc2occc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol), 1-methylpiperazine dihydrochloride (986 mg, 5.71 mmol) and triethylamine (1.5 mL, 11.4 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (570 mg, 78%).
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.CO.C[C:17]([O:19][CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O>CCCCCC.O1CCOCC1>[NH2:28][CH:25]1[C:26](=[O:27])[N:23]2[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH2:20][O:19][CH3:17])[CH2:30][S:29][C@H:24]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -15 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
20.28 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2), 2.20 g of trimethyl borate and 1.15 g of methanol were added to 3.5 ml of dioxane. The mixture was cooled to -15° C., and a suspended slurry of 2.74 g of 7-ACA in 15 ml of hexane were added thereto, followed by stirring at -6° C. for 5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.11 g (yield 86%) of the desired compound at a high purity.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][C:33]#[N:34]>CN(C)C=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:32][C:33]#[N:34])[CH2:21]1
Reactant: N#CCCl
Reactant: c1ccc(Cn2c(NC3CCNC3)nc3ccccc32)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirred and heated (60° C.) suspension of 14 parts of 1-(2-pyridinylmethyl)-N-(3-pyrrolidinyl)-1H-benzimidazol-2-amine dihydrochloride and 9.5 parts of sodium carbonate in 113 parts of N,N-dimethylformamide were added dropwise 3.2 parts of 2-chloroacetonitrile. Upon completion, stirring was continued for 3 hours at 60° C. After cooling, the mixture was poured into ice water and the product was extracted six times with methylbenzene. The combined organic layers were washed with water, dried, filtered and evaporated, yielding 11 parts (87%) of 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidineacetonitrile as a residue (compound 133).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@@H:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][CH3:42])=[CH:45][CH:46]=2)[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H](C)NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 106.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(4-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (56 mg, yield 50%).
Reaction SMILES: [CH2:1]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][N+](=O)[CH2:2]1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-].B(F)(F)F.C[CH2:31][O:32]CC.C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[O:32]=[C:31]1[CH2:5][CH2:6][N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:1][CH2:2][CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOCC
Reactant: O=C(OCc1ccccc1)N1CC[N+](=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Yield: 102.7 %

Procedure:
To a suspension of benzyl 4-oxo-1-piperazinecarboxylate (11.7 g, 50.3 mmol) in diethyl ether (100 ml) at −78° C. was added ethyl diazoacetate (6.84 ml, 65.3 mmol) followed by BF3.OEt2 (6.30 ml, 50.3 mmol). After 1 hour the reaction was raised to room temperature giving a clear yellow solution. A saturated aqueous solution of K2CO3 was added dropwise until no further gas evolution was observed. The organic layer was separated and washed with saturated aqueous K2CO3 (2×50 ml), dried (MgSO4), filtered and concentrated giving the title product as yellow oil (16.5 g, quant. yield). The product was used without further purification.
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)C=C.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1.[CH:22](O)([CH3:24])[CH3:23]>>[CH2:24]([C:10]1[C:9](=[O:11])[C:8]2[CH:19]=[CH:18][C:17]3[C:20]([C:7]=2[C:6](=[O:12])[C:5]=1[OH:4])=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH:22]=[CH2:23]
Reactant: CC(C)O
Reactant: C=Cc1ccc(Cl)cc1
Reactant: C=CCOC1=CC(=O)C=CC1=O
Product: C=CCC1=C(O)C(=O)c2c(ccc3ccc(Cl)cc23)C1=O

Procedure:
2-Allyloxy-1,4-benzoquinone (6.56 g, 40 mM) and p-Chlorostyrene (60 g, 0.44 M) were dissolved in 80 ml of isopropanol to give 0.74 g (2.48 mM) of 2-Allyl-3-hydroxy-6-chloro-1,4-phenanthrenequinone in the same manner as in Example 7.