Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][Cl:37])[C:30](O)=[O:31])[N:28]=1)=[O:22]>>[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][Cl:37])[C:30]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[S:12][CH:13]=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:31])[N:28]=1)=[O:22]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Product: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 73.3 %

Procedure:
7-Amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) and 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 1.4 g.) were treated in a similar manner to that of Example 24-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.18 g.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CO
Solvent: CCOCC
Product: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2Cl2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/MeOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2–10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139–142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46–7.40 (m, 1 H), 7.28–7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14](Cl)(=[O:16])=[O:15]>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH:2][CH3:1])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: CN
Product: CNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using methylamine and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CDCl3) δ 8.46-8.29 (d, J=2.4, 1H), 7.99-7.79 (d, J=8.3, 1H), 7.79-7.59 (dd, J=8.3, 2.3, 1H), 5.20-5.01 (d, J=6.4, 1H), 2.80-2.56 (d, J=5.3, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:14].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].N12CCCN=C1CCCCC2>O1CCOCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([C:22]2[O:14][C:4]3[C:3]([O:2][CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]=3[CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: COc1cc([N+](=O)[O-])cc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])cc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 100 °C
Yield: 57.1 %

Procedure:
5.0 g (1.0 equivalent) of 3-methoxy-5-nitrosalicylaldehyde and 6.03 g (1.1 equivalents) of p-nitrobenzyl bromide were dissolved in 15 ml of 1,4-dioxane, and then 13.5 g (3.5 equivalents) of 1,8-diazabicyclo[5.4.0]undeca-7-ene was added thereto. The resulting mixture was heated at about 100° C. for three hours with stirring, and then cooled to room temperature. Thereafter, the resulting solid substance was filtered off and sufficiently washed with ethanol. Thus, 4.55 g of 2-(p-nitrophenyl)-5-nitro-7-methoxybenzo[b]furan was obtained (yield: 70%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.CN(C=O)C.Br[CH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Potassium carbonate (152 g, 1.1 mol) and 4-bromophenol (95.2 g, 550 mmol) were added to a DMF (500 mL) solution of methyl 2-bromomethylbenzoate (115 g, 500 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and thereafter the solvents were distilled off under a reduced pressure. The residue was purified by column chromatography (hexane-toluene=1:1), to give 139 g (86%) of the captioned compound in the form of a colorless oily product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N:13]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCc2cc(N3CCC3)ccc21
Temperature: 100 °C

Procedure:
5-fluoro-1-indanone (7.44 g, 49.5 mmol), Azetidine HCl (5.1 g, 54.4 mmol) and K2CO3 (13.6 g, 99 mmol) were taken up in 60 ml of DMSO. The reaction mixture was heated at 100° C. for 6 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[OH:12][NH2:13]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:13][OH:12])=[NH:11])=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#CC=Cc1ccc(Cl)cc1
Solvent: CCO
Product: N=C(C=Cc1ccc(Cl)cc1)NO
Yield: 50.9 %

Procedure:
A solution of 3-(4-chloro-phenyl)-acrylonitrile (1.63 g, 10 mmol) and hydroxyamine (0.74 ml, 12 mmol) in ethanol (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by column chromatography (EtOAc:Hexane=1:3) to give 1.0 g (51%) of 3-(4-chloro-phenyl)-N-hydroxy-acrylamidine.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([CH:11]=O)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:7]2[C:8]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1csc2cccc(Br)c12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)NCc1csc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Bromobenzothiophene (1.80 g, 8.45 mmol) and dichloromethyl methyl ether (1.46 g, 12.7 mmol) were dissolved in anhydrous DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×150 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 4-bromobenzothiophene-3-carboxaldehyde (0.910 g). The 4-bromobenzothiophene-3-carboxaldehyde (0.910 g, 3.77 mmol) and sulfamide (3.0 g, 31 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:5]([N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)[CH3:8])=[O:6].C1(P([CH:53]2[CH2:58][CH2:57]CCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O>[Cl:39][C:38]1[CH:37]=[CH:36][C:4]([C:5]([N:7]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:10]2)[CH3:8])=[O:6])=[CH:3][C:2]=1[CH:57]1[CH2:58][CH2:53]1
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C(=O)c1ccc(Cl)c(C2CC2)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 821.9 %

Procedure:
To a solution of 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide (78 mg, 0.12 mmol) in toluene (1 mL) and water (0.048 mL) was added under an atmosphere of nitrogen potassium phosphate, tribasic mono hydrate (88 mg, 0.42 mmol), tricyclohexylphosphine (4 mg, 0.014 mmol) palladium(II) acetate (2 mg, 0.009 mmol). The reaction mixture was stirred for 18 h at 80° C. under an atmosphere of nitrogen. It was concentrated and purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 85:15) afforded the title compound (71 mg, 97%) as a light brown foam. MS m/e: 616.2 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)ccc1OC
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Methyl 5-bromo-2-methoxybenzoate (29.3 g) obtained in step A of Example 1-1-1, and 33.1 g of zinc cyanide were dissolved in 650 mL of N,N-dimethylformamide. N,N-Dimethylformamide was degassed under reduced pressure, and then the interior of the reactor was purged with nitrogen. After 9.8 g of tetrakistriphenylphosphine palladium was added, N,N-dimethylformamide was deaerated again under reduced pressure, and then the interior of the reactor was purged with argon. This solution was stirred for 2 hours at 100° C., whereafter the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The insolubles were removed by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, water was added, and then the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure. The resulting residue was washed with diethyl ether. The resulting solid was dried under reduced pressure to obtain 13.5 g (42%) of methyl 5-cyano-2-methoxybenzoate. The mother liquor and the washings were combined, and concentrated, whereafter the residue was recrystallized from t-butyl methyl ether. The resulting crystals were separated by filtration, then washed with a 1:1 solvent mixture of n-hexane and diethyl ether, and then dried under reduced pressure to obtain 4.6 g (14%) of methyl 5-cyano-2-methoxybenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+].CO>O>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Yield: 81.7 %

Procedure:
In similar way to that in Stage IV-1 Example 3 above except that 5 g of methyl 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylate (purity: 95.8%, cis/trans: 92.7/7.3) were added to a mixture of 4 g of sodium hydroxide, 20 ml of methanol and 30 ml of water to heat the resulting mixture for 10 hours under reflux, 3.31 of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 98.8/1.2, purity 96.4%, yield 81.7% were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.I[CH3:31]>CC#N.[Ag]=O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([O:28][CH3:31])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: CI
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: O=[Ag]
Solvent: CC#N
Product: COC(=O)[C@H](OC)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (610 mg, 1.45 mmol) in CH3CN (20 mL) are added iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol). After being stirred at room temperature for 16 h, additional iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol) are added and stirred for 3 days. The reaction mixture is filtered through celite pad and the filtrate is washed with brine. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg). HPLC retention time=1.20, 1.25 minutes (condition B): MS (m+1-Boc)=334. 1H-NMR (400 MHz, CDCl3) δ ppm 1.37, 1.41 (s, 9 H), 2.72-3.03 (m, 2 H), 3.43, 3.71 (s, 3H), 3.63-3.82 (m, 1 H), 4.27-4.41 (m, 1 H), 4.68-5.04 (m, 1 H), 7.28-7.40 (m, 4 H), 7.41-7.61 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][C:12]([CH3:26])([CH3:25])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl>[CH3:25][C:12]1([CH3:26])[O:11][C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:13]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(OC(=O)Cc1cccc(F)c1)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of the product from Step 2 (120 g) in CH2Cl2 (1 L) was treated with DBU (81.6 g) and stirred for 1 h at r.t. The reaction mixture was then treated with 1M HCl (550 mL) and the organic phase was separated, washed with saturated NaHCO3 and dried over MgSO4. After concentration, the crude was swished from 20% EtOAc/hexanes (450 mL) to give the title compound as a white solid (108.4 g, m.p. 172.7° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1.S(=O)(=O)(O)[OH:15].O>O1CCOCC1.O>[CH3:1][C:2]([OH:15])([CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1)[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=CCn1ccc([N+](=O)[O-])n1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)CCn1ccc([N+](=O)[O-])n1
Temperature: 85 °C
Yield: 43 %

Procedure:
1-(3-Methyl-but-2-enyl)-3-nitro-1H-pyrazole (1.29 g, 7.13 mmol) was dissolved in dioxane (30 mL). While stirring, a solution containing 50% concentrated sulfuric acid/water (3 mL) was added dropwise. The reaction was heated to 85° C. while stirring for 12 h. The reaction was diluted with water (50 mL) and the product extracted into ethyl acetate (3×60 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to an oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-methyl-4-(3-nitro-pyrazol-1-yl)-butan-2-ol (608 mg, 43%) as a thick golden oil: H1-NMR (400 MHz, CDCl3) δ 1.30 (6H, s), 1.54 (1H, bs), 2.11-2.15 (2H, m), 4.36-4.39 (2H, m), 6.87 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=2.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.CO>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1N

Procedure:
The appropriate 2-nitrobenzoic acid was initially reacted analogously to general methods 2 and 5 with the respective amine to give a 2-nitrobenzamide. Then 4 mmol of the 2-nitrobenzamide were hydrogenated in 50 ml of THF and 50 ml of methanol in the presence of a spatula tip of 10% palladium on carbon at RT under atmospheric pressure. The catalyst was filtered off with suction, the reaction mixture is concentrated, and the corresponding 2-aminobenzamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:38]([O:45][NH:46][C:14](=[O:15])[CH:13]([CH2:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl-propionic acid (1.05 g, 3.14 mmol) and 0.69 mL (6.3 mmol) of NMM in dry THF, under nitrogen, is cooled in an ice bath. Ethyl chloroformate (0.33 mL, 3.5 mmol) in 7 mL of THF is added dropwise over 5 minutes. The suspension is stirred at 0° C. for 10 minutes, after which a slurry of O-benzylhydroxylamine hydrochloride (0.64 g, 4 mmol) and NMM (0.44 mL, 4 mmol) in 7 mL of THF is introduced in several portions. The mixture is stirred for 10 minutes and stored at 10° C. overnight. The mixture is allowed to warm to room temperature for 0.5 hours, and is then partitioned between ethyl acetate and aqueous 10% HCl. The organic phase is washed with water, three portions of 1M sodium bicarbonate and brine. It is dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel, eluting with 40%-50% ethyl acetate in hexanes. This affords 1.26 g of the title compound as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([NH:7][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])(=[O:34])=[O:33])[CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1)#[N:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N#Cc1ccc(CCOc2cccc(N)c2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3Cl)c2)cc1
Yield: 36.6 %

Procedure:
Pyridine (0.255 mL; 3.15 mmol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy]benzene (0.15 g; 0.629 mmol; from step (ii) above) and 2-chlorobenzenesulfonyl chloride (0.173 mL; 0.818 mmol) in CH2Cl2 (4 mL). After 45 minutes at room temperature the solvent was removed in vacuo. To remove traces of pyridine, EtOH was added and evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with 0.1M aqueous HCl and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene:EtOAc (1:0 to 9:1)) afforded 0.095 g (35%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N+:11]([O-:16])([N+]([O-])=O)=[O:12]>>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[N+:11]([O-:16])=[O:12]
Reactant: Brc1coc2ccccc12
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=[N+]([O-])c1oc2ccccc2c1Br
Reaction time: 0.08 h

Procedure:
To a stirred 80 g. sample of solid 3-bromobenzofuran is added a large excess of dinitrogen tetraoxide. The mixture liquifies within 5 minutes. After 2 hours, the mixture is triturated with ethanol and filtered to provide yellow crystals of 3-bromo-2-nitrobenzofuran. The product is identical to the product of Example 1 according to infrared spectral analysis.
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: C1CCNCC1
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(CN3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 120 °C
Yield: 12.5 %

Procedure:
A 2.0˜5.0 mL process vial was charged with 50 mg methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester, 50 mg piperidine, 75 mg K2CO3 in 3 mL THF/EtOH(1:1). The vial was heated at 120° C. for 30 min under microwave irradiation. After cooling, the reaction mixture was filtered through a short silica gel column, and the solvent was removed under reduced pressure. The residue in MeOH was sent to prep-HPLC to get 5 mg of (6-Methoxy-1-piperidin-1-ylmethyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).