Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[OH:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH3:23])[N:16]=2)[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COCn1cc2cc(C[C@@H](OC(C)=O)C(=O)OC)cc(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCn1cc2cc(C[C@@H](O)C(=O)O)cc(C)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-methyl 2-acetoxy-3-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)propanoate (2.70 g, 8.4 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (1.41 g, 4.0 equiv) in water (20 mL). The reaction was stirred at 0° C. for 1 h. The reaction was concentrated, dissolved in water (5 mL), cooled to 0° C., and treated with 1M hydrochloric acid until mildly acidic. The solution was was extracted extensively with ethyl acetate and then dichloromethane. The organics were combined, dried over magnesium sulfate, and concentrated to give 1.40 g (63%) as an oil which solidified to a crystalline solid upon standing. 1H-NMR (CDCl3, 500 MHz) δ 2.40 (s, 3H), 2.78 (dd, J=14.0, 7.9, 1H), 3.00 (dd, J=14.0, 4.0, 1H), 3.18 (s, 3H), 4.24 (dd, J=7.9, 4.3, 1H), 5.47 (s, 2H), 6.85 (s, 1H), 7.22 (s, 1H), 7.90 (s, 1H). Mass spec.: 265.08 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:19]#[N:20])[C:16]([F:21])=[CH:15][C:14]=3[CH3:22])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[C:16]([F:21])=[CH:15][C:14]([CH3:22])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH2:8][O:7][C:6]([CH2:23][CH2:24][CH3:25])([CH2:5][C:4]([OH:26])=[O:3])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 5-cyano-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (404 mg, 1.13 mmol) in THF/MeOH (2.5 mL/5 mL) was added 1 N NaOH (2.26 mL, 2.26 mmol). The reaction mixture was stirred at ambient temperature overnight. Most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated to provide 341 mg (91%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:23]([Cl:28])(Cl)(Cl)(Cl)[Cl:24].C(O)=[O:30]>C(Cl)(Cl)(Cl)Cl.[N+](C)([O-])=O>[Cl:24][P:23]([Cl:28])([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH:15]=1)=[O:30]
Reactant: O=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: O=C(NP(=O)(Cl)Cl)c1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1

Procedure:
A suspension of 32.1 g (0.1 m) of 3-[[(4-nitrophenyl)sulfonyl]-amino]-benzamide and 208 g (0.1 m) of phosphorous pentachloride in a mixture of 300 ml of carbon tetrachloride and 100 ml of nitromethane was stirred and heated for 90 min. The resulting solution was cooled to 20° and 4.7 g (0.1 m) of 97% formic acid added. The reaction was stirred overnight, then the product collected by filtration, washed with carbon tetrachloride and air-dried to give 36.7 g, melts 133°-134°, solidifies 138°, melts 188°-193°.
Reaction SMILES: C[C:2]1[C:3]([O:15][CH3:16])([C:12](O)=[O:13])[CH:4](C)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[H-].[CH2:18]([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:8][C:6](=[O:7])[C:5]1[CH2:4][C:3]([O:15][CH3:16])([CH:2]=[CH:10][CH:9]=1)[CH:12]=[O:13]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC1(C(=O)O)C(C)=CC=C(C(=O)O)C1C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C1=CC=CC(C=O)(OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a -78° C. to -100° C. solution of 1.0 mole of dimethyl 3-methoxyisophthalic acid in 5 liters of toluene is slowly added 1.0 mole of diisobutyl-aluminum hydride as a 1 M solution in n-hexane (reaction t≤-78° C.). The reaction mixture is stirred for 3 hours following the addition and is then quenched by the addition of 10 moles of anhydrous methanol. The reaction mixture is allowed to warm to room temperature and is stirred until a filterable precipitate forms. The reaction mixture is filtered and the filtrate evaporated. The residue is purified by vacuum distillation to yield 3-methoxyisophthalaldehydic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(OCC)(=O)C>[Si:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][C:2]=1[Cl:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: NC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(N)=O)cc1Cl
Yield: 77.4 %

Procedure:
A solution of 2-(3-chloro-4-hydroxy-phenyl)-acetamide (100 mg), imidazole (184 mg), and tert-butyldimethylsilyl chloride (163 mg) was stirred for 2 h in 5 mL of dimethylformamide. The solution was diluted with 50 mL of ethyl acetate and washed with 50 mL of sodium carbonate. The ethyl acetate was evaporated to afford 125 mg of 2-[4-(tert-butyldimethylsilanyloxy)-3-chlorophenyl]acetamide.
Reaction SMILES: N1C2C(=CC=CC=2)C=N1.Br[C:11]1[CH:24]=[CH:23][C:14]2[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][O:17][C:13]=2[CH:12]=1.BrC1C=CC(Br)=CC=1[N+]([O-])=O.C(OCC)(=O)CC(OCC)=O.C(ON=O)CC(C)C>>[O:17]1[C:13]2[CH:12]=[CH:11][CH:24]=[CH:23][C:14]=2[CH:15]=[N:16]1.[O:17]1[C:13]2[CH:12]=[CH:11][CH:24]=[CH:23][C:14]=2[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16]1
Reactant: CCOC(=O)c1noc2cc(Br)ccc12
Agent: CC(C)CCON=O
Agent: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: c1ccc2[nH]ncc2c1
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)c1noc2ccccc12
Product: c1ccc2oncc2c1

Procedure:
The benzisoxazole-, benzisoxazole-, and benzothiazolecarboxylic acids were prepared using similar strategies outlined for the indazole acids. For example, ethyl 6-bromobenzisoxazole-3-carboxylate was prepared from 2,5-dibromonitrobenzene by reaction with diethyl malonate, saponification and decarboxylation, and reaction with isoamylnitrite. Ethyl benzisoxazole-3-carboxylate was obtained by hydrogenolysis of the 6-bromo derivative. 4-Benzothiazolecarboxylic acid was prepared from 2-amino-4-chloro-benzothiazole by reaction with isoamyl nitrite followed by metal-halogen exchange and trapping with carbon dioxide. 5-Benzothiazolecarboxylic acid was prepared from 4-chloro-3-nitrobenzoic acid by reaction with Na2S and sodium hydroxide followed by reduction with zinc in formic acid. 3-Benzisothiazolecarboxylic acid was prepared from thiophenol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide, and sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH3:8])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[S:6][C:5](/[C:7](=[N:11]/[OH:12])/[CH3:8])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Cl)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(=N\O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined 1-(5-chlorothiophen-2-yl)ethanone (100 g, 622 mmol), hydroxylamine hydrochloride (47.6 g, 685 mmol, 1.1 eq) and sodium acetate (56.2 g, 685 mmol, 1.1 eq) in 1 L of ethanol and 300 mL of water. The reaction was heated to reflux. After 3 h, the reaction was cooled to rt and concentrated. The residue was slurried in 500 mL of water overnight, filtered and dried to afford the crude solid. Purified by extraction of the solid with hot dichloromethane, cooling to rt and filtering to remove unreacted starting material. The solid was slurried in hot dichloromethane several times to extract the solid enriched in the first eluting (E-oxime) compound (100% DCM) after concentration. The highly crystalline material was purified by column chromatography using 100% dichloromethane to afford (E)-1-(5-chlorothiophen-2-yl)ethanone oxime. NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.21 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 2.12 (s, 3H) ppm.
Reaction SMILES: [O:1]([C:8]1[C:9]([OH:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:40])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:39]>>[CH3:39][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:32]=[C:33]([O:18][C:9]3[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:11][N:10]=3)[CH:34]=[C:35]([CH3:37])[CH:36]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:40])=[O:20]
Reactant: Oc1ncc(C(F)(F)F)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ncc(C(F)(F)F)cc2Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 85 by using 3-phenoxy-5-trifluoromethyl-pyridin-2-ol and 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 32 mg (6%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H24O5NF3 523, found 524 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C(F)(F)F)ccc2N)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A solution of 3-amino-2-chloro-6-trifluoromethyl-pyridine (0.890 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.4 g) (prepared as described in WO 2006/003494) and tetrakis(triphenyl-phosphine)palladium (0.200 g) in 1,2-dimethoxyethane (45 ml) was treated with aqueous potassium phosphate (1.1 M) (1.92 g). The reaction mixture was stirred at 80° C. for 3 hours. Aqueous workup with ethyl acetate furnished a residue which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) to give 3-amino-6-trifluoromethyl-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.5 g) as a white solid. MS (ES+) 288 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.50 (s, 9H), 2.61 (m, 2H), 3.67 (t, 2H), 4.10 (m, 2H), 4.21 (s, 2H), 6.11 (s, 1H), 7.03 (d, 1H), 7.33 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:2][C:3]([NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(C)c1NC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving 2-chloro-N-(2,6-dimethylphenyl)acetamide (1.8 g, 0.0091 mole) and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.17 g, 0.0091 mole) in acetonitrile (20 ml) under argon. Triethylamine (1.25 ml) was added and the solution stirred at room temperature under argon for 12 hours. The solution was acidified with 10% hydrochloric acid with stirring, extracted with ethyl acetate (3X), the extracts combined, washed with water and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the product purified by chromatography over silica and recrystallized from ethyl acetate/benzene, m.p. ca. 137.7° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]1(C)[CH:16]=C[CH:14]=[CH:13][CH:12]=1.[Br-].[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH2:38][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=[CH:36][CH:37]=3)=[N:27]2)=[CH:22][CH:21]=1.[CH2:58]1[CH2:62][O:61][CH2:60][CH2:59]1>>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:38]=[CH:14][CH2:13][C:12]4[CH:11]=[CH:16][CH:60]=[CH:59][C:58]=4[CH2:62][OH:61])[CH:35]=[CH:36][CH:37]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: Clc1ccc2ccc(COc3cccc(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)c3)nc2c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: OCc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
At -10° C., a solution of 0.65M KHMDS (potassium hexamethyldisilazide) in toluene (21 mL, 13.65 mmol) was added dropwise to a suspension of the phosphonium salt of Step 4 (8.457 g, 13.53 mmol) in THF (70 mL) and the mixture was stirred at 0° C. for 30 min. At -78° C., a solution of 1H-3-hydroxy-3,4-dihydrobenzo(c)pyran (1.141 g, 7.60 mmol) in THF (14 mL) was added slowly. The mixture was allowed to warm to r.t. and was stirred for a further 3 hours. Aqueous NH4OAc 25% was added and the products were extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 10:90 and 15:85. The title compound (2.84 g, 90% yield) was obtained as a cis:trans mixture and was used as such for the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.NC1[CH:11]=[C:12]([C:22](=[O:24])[CH3:23])[CH:13]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]=1[O:16][CH3:17].C(OCC)(=O)C.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[C:18]([C:14]1[CH:13]=[C:12]([C:22](=[O:24])[CH3:23])[CH:11]=[C:33]([N:32]([CH3:35])[CH3:31])[C:15]=1[O:16][CH3:17])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C)C=O
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1c(N(C)C)cc(C(C)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Potassium carbonate (8.5 g, 62 mmol) and methyl iodide (8.8 g, 62 mmol) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (6 g, 21 mmol) in dimethylformamide (50 ml) and the mixture was stirred at room temperature for 13 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.9 g) as a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([CH:40]=[O:41])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[C:31]([C:40](=[O:41])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:32][C:33]3[NH:37][CH:36]=[N:35][C:34]=3[C:38]=2[F:39])=[C:25]([Cl:42])[CH:24]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a solution of methyl sulfone (65 mg, 0.68 mmol) in THF (1.5 mL) is added a solution of n-BuLi (0.27 mL, 0.68 mmol, 2.5 M solution in hexane) at −78° C. After stirring for 5 minutes, HMPA (0.1 mL) is added. After stirring for additional 10 minutes, a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (26 mg, 0.069 mmol) in THF (1 mL) is added. The resulting solution is stirred for 1.5 hours at −78° C. The reaction is quenched with saturated aqueous NH4Cl, warmed to room temperature, and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (3% MeOH in CH2Cl2) to give the crude desired product (31 mg, 96%) which is used directly without further purification: MS APCI (+) m/z 462, 464 (M+, Br pattern) detected.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCCCCCCO
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NCCCCCCO
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A solution of 31.5 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonylglycine [J. Am. Chem. Soc., 86, 1839, (1964)] in 100 ml of tetrahydrofuran is reacted dropwise with 12 g of 6-amino-1-hexanol in 50 ml of 50% methanol in tetrahydrofuran. The reaction is stirred for 12 hours at 23° C. and poured into water. The resulting precipitate is washed thoroughly with water, filtered, and dried to provide crude N-(benzyloxycarbonylglycyl)-6-amino-1-hexanol. The pure compound recrystallized from ethyl acetate has a melting point of 104°-5° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:17]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:6]=1.CO.Cl.O1CCOCC1>>[NH2:17][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:6]=1)[CH2:2][OH:1]
Reactant: Cn1cc(-c2cccc(C[C@@H](CO)NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(-c2cccc(C[C@H](N)CO)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Step A (0.45 g, 1.4 mmol) was combined with methanol (2.0 mL, 49 mmol) and 4.0 M HCl in dioxane (6.0 mL, 24 mmol). The reaction mixture was stirred at rt for 30 min yielding the titled compound. LC-MS found: 232.2 (m+1).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid, m.p. 227°-229° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: OC1CCNCC1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 46 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and 4-hydroxypiperidine to give the title compound in 46% yield; NMR Spectrum: 1.36 (d, 2H), 1.69 (d, 2H), 2.18 (t, 2H), 2.78 (m, 4H), 3.80 (s, 3H), 4.42 (t, 2H), 4.55 (d, 1H), 5.11 (s, 2H), 7.02 (d, 1H), 7.16 (m, 2H), 7.30 (m, 2H), 7.36 (d, 1H), 7.44 (q, 1H), 8.25 (s, 1H), 8.45 (s, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+].ICI.[CH3:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][C:35]=1[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[CH3:36])[O:23][CH2:20][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1
Reactant: Cc1ccc(O)cc1C
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ICI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(OCn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.15 g, 0.59 mmol, Example 6a), potassium carbonate (0.325 g, 2.36 mmol), diiodomethane (0.16 g, 0.59 mmol) and 3,4-dimethylphenol (0.072 g, 0.59 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 132-135° C.