Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:9]3[C:5]4[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=4[CH:11]=[CH:10]3)[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 79.7 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 12, 385 mg (1.5 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl) piperazine and 207 mg (1.5 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:chloroform), whereby 335 mg of the title compound were obtained yield: (80%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[C:61]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:59]=[CH:58][N:57]=1)[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[C:61]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:60][CH:59]=[CH:58][N:57]=1)[CH3:54]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: CCOc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
DIEA (0.013 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-Ethoxy-pyridin-3-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.016 g of product in 48% yield: LCMS (ESI) m/z 471 (MH+).
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1.O>C(#N)C>[C:1]([C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1)#[N:2]
Reactant: Clc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2

Procedure:
To a solution of 200 mg of potassium cyanide and 300 mg of 18-crown-6 in 20 mL of acetonitrile was added 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (220 mg). The mixture was refluxed for 2 hours, cooled and poured into water. The aqueous layer was extracted with dichloromethane, the organic layer separated and dried and the solvent removed in vacuum. The resultant crude reaction mixture was chromatographed using 15% ethyl acetate/hexane as eluent to yield 5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 44), m.p. 203°-205° C. "
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3].[ClH:34].C(O)C.C(=O)([O-])[O-].[NH4+:42].[NH4+]>ClCCl.C(O)C>[ClH:34].[CH2:1]([N:4]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([C:7]1[CH:26]=[CH:25][C:10]2[N:11]([CH3:24])[C:12]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:42])[NH2:23])=[CH:18][CH:17]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]
Reactant: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: C#CCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 81 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-propargyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 81% of theory, C25H28N6O3 (460.6); Rf value: 0.094 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=461; (M+H+Na)++=242; (M+2H)++=231.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=O.C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]4[CH2:29][CH2:30][CH2:31][C:32]4=[O:34])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN3CCCC3=O)cc2C)ncn1
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 4-aminobutanoate hydrochloride (Bachem, 244.6 mg; 1.25 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (85 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([CH:14](O)C)[CH:10]=2)=[CH:5][CH:4]=1.CC1C=C(C2C=CC(C(F)(F)F)=CC=2)S[C:21]=1[CH:35]=[O:36].C[Mg]Br>>[CH3:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=2)[S:13][C:12]=1[CH:35]([OH:36])[CH3:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Mg]Br
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of 1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126) using 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 74) and methyl magnesium bromide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][NH:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][N:10]2[S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a stirring suspension of sodium hydride (0.677 g, 16.92 mmol) in THF (25 ml) at 0° C. was added a solution of 6-bromo-3-fluoro-4-nitro-1H-indazole (4 g, 15.38 mmol) in THF (25 ml) dropwise. The reaction mixture was allowed to stir for 30 min then allowed to warm to room temperature before benzenesulfonyl chloride (2.170 ml, 16.92 mmol) was added. after approximately 2 h the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous was then extracted again with ethyl acetate. The combined organics were then washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with 50 ml methanol and filtered to yield the title compound as a yellow solid (5.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[I:8].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[I:8])[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1I

Procedure:
A suspension of 40.4 g (160 mmol) of the compound from Example XXXI in 400 ml of carbon tetrachloride, 31.3 g of N-bromosuccinimide (176 mmol) and 2.63 g of azobisiso-butyronitrile (16 mmol) is heated under reflux overnight. After cooling, the precipitate is filtered off with suction and washed with carbon tetrachloride. The combined filtrates are concentrated and the residue is further reacted in the crude state.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Reactant: Nc1ccc(I)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(biphenyl-4-yl)glutaric anhydride (0.53 g) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.74 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1 h. All volatiles were removed at the water aspirator and the amorphous residue is fractionally crystallised to provide 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)butanoic acid HCl (0.43 g) as off-white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([O:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].C(N(CC)CC)C>C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccc[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1
Temperature: 25 °C

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (1.0 g, 4.7 mmol), 2-ethoxycarbonylcarbonylpyrrole (2.5 g, 14.5 mmol) in ethanol (120 mL) was treated with triethylamine (1.0 mL, 7.2 mmol). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated to approximately 20 mL, treated with additional triethylamine (0.2 mL, 1.44 mmol) and refluxed for 55 hoursr. The reaction was then cooled to ambient temperature and concentrated. Reverse phase HPLC using acetonitrile/water afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethoxycarbonyl)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.35 (t, 3H), 4.50 (q, 2H), 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25(s, 2H), 7.48 (br s, 1H), 7.50 (s, 1H), 7.68 (d, 1H), 11.50 (s, 1H) ppm; (45 mg) and 5-aminosulfonyl-3-[(pyrrol-2-yl)(carboxy)methylene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 6.40 (s, 1H), 6.65 (s, 1H), 7.06 (d, 1H), 7.25 (s, 2H), 7.48 (br s, 1H), 7.68 (d, 1H), 7.85 (s, 1H), 11.50 (s, 1H) ppm; (48 mg).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][C:18]([NH:17][CH:16]2[C:15](=[O:27])[N:10]3[CH:11]([C:12]([OH:14])=[O:13])[C:6]([CH2:5][O:31][C:30](=[O:32])[C:29]([F:34])([F:33])[F:28])=[CH:7][S:8][C@H:9]23)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(COC(=O)C(F)(F)F)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.8 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid in 4 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature and is then diluted with an equal quantity of toluene. The volatile constituents are evaporated under reduced pressure and at room temperature. The residue is taken up in 100 ml of chloroform and the mixture is filtered. The filtrate is concentrated to a small volume under reduced pressure and cooled. The resulting solid material is filtered off and yields 7-(N-phenylacetyl-amino)-3-trifluoroacetoxymethyl-ceph-2-em-4ξ-carboxylic acid, melting at 139° - 140°C; infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.60μ, 5.65μ, 5.73μ, 5.77μ, 6.02μ and 6.54μ. A further quantity of the desired product can be obtained by further concentration and cooling of the filtrate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([F:17])([F:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:27])[C@H:9]([CH2:18][O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]([F:17])([F:16])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(F)(F)C[C@@H](COC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(F)(F)C[C@@H](COC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(tert-butoxycarbonyloxy)-2,2-difluoropentanoate (46.0 g, 0.12 mol) and MeI (15.0 mL, 0.24 mol) in DMF (300 mL) was added sodium hydride (60%, 7.2 g, 0.18 mol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and LC-MS showed the reaction was completed. The reaction was quenched with saturated NH4Cl solution and filtered. The filtrate was concentrated to remove most of DMF and the residue was dissolved in EtOAc (1.5 L). The organic layer was washed with water and brine, dried over Na2SO4. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column (hexanes/EtOAc) to give (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butoxycarbonyloxy)-2,2-difluoropentanoate (42 g, 88%). LRMS (M+Na+) m/z 420.4.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20].C(OC(=O)C)(=O)C>ClCCl>[CH:19]([N:9]([CH2:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20]
Reactant: CC(C)CC(CNOCc1ccccc1)C(=O)O
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(C)CC(CN(C=O)OCc1ccccc1)C(=O)O

Procedure:
Formylation of 2-(benzyloxyaminomethyl)-4-methylpentanoic acid was carried out in dichloromethane with formic acid/acetic anhydride to give N-formyl-2-(benzyloxyaminomethyl)-4-methylpentanoic acid. Coupling with a compound of formula (J): To N-formyl-2-(benzyloxyamino-methyl)-4-methylpentanoic acid (175 mg) and (J) (230 mg) in 5% pyridine/dichloromethane (30 mL) was added 4-dimethylaminopyridine (DMPA) (200 mg) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) at room temperature. The reaction mixture was stirred for 8 h and then concentrated, partitioned between 30 mL of ethyl acetate and 30 mL of 20% HCl. The organic portion was washed with water (20 mL), 5% NaHCO3 (20 mL) and brine, dried over MgSO4 and concentrated. Purification on silica gel, eluting with 50% ethyl acetate/hexane gave the product as a mixture of two isomers. Hydrogenolysis in methanol over 10% Pd/C afforded (2RS, 10S)-2-[N-formyl, N-hydroxyaminomethyl]-4-methyl-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19)13(18),14,6-tetraen-10-yl]pentamide, as a mixture of 2 isomers, MS 455 (M-H)+, (Compound 6).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[CH:38]=[CH:37][N:36](S(C4C=CC(C)=CC=4)(=O)=O)[C:14]=3[N:15]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:34][CH3:35])[N:17]=2)[C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[CH:21][C:20]=3[O:34][CH3:35])[NH:15][C:14]3=[N:36][CH:37]=[CH:38][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 85 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a suspension of the 2-fluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (15.7 g, 23.4 mmol) in methanol (250 mL) and tetrahydrofuran (125 ml) was added K2CO3 (32.3g 234 mmol in 125 ml of water), The reaction mixture was stirred at 85° C. for 6 hours. The organic layer was subsequently washed with water and brine, dried over sodium sulfate, filtered, stripped onto celite, and purified by chromatography on SiO2 (400 g SiO2, 0% to 10% MeOH/CH2CL2 with 0.1% added NH3) to afford the 2-fluoro-6-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (11.2 g, 92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (d, J=6.59 Hz, 6 H), 2.59 (d, J=3.85 Hz, 4 H), 2.67 (m, J=6.41 Hz, 1 H), 3.10 (br. s., 4 H), 3.81 (s, 3H), 6.22 (s., 1 H), 6.47 (d, J=8.79 Hz, 1 H), 6.63 (d, J=1.28 Hz, 1 H), 6.89-6.98 (m, 2 H), 7.36-7.46 (m, 2 H), 7.90 (d, J=8.61 Hz, 1 H), 8.02 (s., 1 H), 8.10 (s, 1 H), 8.50 (d, J=8.42 Hz, 1 H), 10.47 (s, 1 H), 11.31 (s., 1 H). MS(ESI): m/z 519 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (147 mg, 0.4 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.44 mmole, 1.1 eq) and diisopropylethyl amine (0.44 mmol, 1.1 eq) were dissolved in THF (3 mL) and then stirred at room temperature over night. THF was removed in vacuo and the solid residue was re-dissolved in 30/70 mixture of water and ACN gave yellow solid. The solid was washed with water and dried in vacuo provided compound A44 as creamy green solid (179 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 1.43 (s, 9H), 1.75 (m, 2H), 1.98–1.97 (m, 2H), 2.04 (m, 2H), 2.95 (sb, 2H), 4.12 (q, 1H), 4.62 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 8.94 (m, 2H). Exact mass calculated for C24H26F6N6O2 544.2, Found 545.5 (MH+).
Reaction SMILES: [N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2Cl)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:21]>>[N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2[OH:21])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 50 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 1-(azetidin-1-yl)sulfonyl-2,6-dichloro-3-nitrobenzene (510 mg, 1.64mmol), 60% NaH (197 mg, 4.92 mmol) and water (35 μL, 1.97 mmol) were reacted to form the desired product (240 mg, 50%). 1H NMR (MeOD-d4): δ 8.09 (d, 1H), 7.25 (d, 1H), 4.15 (t, 4H), 2.29 (m, 2H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[CH:9]=1.[CH2:18]=O>C(O)=O.Cl>[ClH:1].[ClH:1].[CH3:18][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: C=O
Reactant: Cc1ccc2oc([C@@H]3CCCN3)cc2n1
Agent: Cl
Solvent: O=CO
Product: Cc1ccc2oc([C@@H]3CCCN3C)cc2n1

Procedure:
A 315 mg (1.04 mmol) sample of 2-(2-(S)-pyrrolidinyl)-5-methylfuro[3,2-b]pyridine dihydrochloride, from Example 5b above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 0.5 hours. The reaction mixture was cooled, diluted with 2 N HCl and extracted with ether. The aqueous solution was adjusted to pH 10 with K2CO3 and extracted with CH2Cl2. The CH2Cl2 extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :EtOH The residue was converted to the salt by treatment with HCl/ether, and the salt was recrystallized from EtOH/EtOAc to give 332 mg of title compound: 1H NMR (DMSO, 300 MHz) δ 2.13-2.23 (m, 2H), 2.35-2.60 (m, 3H), 2.71 (s, 3H), 2.88 (s, 2H), 3.33 (br s, 1H), 3.70 (br s, 1H), 4.88 (m, 1H), 7.54 (d, 1H, J=8.8 Hz), 7.61 (s, 1H), 8.36 (d, 1H, J=8.5 Hz); MS m/z: 217 (M+H)+, 234 (M+NH4)+ ; Anal. Calcd for C13H16N2O.2.0 HCl.1.0 H2O: C, 50.82; H, 6.55; N, 9.12. Found: C, 50.47; H, 6.77; N, 8.92.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9]2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: CNC
Agent: Cl
Product: CN(C)Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1

Procedure:
Prepared from the product of Example 9 and dimethylamine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:13][CH:15]2[CH2:16][O:17]2)=[CH:8][CH:9]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.