Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].CO.O>O1CCCC1>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([CH2:11][C:5]4([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)(=[O:14])=[O:13])[CH2:16][CH2:17]3)=[CH:26][CH:25]=2)[CH:28]=1
Reactant: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 70.6 %

Procedure:
4-[4-(4-Pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid methyl ester (0.19 g) and lithium hydroxide monohydrate (0.087 g) were combined in tetrahydrofuran (10 ml), methanol (5 ml) and water (5 ml) and heated to reflux for 2 h. The solvents were then removed in vacuo and the residue diluted with 1 M sodium hydroxide (50 ml) and washed with ethyl acetate (3×20 ml). The aqueous phase was then acidified pH 5 and the suspension formed extracted with 10% methanol/dichloromethane (5×40 ml). The combined extracts were then washed with water (2×20 ml), saturated brine (20 ml), dried (Na2SO4) and reduced in vacuo to provide the title compound as a white solid (0.13 g, 72%).
Reaction SMILES: C([O:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][C:12]2[N:15]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])[N:16]=[C:17]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[C:11]=2[CH2:10]1)=[O:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][N:15]1[C:12]2[CH2:13][CH2:14][N:9]([C:7](=[O:8])[CH2:6][OH:5])[CH2:10][C:11]=2[C:17]([C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:16]1
Reactant: CC(C)(C)OCC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CN(C(=O)CO)CC3)c1
Yield: 60.9 %

Procedure:
A solution of 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8d) (90 mg, 0.193 mmol) and trifluoroacetic acid (221 mg, 1.94 mmol) in CH2Cl2 was stirred at 25° C. for 1 day. Solvents were evaporated and the residue purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (14a).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][N:31]=1>C(O)C>[CH3:39][O:38][C:36]([C:34]1[CH:33]=[CH:32][N:31]2[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[N:29]=[C:30]2[CH:35]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COC(=O)c1ccnc(N)c1
Solvent: CCO
Product: COC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Yield: 46.6 %

Procedure:
A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (4.40 g, 9.91 mmol), methyl 2-aminopyridine-4-carboxylate (3.01 g, 19.8 mmol, 2 equiv) and powdered activated 3A sieves (10 g) in ethanol (37 mL) was heated for 4 h at the reflux temperature. The resulting solution was filtered through a pad of Celite with the aid of CH2Cl2. The resulting solution was separated between CH2Cl2 (50 mL) and a saturated aqueous NaHCO3 solution 50 mL). The organic phase was washed with a saturated aqueous NaCl solution, dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane for 1.0 min., gradient to 80% hexane/20% EtOAc over 1.0 min., 80% hexane/20% EtOAc for 2.0 min., gradient to 75% hexane/25% EtOAc over 1.0 min., 75% hexane/25% EtOAc for 2.0 min, gradient to 50% hexane/50% EtOAc over 4.0 min., 50% hexane/50% EtOAc for 5.0 min., gradient to 25% hexane/75% EtOAc over 9.5 min.) to give 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (2.3 g, 47%):
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]([NH:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C:18](=[O:22])[C:19]([C:20]#[N:21])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(C)NC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.3 g of N-isopropylcyanoacetamide. Yield 1.46 g (50%), m.p. 243-245° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH:53]([OH:56])[CH2:54][OH:55].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[OH:56][CH:53]([CH2:54][OH:55])[CH2:52][NH:51][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:26]
Reactant: NCC(O)CO
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
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
Solvent: CS(C)=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(O)CO)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) in 1:1 DMF/DMSO (2 mL) was cooled to 0° C., followed first by drop-wise addition of 3-aminopropane-1,2-diol (76.5 mg, 0.840 mmol) and then addition of DIEA (366 μL, 2.10 mmol). The reaction was warmed up to ambient temperature, stirred for 20 minutes, and then directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M cartridge, 5 to 50% acetonitrile/water), to provide the product as a white solid (295 mg, 98% yield). MS (apci) m/z=431.1 (M+H).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(OCC)C.N([O-])=O.[Na+].[I-:20].[K+]>O>[Cl:10][C:4]1[CH:3]=[C:2]([I:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: [I-]
Reactant: N#Cc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (30.5 g, 0.2 mol) in 1:1 diethyl ether/3M HCl (600 mL) at 0° C. was treated dropwise over 15 minutes with a solution of sodium nitrite (18 g, 0.26 mol) in water (100 mL), stirred 15 minutes, then treated with a solution of potassium iodide (50 g, 0.3 mol) in water (50 mL) dropwise over 45 minutes, warmed to room temperature, and stirred for 1.5 hours. The organic phase was washed with water (3×100 mL) and the combined aqueous layers were extracted with diethyl ether. The combined organic layers were combined, washed sequentially with saturated NaHCO3, 25% Na2S2O3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 19:1/hexanes:ethyl acetate, triturated in hexanes, filtered, and dried to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH:40]([CH3:44])[CH2:41][C:42]#[N:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH:40]([CH3:44])[CH2:41][C:42]#[N:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(CC#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C(C)CC#N)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanenitrile (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (3.9 mg). LCMS (M+H)+: m/z=472.3.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:18])[C@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH2:13].[CH:19]1[C:32]2[NH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[S:24][C:23]=2[CH:22]=[CH:21][C:20]=1[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][C@H:12]([NH:13][C:33]([C:20]1[CH:21]=[CH:22][C:23]2[S:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:31][C:32]=2[CH:19]=1)=[O:34])[C:11]([O:10][CH3:9])=[O:18]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1S2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reaction time: 15 h

Procedure:
4.6 ml (33 mmoles) of triethylamine is added to a solution of 1.82 g (10 mmoles) of L-Leucine methyl ester hydrochloride, 2.43 g (10 mmoles) of 10H-phenothiazine-2-carboxylic acid (J. Med. Chem.(1998) 41 (2), 148-156), 1.48 g (11 mmoles) of HOBT and 4.21 g (22 mmoles) of EDC in 30 ml of anhydrous DMF. The reaction mixture is stirred for 15 hours. After evaporation of the solvent under vacuum, the residue is divided between 100 ml of AcOEt and 50 ml of a 1M solution of HCl. The organic phase is decanted and washed successively with 50 ml of H2O, 50 ml of a saturated solution of NaHCO3 and 50 ml of salt water. The organic solution is dried over magnesium sulphate, filtered and concentrated to dryness under vacuum. The evaporation residue is taken up in Et2O and filtered. Yellow powder (71%). Melting point: 160.5-161° C.
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:13][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:14])=[O:30])(=[O:25])=[O:24]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(R)-2-[2-(2.6-Difluoro-benzenesulfonylamino)-4-iodo-benzoylamino]-3-phenyl-propionic acid. (R)-2-(tert-Butoxycarbonylamino)-3-phenyl-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-phenyl-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=9.27 min. MS (ESI−): mass calcd. for C22H17F2IN2O5S, 585.99; m/z found, 584/586[M−H]−. 1H NMR (500 MHz, CDCl3): 11.32 (s, 1H), 8.11 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.28 (m, 4H), 7.16-7.15 (m, 2H), 7.00-6.96 (m, 3H), 6.51 (d, J=7.6, 1H), 5.07-5.03 (m, 1H), 3.34 (dd, J=14.0, 5.6, 1H), 3.25 (dd, J=14.3, 5.3, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([N:15]=[C:6]2[N:5]([CH2:16][CH3:17])[C:4]1=[CH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:19]([N:21]1[C:28](=[O:29])[CH2:27][C:25](=[O:26])[N:24]([CH2:30][CH3:31])[C:22]1=[S:23])[CH3:20].[C:32](Br)(Br)(Br)Br.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:30]([N:24]1[C:25](=[O:26])[C:27](=[C:32]=[C:18]=[C:4]2[N:5]([CH2:16][CH3:17])[C:6]3=[N:15][C:14]4[C:9]([N:8]=[C:7]3[N:3]2[CH2:1][CH3:2])=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:28](=[O:29])[N:21]([CH2:19][CH3:20])[C:22]1=[S:23])[CH3:31]
Reactant: C=C1N(CC)c2nc3ccccc3nc2N1CC
Reactant: CCN1C(=O)CC(=O)N(CC)C1=S
Reactant: BrC(Br)(Br)Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=C=C=C2N(CC)c3nc4ccccc4nc3N2CC)C(=O)N(CC)C1=S

Procedure:
A solution of 1,3-Diethyl-1,2-dihydro-2methyleneimidazo[4,5-b]quinoxaline (6.0 g, 0.025 mol), 1,3-diethyl-2-thiobarbituric acid (5.0 g, 0.025 mol) and carbon tetrabromide (8.3 g, 0.025 mol) in benzene (60 ml) is warmed to 50°-55°, at which point an exothermic reaction occurs, with separation of solid. The mixture is allowed to cool, then filtered. The filtrate is evaporated to dryness, the residue treated wth methanol (50 ml), and the solid dye collected. Treatment of the filtrate with triethylamine (5 ml) yields a further portion of dye. The dye is purified by precipitation from chloroform solution by addition of methanol. The yield of purified dye is 0.50 g, mp indistinct. The yield can be improved by using the quaternary salt and conducting the reaction in the presence of triethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][NH:12][CH3:13].[CH2:14]([O:21][C:22]([O:24]N1C(=O)CCC1=O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:22](=[O:24])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CNCc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])ccc1Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 1-(2-bromo-5-nitrophenyl)-N-methylmethanamine (7 g, 28.6 mmol, see WO 2008/079836 for preparation) in DMF (30 ml), was added N-(benzyloxycarbonyloxy) succinimide (8.54 g, 34.3 mmol) and N,N-diisopropylethylamine (9.98 ml, 57.1 mmol). The mixture was stirred rt for 1 h, then quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexane) to yield 36A (10.66 g, 28.1 mmol, 98% yield). MS (ESI) m/z: 379.2 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.92-8.02 (m, 2H) 7.74 (d, J=6.15 Hz, 1H) 7.33-7.42 (m, 2H) 7.28 (s, 3H) 5.22 (s, 1H) 5.15 (s, 1H) 4.61 (d, J=18.46 Hz, 2H) 3.02 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:44])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:36]C3CCCCO3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:44])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][OH:36])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M261) (0.54 g, 0.83 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (170 mg, 46%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][OH:32].Cl.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][OH:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc2c(c1)C(=NO)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reaction time: 2 h
Yield: 105.2 %

Procedure:
A mixture of (E)-3-{1′-Benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OH.HCl (53 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-hydroxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (150 mg) as a 98/2 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32].C(O)(=O)C>CC(C)=O.C(#N)C>[CH2:31]([N:7]1[C:3]([S:2][CH3:1])=[N:4][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[O:10])=[N:6]1)[CH3:32]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1n[nH]c(SC)n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCn1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc1SC
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1.0 gram (0.0027 mole) of methyl 2-[(5-methylthio-1H-1,2,4-triazol-3-yl)aminocarbonyl]aminosulfonylbenzoate and 0.7 grams of potassium carbonate in 30 ml of acetone at room temperature, 0.8 ml of ethyl iodine was added by way of syringe and the resulting white suspension stirred 3 days. The mixture was poured into 250 ml of ice water and acidified to pH 3-4 with glacial acetic acid. The aqueous acidic mixture was extracted with 1:1 mixture of ethyl ether/ethyl acetate and the extract washed with brine, dried (MgSO4), and evaporated to yield a white solid residue which was suspended in acetonitrile and filtered, yield 0.3 grams, m.p. 188°-191°.
Reaction SMILES: CS([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=O)=O.[CH3:25][Mg]Br.[Cl-].[NH4+].O>CCOCC>[CH3:25][C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C[Mg]Br
Reactant: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Yield: 95 %

Procedure:
To a solution of 2-(methylsulfonyl)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.80 g, 2.2 mmol) that was obtained in Example 24 (24b) in ether (10 ml) was added a 3.0 M solution of methylmagnesium bromide in ether (1.5 ml, 4.4 mmol) at −78° C. with stirring, and the resulting mixture was stirred at the same temperature for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (1 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 1:9) as the eluent to afford the title compound (0.64 g) in a yield of 95% as a white crystalline solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[CH3:17]O>C(OCC)C>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (588 μL) was added to a solution of 3-bromophenyl acetic acid (10 g, 46.5 mmol) in methanol (100 mL). The mixture was refluxed for 1.5 h and then cooled to ambient temperature and evaporated under reduced pressure to afford a residue. The residue was redissolved in diethyl ether (500 mL), washed with water (2×100 mL), brine (100 mL), dried (MgSO4) and then evaporated under reduced pressure to afford 3-bromophenyl acetic acid methyl ester (10.65 g). The 3-bromophenyl acetic acid methyl ester was dissolved in toluene (117 mL) then phenyl boronic acid (6.8 g, 55.69 mmol) added, followed by a aqueous solution of sodium carbonate (93 mL, 2M) and tetrakis(triphenylphosphine)palladium (1.6 g, 1.41 mmol). The mixture was stirred overnight then cooled to ambient temperature and an aqueous solution of saturated ammonium chloride (100 mL) added. The mixture was extracted with ethyl acetate (2×200 mL), died (Na2SO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (200 g) using ethyl acetate:heptane (3:48) as the eluent gave biphenyl-3-yl acetic acid methyl ester, yield 10.5 g, (99%), TLC (single UV spot, Rf=0.24, 10% ethyl acetate in heptane), analytical HPLC Rt=19.55 min, HPLC-MS (single main UV peak with Rt=9.35 min, 227.1 [M+H]+).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][Cl:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCO>[ClH:30].[C:19]1([C:25]2[CH:26]=[CH:27][C:28]([CH2:29][S:18][C:9]3[NH:8][C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C@H:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:10]=3)=[CH:31][CH:32]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc(-c2ccc(CSC3=N[C@@H](c4ccccc4)[C@@H](c4ccccc4)N3)cc2)cc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-phenylbenzyl chloride (0.318 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 205 mg of the product 207. 1H NMR (DMSO-d6) δ 11.24 (s, 2H), 7.90-7.60 (m, 6H), 7.60-7.30 (m, 3H), 7.20-6.90 (m, 6H), 6.90-6.65 (m, 4H), 5.79 (s, 2H), 4.85 (s, 2H); MS: m/z 421 (M++1).