Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:26]3[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=3[O:24][CH2:23]1)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[F:32][C:28]1[C:29]([F:31])=[CH:30][C:25]2[O:24][CH2:23][C:4]3([C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)[N:6]([CH2:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[O:13])[C:5]3=[O:22])[C:26]=2[CH:27]=1
Reactant: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21)Nc1ccccc1F
Reactant: OB(O)c1cncnc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(-c3cncnc3)cccc21)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of 2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′ H)-yl)-N-(2-fluorophenyl)acetamide (0.15 g, 0.30 mmol) in anhydrous 1,4-dioxane (5.00 mL) was added Pd(PPh3)4 (0.03 g, 0.03 mmol) and stirred at ambient temperature for 10 min. Pyrimidine-5-boronic acid (0.06 g, 0.45 mmol) and sodium carbonate (0.90 mL of 2 M solution, 1.80 mmol) were added. The reaction mixture was reluxed at 120° C. for 16 h, diluted with ethyl acetate (50.0 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.13 g, 84%): 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.29-8.10 (m, 3H), 7.62 (s, 1H), 7.44 (t, 1H), 7.16-7.03 (m, 4H), 6.91 (d, 1H), 6.85-6.76 (m, 1H), 6.46-6.37 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.47 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 163.9, 157.7, 156.4, 155.7, 141.9, 132.9, 130.0, 126.0, 124.7, 121.9, 115.0, 111.6, 109.8, 100.2, 79.4, 57.9, 44.7; MS (ES+) m/z 503.5 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH2:15][OH:16])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:21](OCC)(=O)C>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1([CH2:15][O:16][CH3:21])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC1(CO)COCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COCC1(C)COCCN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyl-3-hydroxymethyl-3-methylmorpholine (1 g) in tetrahydrofuran (10 ml) was added dropwise to a suspension of sodium hydride (60% oil suspension; 0.27 g) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and the whole was stirred at 70° C. for 1 hour. After cooling, methyl iodide (0.34 ml) was added to the mixture and the whole was stirred at 40° C. for 1 hour. After cooling, ethyl acetate and water were added to the mixture and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:4) as an eluent to give 4-benzyl-3-methoxymethyl-3-methylmorpholine (0.77 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CC(O)C>[CH2:18]([N:25]([CH3:41])[C:26]1[CH:27]=[C:28]([NH:33][C:34]2[N:35]=[C:36]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:11])([F:13])[F:12])[C:3]=3[S:14]([NH2:17])(=[O:16])=[O:15])[CH:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[CH3:32])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(Nc2nccc(Cl)n2)cc1N(C)Cc1ccccc1
Reactant: Nc1cccc(OCC(F)(F)F)c1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(Nc2nccc(Nc3cccc(OCC(F)(F)F)c3S(N)(=O)=O)n2)cc1N(C)Cc1ccccc1

Procedure:
A solution of 2-amino-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (54 mg, 0.2 mmol) and N3-benzyl-N1-(4-chloro-pyrimidin-2-yl)-N3,4-dimethyl-benzene-1,3-diamine (according to step a), 55 mg, 0.163 mmol) in 2-propanol (6 mL) and 1M HCl (0.32 mL) is heated under reflux for 1 h. Solvents are evaporated and the residue is adjusted to pH 8 by the addition of aqueous NH3. Partition between EtOAc and water, washing with 10% brine, drying of the organic phase (Na2SO4), evaporation of solvents, and chromatography (silica gel) of the residue gives 2-{2-[3-(benzyl-methyl-amino)-4-methyl-phenylamino]-pyrimidine-4-ylamino}-6-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide, eluted with EtOAc/hexanes 2:3. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, CH3C(4″)); 2.43 (s, NCH3); 3.90 (s, NCH2C6H5); 4.90 (q, J=9, OCH2CF3); 6.20 (d, J=5, H—C(5′)); 6.93 and 6.97 (2d, J=9; H—C(5), H—C(5″)); 7.14-7.20, 7.20-7.34, and 7.34-7.4 (3m, NCH2C6H5, H—C(2″), H—C(6″), SO2NH2); 7.45 (t, J=8, H—C(4)); 8.05 (d, J=5, H—C(6′)); 8.12 (db, J=9, H—C(3′)); 9.12 (b, NH); 8.9-10.3 (NH).
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[N:27]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)n(C)n1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 80.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (117 mg, 0.322 mmol) and triethylamine (134 μL, 0.966 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (38.0 μL, 0.419 mmol), and the mixture was stirred at room temperature for 12 hr. Cyclopropanecarbonyl chloride (29.3 μL, 0.322 mmol) was further added and the mixture was stirred for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (100 mg), methanol (2 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (112 mg, 60%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1([CH3:22])[CH2:20][NH:19][C:18](=[O:21])[CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:19]2[CH2:20][C:16]([CH3:22])([CH3:15])[CH2:17][C:18]2=[O:21])[C:11]=1[CH3:12]
Reactant: CC1(C)CNC(=O)C1
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)ccc2c1Cl

Procedure:
Prepared according to Procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (0.300 g, 1.304 mmol), 4,4-dimethyl-2-pyrrolidinone (0.162 mL, 1.434 mmol), cesium carbonate (0.600 g, 1.826 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.060 g, 0.065 mmol), XantPhos (0.113 g, 0.196 mmol), and dioxane (2.6 mL). Purification by column chromatography (silica; 0-20% EtOAc in hexanes) afforded 1-(4-chloro-7-fluoro-3-methylquinolin-2-yl)-4,4-dimethylpyrrolidin-2-one as a white amorphous solid. Mass Spectrum (ESI) m/e=307.0 (M+1).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccccc1

Procedure:
After dissolving 4.9 g. (0.05 mole) of 2 -imino-1 -methylpyrrolidine in anhydrous benzene, 5.96 g. (0.05 mole) of phenylisocyanate is added dropwise with stirring (heat evolves). The reaction mixture is stirred for one-half hour. The solid product which is formed, 1 -(1 -methyl-2 -pyrrolidylidene)-3 -phenylurea, is collected (m.p. = 140-144° C.); recrystallized from methanol to give the pure product, m.p. = 146-147.5° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([I:15])[C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>O1CCOCC1>[I:15][C:7]1[C:8]([CH3:14])=[C:9]([CH:13]=[C:5]([S:2]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:4])=[O:3])[CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: C1CCNC1
Reactant: Cc1c(I)cc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1c(I)cc(S(=O)(=O)N2CCCC2)cc1C(=O)O
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 5-(chlorosulfonyl)-3-iodo-2-methylbenzoic acid (1.00 g, 2.77 mmol), pyrrolidine (0.278 mL, 3.33 mmol), 1,4-dioxane (4 mL) and pyridine (0.20 mL, 2.5 mmol). The mixture was stirred for 30 minutes. The solvent was removed and the residue was purified by flash chromatography to yield the compound as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[OH:38])=O)[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH:7]([N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][NH:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[OH:38])[CH2:24][CH2:25]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(O)c(NC(=O)CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(O)c(NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminium hydride (606 mg, 16.0 mmol) was added to tetrahydrofuran (25 ml) in several divided portions under ice-cooling, and thereto was added dropwise a solution of the compound (2) (3.43 g, 7.98 mmol) obtained above in tetrahydrofuran (15 ml). The mixture was heated under reflux for 3 hours, and thereto was added water (0.5 ml), 10% sodium hydroxide (0.5 ml) and water (1.0 ml) in that order under ice-cooling. The mixture was stirred at room temperature for 30 minutes. The inorganic substance was removed from the reaction mixture by filtration. The filtrate was dried over anhydrous magnesium sulfate and evaporated to give a yellow-orange glassy substance, which was then purified by column chromatography on silica gel to give a yellow-orange solid. Yield 2.35 g (71%). The thus-obtained solid was recrystallized from ethyl acetate to give colorless needle-like crystals (Compound 14). Yield 987 mg (30%). m.p. 178°-179° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1cc(N2CCOCC2)nc(Cl)n1)c1ccccc1
Temperature: -5 °C
Yield: 57.1 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (6 g, 19.8 mmol) was dissolved in DCM (50 mL) and stirred (under nitrogen) at −5° C. Triethylamine (3.06 mL, 21.8 mmol) was added to give a clear brown solution. Morpholine (1.65 mL, 19.8 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (4 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:6]([CH3:8])[N:7]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75c, the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was treated with 4-(4-fluoro-phenyl)-piperidine and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-5-methyl-6-phenyl-pyrazine-2-carbonitrile as yellow oil; MS: 373 (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:17])[C:9]2[CH:10]=[CH:11][N:12]=[C:13]([O:14]C)[C:8]=2[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2].[I-].[Na+].Cl[Si](C)(C)C.S([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>O.C(#N)C>[CH2:1]([C@:3]1([OH:17])[C:9]2[CH:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=2[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1ccnc2OC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CC[C@@]1(O)CC(=O)OCc2c1cc[nH]c2=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
To a dry round-bottom flask was added lactone 10b (0.07 g, 0.3 mmol) followed by dry acetonitrile (1 mL). Sodium iodide (0.07 g, 0.49 mmol) was added followed by chlorotrimethylsilane (0.06 mL, 0.49 mmol). The resulting mixture was stirred at rt for 15 min at which point H2O was added (2.7 μL, 0.15 mmol) and the reaction mixture was heated to 60° C. for 7 h. The mixture was then poured into a 1:1 solution of 5% sodium sulfite/brine (7 mL) and then quickly extracted with ethyl acetate (4×5 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was subjected to flash chromatography (MeOH/CH2Cl2 5:95) to afford pure 11 as pale yellow oil (10.4 mg, 16%). IR (MeOH, NaCl,cm−1) 3370(br), 1655, 1049, 1025, 823, 768; 1H NMR (300 MHz, CD3OD) δ0.91 (t, J=7.5 Hz, 3H), 1.82 (m, 2H), 3.10 (d, J=13.8 Hz, 1H), 3.40 (d, J=13.8 Hz, 1H), 5.30 (d, J=15.2 Hz, 1H), 5.46 (d, J=15.2 Hz, 1H), 6.57 (d, J=7 Hz, 1H), 7.35 (d, J=7 Hz, 1H); 13C NMR (75 MHz, CDCl3/CD3OD) δ6.76, 35.22, 41.46, 60.98, 72.43, 105.93, 122.42, 132.76, 156.35, 161.60, 172.57; HRMS (EI) m/z calcd for C11H13NO4 (M+) 223.0845, found 223.0851; LRMS (EI) m/z 224(M+H, 32), 195(21), 163(43), 153(100), 91(40), 77(19), 55(24); [α]D23=+35.0 (c=0.08, MeOH).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2
Reactant: OB(O)c1ccccc1O
Reactant: Brc1ccc2nonc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccccc1-c1ccc2nonc2c1

Procedure:
A stirred mixture of 5-bromobenzofurazan (11.94 g, 60 mmol), 2-hydroxyphenylboronic acid (9.10 g, 66 mmol). tri-o-tolylphosphine (1.82 g, 6 mmol), palladium (II) acetate (0.672 g, 3 mmol), potassium carbonate (12.4 g, 90 mmol), and water (90 mL) in dimethylformamide (180 mL) is heated at 80° C. under an argon atmosphere for 30 minutes. The mixture is then treated with water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 20%-100% ethyl acetate in cyclohexane) and recrystallised from ethyl acetate-hexane to give 5-(2-hydroxyphenyl)benzofurazan as a pale-yellow crystalline solid, m.p. 166-169° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)#[N:2].C([O-])([O-])=[O:34].[K+].[K+].OO.Cl>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:16][NH:17][C:18]2[C:19]([F:32])=[C:20]([CH:28]=[CH:29][C:30]=2[F:31])[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:8]=1)(=[O:34])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(C#N)cc(-c3cccc(F)c3)c2)c1F
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
To a mixture of ethyl 2-[3-[[3-cyano-5-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (see example 24) (200 mg, 0.45 mmol, 1 eq) and K2CO3 (310 mg, 2.3 mmol, 5 eq) in DMSO (10 mL) at 40° C. was added H2O2 (30% aqueous solution, 10 mL) dropwise. The mixture was stirred for 20 min then cooled to room temperature. Water was added, and the reaction neutralised by addition of diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as white solid (90 mg, 46%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:21][O:20][C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: COc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(N2CCNCC2)nc1

Procedure:
953 mg 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 16 mL 4 mol/L HCl solution in dioxane for 45 min The precipitate was filtered, washed with dioxane and dried to yield 723 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH2:13])([O-:3])=[O:2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:14]([NH:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]nc(NCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 32.9 %

Procedure:
To a suspension of 5-nitro-1H-indazol-3-ylamine (0.025 g, 0.140 mmol) and benzaldehyde (0.067 g, 0.60 mmol) in CH2Cl2 (3.0 mL) was added acetic acid (0.024 mL, 0.42 mmol) followed by sodium triacetoxyborohydride (0.059 g, 0.28 mmol). The resulting solution was allowed to stir at room temperature for about 19 hours. The reaction solution was diluted with CH2Cl2 (5 mL) and treated with an aqueous solution of NaOH (1N, 5 mL). The two phases were separated and the organic solvent was removed under reduced pressure. The residue was further purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8 Hypersil® HS C18 column; 5% acetonitrile/0.1 M aqueous ammonium acetate-100% acetonitrile over 20 min, 100% acetonitrile hold 5 minutes, 21 mL/min) to give benzyl-(5-nitro-1H-indazol-3-yl)-amine (0.012 g, 0.046 mmol) as an orange solid. RP-HPLC (Table 1, Method e) Rt 2.15 min.; m/z: (M+H)+ 269.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Yield: 86 %

Procedure:
A mixture of p-bromochlorobenzene (1.91 g, 9.99 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (2.0 g, 9.99 mmol), palladium acetate (45 mg, 0.2 mmol), (R)-(+)-BINAP (187 mg, 0.3 mmol) and sodium tert-butoxide (1.35 g, 14.0 mmol) in toluene (20 ml) was refluxed under a nitrogen atmosphere for 1 hour. Ethyl acetate and water were added to the reaction mixture while stirring, the insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(4-chlorophenylamino)piperidine-1-carboxylate (2.67 g, yield 86%) as a yellow powder.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.[C:9]([C:17](O)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:2]([NH:6][N:7]=[C:17]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: O
Product: CC(C)(C)NN=C(O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 296 grams (g) (2.37 mol) of t-butyl hydrazine hydrochloride, 20 milliliters (mL) of concentrated hydrochloric acid (HCl) and 2 liters (L) of water was stirred at room temperature to give a clear solution. Benzoylformic acid (400 g, 2.61 mol) was added in four equal portions at 3 minute intervals. The mixture was stirred overnight at room temperature and filtered. The solid collected was washed with water and dried in vacuo to furnish 520 g (99%) of the compound, mp 138°-139° C.