Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.I(O)(=O)=O.[CH3:7][O:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10].S(=O)(O)[O-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[CH3:7][O:8][C:9]([C:11]1[C:20]2[C:15](=[C:16]([I:1])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: II
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(I)c(OC)ccc12
Temperature: 50 °C

Procedure:
Iodine (7.08 g) and iodic acid (2.78 g) were added to a stirred solution of 6-methoxy-1-naphthalenecarboxylic acid methyl ester [15 g, 69.4 mmoles, described by C. C. Price et al., J. Amer. Chem. Soc., 69, 2261 (1947)] in 80% acetic acid (110 ml) and 98% sulfuric acid (0.97 ml). The solution was heated at 50° C. for 5 hr, cooled and poured into water (100 ml). After the addition of sodium bisulfite to destroy the unreacted iodine, the precipitate was collected, washed with water and recrystallized from ethanol to afford the title compound; mp 98°-99° C.; NMR (CDCl3) δ 3.95 (s, 3H), 4.00 (s, 3H), 8.00 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]>C(O)(=O)C.Cl.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(CCCCC(=O)O)cc(Cl)c1OC

Procedure:
A solution containing 6.2 g of the above product obtained in Example 32 was dissolved in a mixture of 30 ml of acetic acid and 3 ml of conc. hydrochloric acid. Palladium on charcoal catalyst (10% Pd) was added and the mixture was hydrogenated at normal pressure and room temperature. After filteration the solvents were evaporated in vacuo. Yield 3.2 g (55%), a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].Cl.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([CH3:13])[CH:23]=3)=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COCCC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a mixture of 0.5 g (2.79 mmol) of 4-amino-tetrahydro-pyran-3-carboxylic acid methyl ester [WO 01/70673, Example 207] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (1.0 g, 2.94 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (1.02 mL, 5.88 mmol) at 0° C. The solution was allowed to warm to 25° C. over 19 h. The DMF was removed in vacuo and the resulting solid was partitioned between ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (2×50 mL). ). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude oil (1.48 g). The crude product was purified by Biotage Flash 40M chromatography, eluting with 1:4 ethyl acetate-hexanes, to afford 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester as a white solid (1.08 g, 78%). MS: 471 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].C([O-])([O-])=[O:26].[K+].[K+].OO.CCOC(C)=O>CO.CS(C)=O>[C:23]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:7][C:2]=1[Cl:1])(=[O:26])[NH2:24]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C(N)=O)c(Cl)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (300 mg) was dissolved in 20 mL methanol and 10 mL DMSO. To it were added K2CO3 powder (300 mg) and then 3 mL H2O2 (50% solution). The mixture was stirred at 40° C. for 1 h. To it was poured 200 mL EtOAc. The mixture was then washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and pumped to dryness to afford tert-butyl (1S,2R)-2-(5-carbamoyl-6-chloropyrazin-2-ylamino)cyclohexylcarbamate in quantitative yield. Tert-butyl (1S,2R)-2-(5-carbamoyl-6-chloropyrazin-2-ylamino)cyclohexylcarbamate (60 mg, 0.16 mmol) was dissolved in 3 mL NMP. To it were added 4-aminoterahydropyran (100 mg, 0.96 mmol) and DIEA (55 μL, 0.32 mmol). The mixture was stirred at 100° C. for overnight in a sealed tube. It was cooled to RT, diluted with EtOAc, washed with sat. NH4Cl solution, dried over MgSO4, concentrated in vacuo to afford crude tert-butyl (1S,2R)-2-(5-carbamoyl-6-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-ylamino)cyclohexylcarbamate. It was treated with 1:1 DCM and TFA at RT for 1.5 h. It was concentrated and subjected to reverse phase preparative HPLC to isolate the title compound as HCl salt (57 mg). MS found for C16H26N6O2 as (M+H)+335.5. UV: λ=282 nm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27]>O1CCOCC1.C(OCC)C>[ClH:27].[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:25])[CH2:16][NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
N-t-butyloxycarbonylglycyl-L-proline benzylester (18.12 g, 50 mmole) was dissolved in 4N hydrochloric acid in dioxane (220 ml) solution, and stirred for 20 minutes at room temperature. The solvent was distilled off and the residue thus obtained was powdered in diethyl ether to obtain glycyl-L-proline benzylester hydrochloride (yield: 13.21 g; 88.4%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>O1CCOCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 99.7 %

Procedure:
To an ambient temperature solution of 4-(trifluoromethyl)phenylboronic acid (4.64 g, 24.43 mmol) in dioxane/water (15/15 mL) is added 4-bromo-benzaldehyde (4.42 g, 22.21 mmol), tetrabutylammonium bromide (7.16 g, 22.21 mmol, potassium carbonate (7.67 g, 55.53 mmol) and degassed for 10 min. Palladium(II) acetate (748 mg, 1.11 mmol) is added and the reaction mixture is heated to 70° C. After 2 h TLC (20% EtOAc/hexane) indicates complete consumption of starting material. The reaction is cooled to room temperature diluted with water and extracted with EtOAc (3×200 mL). The combined organic extracts are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (330 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (5.54 g, 94%). 1NMR (400 MHz, CDCl3) δppm: 10.09 (s, 1H), 8.01-8.00 (m, 1H), 7.99-7.98 (m, 1H), 7.78-7.75 (m, 2H), 7.74 (s, 4H).
Reaction SMILES: [NH2:1][N+:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH2:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=O>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][N:2]2[N:1]=[C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([O:24][CH3:23])[CH:26]=3)[N:9]=[C:3]2[CH:4]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: c1ccncc1
Product: COc1cccc(-c2nc3cc(Br)ccn3n2)c1
Temperature: 85 °C

Procedure:
To a solution of 1,2-diamino-4-bromo-pyridinium-2,4,6-trimethyl-benzenesulfonate (Example 1, step a) (8 g, 20.7 mmol) in pyridine (50 ml) was added 3-methoxybenzoyl chloride (6 ml, 41.3 mmol). The reaction mixture was heated at 85° C. for 3 h. Volatiles were removed in vacuum, and the resultant residue was diluted with EtOAc (300 ml). The organic layer was washed successively with water (2×250 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (10-15% EtOAc/hexane) to afford 7-bromo-2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (8 g, quant) as white solid. LC-MS: m/z=303.8 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (40.5 mg, 77%), MS (ISP) m/z=309.5 [(M+H)+], mp 234.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-fluoro-phenylboronic acid (31 mg, 0.22 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=[O:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd].Cl>[OH:31][C:16]12[CH2:28][CH2:27][C@:26]3([CH3:29])[C:21](=[C:22]([CH3:30])[CH2:23][CH2:24][CH2:25]3)[C@@H:17]1[O:18][C:19](=[O:20])[CH:15]2[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1=C2[C@@H]3OC(=O)C(CN4CCNCC4)C3(O)CC[C@@]2(C)CCC1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Compound of example 27 (100 mg, 0.24 mmol) was dissolved in ethanol (10 mL) and to it 10% Pd/C & 10% aqueous HCl (0.1 mL) was added. The reaction mixture was stirred under hydrogen pressure for 30 hours at room temperature (25° C.). The reaction mixture was filtered over celite and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:3]1.C([O:17][C:18](=O)[C:19]([C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH:22]=1)=O)C.C(O[K])(C)(C)C>C1COCC1>[O:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:21]([C:19]2[C:18](=[O:17])[NH:14][C:12](=[O:13])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:22]1
Reactant: CCOC(=O)C(=O)c1coc2ccccc12
Reactant: Cn1cc(CC(N)=O)c2ccccc21
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3coc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a suspension of commercially available 2-(1-Methyl-1H-indol-3-yl)-acetamide (54 mg, 0.28 mmol) and benzofuran-3-yl-oxo-acetic acid ethyl ester (63 mg, 0.28 mmol) in dry THF (2.5 mL) at 0° C. was added dropwise a 1.0 M solution of tert-BuOK in THF (1.15 mL), and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with 12 N HCl and diluted with EtOAc. The organic solution was washed with saturated NaHCO3, brine, then dried over Na2SO4, evaporated in vacuo and purified by preparative TLC (ethyl acetate:hexane; 2:3) to afford product 3-benzofuran-3-yl-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (1) (44 mg, 44%) as an orange solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[O:4][CH2:3]1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[O:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1COC(c2ccccc2F)OC1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccccc1C1OCC(OCc2ccccc2)CO1
Yield: 46.6 %

Procedure:
5-Hydroxy-2-(2-fluorophenyl)-1,3-dioxane (18.0 g, 0.09 mole) was reacted with sodium hydride and benzyl chloride (13.0 g, 0.09 mole) as described in Example 2, except that the slurry was heated at 80°-100° C for 12 hours. The product was isolated in the manner described in Example 2 to give 12.1 g of oil which was distilled under 1 × 10-5 mm to give a product (6.2 g) which distilled at a pot temperature of 165°-170° C. VPC analysis of this product indicated it to contain 32% cis-5-benzyloxy-2-(2-fluorophenyl)-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH2:20][CH3:21]
Reactant: CCCOc1ccc(Cl)cc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(Cl)cc1C(=N)OCC
Yield: 114.9 %

Procedure:
reaction of 5-chloro-2-propoxybenzamide (16.50 g) with triethyloxonium tetrafluoroborate (0.096 mol) yielded crude ethyl 5-chloro-2-propoxybenzimidate tetrafluoroborate (29.14 g);
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=O)C.C[O-].[Na+].CO.C(O)(=O)C>CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([SH:4])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(S)CC1
Reaction time: 0.67 h
Yield: 98.9 %

Procedure:
In dry methanol were dissolved 520 mg (2 mmol) of 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine, and 420 μl (2 mmol) of a 28% sodium methoxide-methanol solution were added to the mixture under ice-cooling and under a nitrogen atmosphere, followed by stirring of the resulting mixture for 40 minutes. Then, 173 μl of acetic acid were added to the mixture and the solvent was distilled off at room temperature, followed by diluting of the residue with ethyl acetate. The mixture was washed successively with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution in the order and the solvent was distilled off to obtain 430 mg of reddish orange oil. This product was used for a subsequent reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:3]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([NH2:30])=[N:22]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:8]1([C:6]2[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:30][C:23]3[C:24]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:21][N:22]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: Nc1n[nH]c2ncccc12
Reactant: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1-c1nc(Nc2n[nH]c3ncccc23)cc(C2CC2)n1
Temperature: 130 °C
Yield: 56.6 %

Procedure:
A mixture of 4-chloro-6-cyclopropyl-2-(2-trifluoromethylphenyl)-pyrimidine (7.00 g, 23.4 mmol, prepared as described above in example 8) and 1H-pyrazolo[3,4-b]pyridin-3-ylamine (9.43 g, 70.3 mmol) in N-methylpyrrolidinone (50 mL) was heated at 130° C. for 12 hours. The residue was cooled, dissolved in N-methylpyrrolidinone (2 mL), poured into water (500 mL) and sodium bicarbonate (15 mL) then filtered, washing with water. Purification by flash chromatography [SiO2, ethyl acetate:hexanes (35:65)] provided the title compound (5.25 g, 57% yield) as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ 13.1 (br s, 1H), 10.5 (br s, 1H), 8.50 (m, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.73 (m, 3H), 7.66 (t, J=7.7 Hz, 1H), 7.12 (m, 1H), 2.07 (m, 1H), 1.02 (m, 2H), 0.97 (m, 2H) ppm; LC-MS 397.22 (M+H); Rt (Method A) 3.412 minutes.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1.CO>[NH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:13][CH2:14]1.[ClH:1]
Reactant: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl{4-[(dimethylamino)carbonyl]cyclohexyl}carbamate (0.20 g, 0.74 mmol) in methanol (1.0 mL). The reaction mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford the desired product as an HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9](I)[CH3:10].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:10]
Reactant: Oc1cccc(F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(F)c1

Procedure:
3-Fluorophenol (20.0 g, 178.4 mmol), ethyl iodide (83.5 g, 535.2 mmol) and K2CO3 (49.3 g, 356.8 mmol) in 250 ml of acetone were stirred at 50° C. overnight. The mixture was filtered and evaporated to give 1-ethoxy-3-fluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Cl.[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][N:23]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:22]1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: FC1(F)CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (600 mg, 2.4 mmol), commercially available 3,3-difluoropiperidine hydrochloride (753 mg, 4.8 mmol), acetic acid (0.20 mL, 3.6 mmol) and triethylamine (0.33 mL, 3.6 mmol) in 1,2-dichloroethane was stirred for 30 minutes. Sodium triacetoxyborohydride (615 mg, 2.9 mmol) was added. When LC/MS indicated the absence of starting material, the reaction was quenched with the addition of sat'd NaHCO3. The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 3,3-difluoro-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (584 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.6 Hz, 1H), 6.55 (dd, J=9.6 and 2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.04 (d, J=12.8 Hz, 1H), 3.87 (s, 3H), 2.90 (t, J=12.0 Hz, 2H), 2.72-2.60 (m, 3H), 2.47 (m under DMSO peak, 2H), 1.87-1.74 (m, 4H), 1.61-1.58 (m, 2H), 1.48-1.38 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.O>C1COCC1>[C:3]([C:2]([NH:1][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:24])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)NC(C)(C(N)=O)C(C)C)cc1
Reaction time: 1 h

Procedure:
A stirred mixture containing 13.0 g (0.10 mol) of 2-amino-2,3-dimethylbutyramide and 15.3 mL (0.11 mol) of triethylamine in 150 mL of dry THF is treated dropwise at 5° to 10° C. with a solution of 15.5 g (0.10 mol) of p-toluoyl chloride in 25 mL dry THF. After being allowed to warm to ambient temperatures over a 16 hour period, the reaction mixture is treated with 50 mL water and stirred for one hour. The resulting three phases are filtered; the filtrate is separated and the aqueous phase is extracted with 150 mL ethyl acetate. All organic phases are combined, washed with 100 mL of a saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. A white solid residue is obtained which weighs 17.3 g, mp 145°-152° C. The nmr spectrum is consistent with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-])=O)[C:18]=2[OH:27])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]([OH:27])=[C:19]([CH:20]=[CH:21][C:22]=2[Cl:23])[NH2:24])(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Yield: 92 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 1-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene (256 mg, 0.61 mmol) was reduced with hydrogen and 10% Pd/C (120 mg) to form the desired product (220 mg, 93%). 1H NMR (MeOD-d4): δ 6.84 (m, 2H), 3.45 (m, 4H), 3.27 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]2[NH:8][C:9]([NH:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[CH:19][CH:18]=3)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Reactant: Nc1ccc2cccnc2c1
Product: FC(F)(F)c1cc(Br)c2[nH]c(Nc3ccc4cccnc4c3)nc2c1

Procedure:
The reaction of 7-bromo-2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (135 mg, 0.45 mmol, prepared according to the procedures described in WO 2004/035549 A1) with 7-aminoquinoline (43 mg, 0.3 mmol, Synchem) under the condition of Example 2 afforded the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 407 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12](OCC)[O:13]CC)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12]=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCOC(OCC)c1cc(CC)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: CCc1cc(C=O)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
A solution of 5-Diethoxymethyl-3-ethyl-thiophene-2-carboxylic acid methyl ester (1.76 g, 6.46 mmol) in dioxane (16 ml) was cooled to 0° C. (ice bath). 88% formic acid (20 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 90 min. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (1.22 g, 95% yield).