Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: C1CNCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCNCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), piperazine (4.5 g, 51.6 mmol), copper(I) iodide (785 mg, 4.1 mmol), N,N-dimethylglycine hydrochloride (1.2 g, 8.2 mmol) and potassium carbonate (4.3 g, 30.9 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120° C. for 16 hours. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×200 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-piperazin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.2 g, 80%) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C24H31N3O2 (M+H)+: 394.53, observed: 394.1.
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:21]([O:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate from step A (535 mg, 2.06 mmol) in DMF (8.2 mL) was carefully added sodium hydride (60% dispersion in mineral oil, 124 mg, 3.09 mmol). The mixture was stirred for 30 minutes at room temperature. Benzyl bromide (0.29 mL, 2.47 mmol) was added, and the reaction was stirred for another 30 minutes. Upon completion as monitored by TLC analysis, the reaction was quenched with 50 mL of 1:1 saturated aq. NH4Cl:water. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, and concentrated under vacuum. Silica gel chromatography (5-10% ethyl acetate:hexanes) provided the title compound as a clear oil (359 mg, 54% yield). MS (ES+) [M+H]+=340.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:10]([F:21])[CH:9]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([F:21])[CH:9]=2)=[N:6][C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][N:3]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)n1

Procedure:
To a solution of ethyl 5-amino-6-(4-(tert-butoxycarbonyl)-3-fluorophenyl)pyrazine-2-carboxylate (0.253 g, 0.7 mmol) in DCM (4 mL) at RT was added TFA (2.157 mL, 28.0 mmol). The resultant solution was stirred at RT for 2 hours. The reaction solution was concentrated and further dried to afford the crude desired product as a TFA salt. This product was directly used at the next step. 0.214 g (100% yield) of light sticky liquid was obtained. LC-MS (m/z): 306.1 (MH+), 0.563 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][CH:16]=1>CN(C=O)C>[N+:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:11][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)([CH3:9])[CH3:10])=[CH:16][CH:17]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: CC(C)(O)c1ccnc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 8.7 %

Procedure:
To a stirred solution of 2-(2-aminopyridin-4-yl)propan-2-ol (40) (1.55 g, 10.0 mmol) in DMF (30 mL), under nitrogen at 0° C., was added sodium hydride (60% wt, 0.61 g, 15.0 mmol) and the resulting mixture was stirred at 0° C. for 5 min. A solution of 1-fluoro-4-nitronaphthalene (14) (1.95 g, 10 mmol) in DMF (30 mL) was added dropwise and the resulting dark-red mixture was stirred at 0° C. for a further 5 min and then at RT for 2 hr. The reaction mixture was quenched by the addition of saturated aq NH4Cl solution (10 mL). Water (150 mL) and EtOAc (150 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, 80 g, 0-60% EtOAc in isohexane, gradient elution) to afford the title compound (41) (282 mg, 8%) as a red oil: m/z 324 (M+H)+ (ES+).
Reaction SMILES: [N+](C1C=CC(C(OCCCCC(O[N+]([O-])=O)CO[N+]([O-])=O)=O)=CC=1)([O-])=O.[N+](C1C=CC(C([O:36][CH2:37][CH2:38][C@H:39]([O:45][N+:46]([O-:48])=[O:47])[CH2:40][O:41][N+:42]([O-:44])=[O:43])=O)=CC=1)([O-])=O>>[N+:42]([O-:44])([O:41][CH2:40][C@@H:39]([O:45][N+:46]([O-:48])=[O:47])[CH2:38][CH2:37][OH:36])=[O:43]
Reactant: O=C(OCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])OC[C@H](CCO)O[N+](=O)[O-]

Procedure:
The title compound was prepared by following step B of the synthesis of intermediate 1, except that the reagent 5,6-bis(nitrooxy)hexyl 4-nitrobenzoate was replaced by (3S)-3,4-bis(nitrooxy)butanyl 4-nitrobenzoate. 1H NMR (300 MHz, CDCl3) δ 5.56 (ddd, J=2.8, 6.4, 13.0 Hz, 1H), 4.89 (dd, J=2.8, 13.0 Hz, 1H), 4.56 (dd, J=6.4, 13.0 Hz, 1H), 3.84 (td, J=2.7, 5.7 Hz, 2H), 2.02 (dd, J=5.7, 6.4 Hz, 2H), 1.73 (bs, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13].B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCS
Reactant: O=CCc1ccccc1
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(CC2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 33.9 g (280 mmol) of phenylacetaldehyde and 35.6 g (330 mmol) of 1,3-propanedithiol in 300 mL of methylene chloride at 0° C., was added, dropwise over a period of 30 minutes, 10 mL of boron trifluoride etherate. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h at ambient temperature. The reaction mixture was made basic by the addition of 180 mL of 5% aqueous potassium hydroxide solution and the resultant mixture was stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic extract was washed with 1N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled to afford 53.62 g (91% yield) of the title compound, b.p. 150° C. (2 mm Hg); 1H NMR (CDCl3) δ1.75-1.95 (1H, m), 2.05-2.17 (1H, m), 2.75-2.91 (4H, m), 3.03 (2H, d, J=9 Hz), 4.25 (1H, t, J=9 Hz), 7.17-7.38 (5H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccccc2OCc2ccccc2)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 62.2 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.74 g, 2.0 mmol) and 2-benzyloxyphenylboronic acid (0.50 g, 2.2 mmol) in saturated sodium carbonate solution (4 ml) and 1,4-dioxane (4 ml) was added palladium(II) acetate (0.09 g, 0.40 mmol) followed by triphenylphosphine (0.105 g, 0.400 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 4-[6-(2-benzyloxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XVI) (0.65 g, 62%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].Br[CH:31]([CH2:33][CH2:34][CH3:35])[CH3:32]>>[CH3:32][CH:31]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)[CH2:33][CH2:34][CH3:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CCCC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0° C. This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. The mixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product 4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine as an oil, LC/MS (M+H)+: 286.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CCN(C)CC1
Yield: 41.7 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (150 mg) and (2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (128 mg) were stirred together in 1,2-dichloroethane (8 ml) and acetic acid (32 mg) with sodium triacetoxyborohydride (146 mg) at room temperature overnight. Dichloromethane/aqueous sodium hydrogen carbonate extraction and purification on silica yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (97 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@:14]2([C:26]2[S:30][N:29]=[CH:28][CH:27]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C[C@@H]2[C@@](C3SC=C(Br)C=3)(N=C(NC(=O)C3C=CC=CC=3)SC2)C1)C=C.FC(F)(F)C(O)=O>ClCCl>[S:30]1[C:26]([C@:14]23[CH2:16][NH:17][CH2:18][C@H:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15]3)=[CH:27][CH:28]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccns2)C1
Agent: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)cs2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Yield: 87 %

Procedure:
To a room temperature solution of tert-butyl (4aR,7aR)-2-benzamido-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate, isomer 2 (1.26 g, 2.83 mmol) in dichloromethane (25 mL) is added trifluoroacetic acid (4.29 mL, 56.68 mmol) drop wise. The resultant solution is stirred for 18 hours at ambient temperature. The solvent is removed under vacuum. The mixture is diluted with ethyl acetate followed by saturated sodium bicarbonate. The layers are separated and the aqueous phase is re-extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum to give the title compound (850 mg, 2.46 mmol, 87%). ES/MS (m/e): 345 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(O)cc1F
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
4-Amino-3-fluorophenol (5.7 g) was dissolved in dimethyl sulfoxide (57 ml) under a nitrogen stream, potassium tert-butoxide (5.6 g) was added at room temperature, and the reaction mixture was stirred for 15 minutes. 4-Chloropyridine-2-carboxamide (5.0 g) was added to the reaction mixture, followed by stirring in an oil bath at 80° C. (external temperature) under a nitrogen stream for 50 minutes. The reaction mixture was allowed to cool down to room temperature. A 1N aqueous solution of sodium hydroxide (85.5 ml) was added to the reaction mixture, followed by stirring. The precipitated solid was collected by filtration and washed with water. The residue was dried under aeration and then dried by hot air at 100° C. to give the title compound (5.88 g, 74.3%) as pale brown powder.
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([F:12])[N:4]=1)#[N:2].N.[OH:14]S(O)(=O)=O>>[F:12][C:5]1[N:4]=[C:3]([C:1]([NH2:2])=[O:14])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(F)ccc1[N+](=O)[O-]
Agent: N
Product: NC(=O)c1nc(F)ccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
A solution or 2-cyano-6-fluoro-3-nitropyridine (1.40 g, 8.39 mmol) in 90% H2SO4 (30 mL) is warmed at 70° C. for 90 min, then cooled, poured onto ice and basified with conc. ammonia. Extraction with EtOAc and workup gives 6-fluoro-3-nitropyridine-2-carboxamide (0.94 g, 61%). 1H NMR (CDCl3) δ 8.70 (1H, dd, J=8.9, 6.5 Hz), 8.30, 8.03 (1H, 1H, brs), 7.62 (1H, dd, J=8.9, 2.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:21](COC)[S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[C:5]([C:8]([C:10]2[C:18]3[N:17]([CH3:19])[C:16](=[O:20])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.O.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=2)(=[O:23])=[O:24])[C:5]([C:8]([C:10]2[C:18]3[N:17]([CH3:19])[C:16](=[O:20])[NH:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc2[nH]c(=O)n(C)c12)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc3[nH]c(=O)n(C)c23)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide in 4 M HCl in dioxane (2 mL) and water (1 mL) was heated at 95° C. for 7 h, then MeOH (1 mL) and water (2 mL) was added and heating was continued overnight. The resulting mixture was purified by HPLC to provide N-[5-chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 10.94 (s, 1 H), 8.28 (d, J=2.0 Hz, 1 H), 8.21 (d, J=1.6 Hz, 1 H), 8.08 (s, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.19-7.17 (m, 1 H), 7.01 (t, J=7.6 Hz, 1 H), 6.82 (d, J=7.6 Hz, 1 H), 3.10 (s, 3 H), 2.53 (s, 3H); MS m/z 524.9 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[C:10](=[O:20])[CH:9]=1.[OH:21][C:22]([CH3:55])([CH3:54])[CH2:23][C@@:24]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:29][C:28](=[O:30])[N:27]([C@H:31]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH3:32])[CH2:26][CH2:25]1>CN(C)C=O>[OH:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][N:11]1[CH:12]=[CH:13][C:8]([C:36]2[CH:35]=[CH:34][C:33]([C@@H:31]([N:27]3[CH2:26][CH2:25][C@:24]([CH2:23][C:22]([OH:21])([CH3:54])[CH3:55])([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[O:29][C:28]3=[O:30])[CH3:32])=[CH:38][CH:37]=2)=[CH:9][C:10]1=[O:20]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(CO)Cn1ccc(Br)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)CO)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.32 mL) was added to a mixture of 4-bromo-1-(3-hydroxy-2,2-dimethyl-propyl)-1H-pyridin-2-one (0.13 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) in N,N-dimethylformamide (3 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium (II) dichloromethane complex (26 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound as a beige solid. Yield: 0.10 g (60% of theory); Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:12]([N:11]([CH2:2][CH:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[OH:4])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccco1
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)c1ccco1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.8 %

Procedure:
2-(Bromoacetyl)furan (95 g) is added slowly to a stirred mixture of 75 g of N-methylbenzylamine and 70 g of potassium carbonate in 300 ml of methanol at 20°-30° C. The mixture is stirred at room temperature for 2.5 hours, and the insoluble matter is filtered off. To the filtrate is added 20 g of sodium borohydride at 10°-20° C. with stirring, and the mixture is stirred at room temperature for 3 hours. The solvent is then distilled off under reduced pressure, water is added to the residue, and the separated oil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Distillation of the residue gives 80 g of 2-(N-benzyl-N-methylamino)-1-(2-furyl)ethanol as pale yellow viscous oil, boiling at 130°-138° C. (0.2 mmHg).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:21]([O-])=O)[CH:8]=2)[O:3]1>CO>[CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(Oc2ccnc(O)c2)C1O
Solvent: CO
Product: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 20° and 1 bar on 0.5 g of 5% Pd--C to completion. The mixture is filtered, evaporated and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol is obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]3[C:23]4[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=4[S:21][C:20]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:16]=[CH:15][N:14]=2)[CH:8]=1)(=O)=O.C(OC([NH:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=O)(C)(C)C.CC(C)([O-])C.[K+].[ClH:58].CCOCC>O1CCOCC1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[ClH:58].[NH2:46][CH:47]1[CH2:51][CH2:50][N:49]([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[C:17]([C:19]4[C:23]5[CH2:24][C:25]([CH3:29])([CH3:30])[CH2:26][C:27](=[O:28])[C:22]=5[S:21][C:20]=4[N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:48]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(OS(=O)(=O)C(F)(F)F)c4)c3)c2C1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(N5CCC(N)C5)c4)c3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
A mixture of Example 360 (100 mg, 0.18 mmol), 3-(tert-butoxycarbonylamino)-pyrrolidine (66 mg, 0.35 mmol), potassium tert-butoxide (28 mg, 0.25 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (20 mg, 0.043 mmol) in 1,4-dioxane (2.0 mL) was heated in a sealed tube at 100° C., under microwave irradiation, for 2 h. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). The obtained solid was taken up in DCM (10 mL), treated with a solution of HCl in Et2O (2M, 1.0 mL, 2.0 mmol) and stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by column chromatography (0-20% MeOH/DCM) to give the title compound (36 mg, 38%) as an orange solid. δH (CD3OD) 8.89-8.77 (1H, m), 8.57-8.44 (1H, m), 8.22-8.09 (1H, m), 7.62-7.51 (1H, m), 7.38-7.20 (2H, m), 7.02 (1H, d, J 7.7 Hz), 4.22-4.08 (1H, m), 3.93-3.48 (8H, m), 3.27-3.05 (4H, m), 2.81 (2H, s), 2.68-2.45 (3H, m), 2.38-2.21 (1H, m), 1.08 (6H, s). LCMS (ES+) 503.4 (M+H)+.