Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][CH:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][CH:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](OCC(O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCC1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Slowly add trichloromethyl chloroformate (8.74 mL; 2.0 equiv; 72.84 mmoles) over 10 minutes to a 0° C. solution of 1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (13.86 g; 1.0 equiv; 36.42 mmoles) and pyridine (23.56 mL; 8 equiv; 291.36 mmoles) in acetonitrile (500 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (50 mL) and concentrate the reaction mixture to 75 mL volume. Add dichloromethane (100 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired 6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (9.48 g; 64%) as a light pink gum: MS (m/z): 407(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1>C(O)C.[Ni].O>[NH2:11][C:5]1[C:6]([CH2:8][C:9]#[N:10])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: N#CCc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(Cl)ncc1N
Reaction time: 2.5 h

Procedure:
A solution of (2-chloro-5-nitro-4-pyridyl) acetonitrile in ethanol (100 mL) was added to a suspension of 50% Raney nickel in water (3.2 g) diluted with ethanol (150 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure for 2.5 hours and then filtered through Celite® (diatomaceous earth) to remove the catalyst. The solvent was removed in vacuo to leave a dark oil which was subjected to flash chromatography on silica gel using 3:1 ethyl acetate/hexanes as eluant. Fractions containing only the title compound were combined and concentrated to afford an oil (850 mg, 32%). Less pure fractions were also combined and concentrated to give an oil (600 mg) of which the title compound was the major component (about 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1
Yield: 81 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 152 mg, 0.5 mmol), tetrabutylammonium iodide (195 mg, 0.52 mmol) and 4-fluorobenzyl bromide (0.33 mL, 2.57 mmol) in dimethylformamide (1 mL) was heated at 100° C. in a sealed tube for 9 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 20-100% ethyl acetate/hexanes, to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(4-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (167 mg, 81%) as an off-white solid. ES(+)-MS (M+H) 395.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:30]2[C@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@@H:32]([C@H:38]([O:40][C:41]([O:43][CH2:44][CH:45]=[CH2:46])=[O:42])[CH3:39])[C:31]2=[O:47])=CC=1>O.C(#N)C>[CH2:44]([O:43][C:41]([O:40][C@@H:38]([C@@H:32]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[NH:30][C:31]1=[O:47])[CH3:39])=[O:42])[CH:45]=[CH2:46]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1OC(C)=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 10°, a solution of 5.37 g of cerium(IV) ammonium nitrate in 15 ml of water is added to a solution of 900 mg (1.18 mmol) of (3R,4R)-1-(p-methoxybenzyl)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-acetoxy-2-azetidinone in 30 ml of acetonitrile, and the whole is stirred for two hours at room temperature. After extraction with ethyl acetate, washing with saturated NaHCO3 solution, drying of the organic phase over sodium sulphate and concentration by evaporation under reduced pressure, the crude title compound, which is purified by chromatography over silica gel using toluene/ethyl acetate (4:1 and 1:1), is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Br.[NH2:25][C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:15]2=[O:17]
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(OC)c1
Reactant: C[C@]1(N)CCC(=O)NC1=O
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N([C@@]2(C)CCC(=O)NC2=O)C3=O)c(OC)c1
Yield: 41 %

Procedure:
A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid (0.37 g, 1.2 mmol) and (3S)-3-amino-3-methyl-piperidine-2,6-dione hydrobromide (0.28 g, 1.2 mmol) in pyridine (10 mL) was heated to reflux for 24 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting 0.20 g of the product, an orange solid, at 50:50 hexanes-ethyl acetate, in 41% yield: mp 255-257° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 65/35 (CH3CN/0.1% H3PO4): tR=2.72 (97.30%); 1H NMR (DMSO-d6) δ 1.91 (s, 3H), 2.05-2.08 (m, 1H), 2.59-2.73 (m, 3H), 3.79 (s, 6H), 6.57 (d, J=7.5 Hz, 1H), 6.71 (s, 1H), 6.97-7.08 (m, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.52 (m, 1H), 7.94 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.6, 29.2, 55.4, 55.7, 58.5, 99.5, 104.7, 110.2, 111.8, 118.1, 120.1, 125.0, 131.9, 136.0, 144.0, 153.6, 157.9, 167.8, 169.8, 172.1, 172.4; Anal. calcd for C22H21N3O6.0.2H2O: C, 61.88; H, 5.05; N, 9.84. Found: C, 61.91; H, 5.01; N, 8.52.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.C(=O)(O)[O-].[Na+].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].CN(C=O)C>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(Br)ccc1N
Temperature: 80 °C
Yield: 55.8 %

Procedure:
To a microwave vial was added, 4-bromo-2-iodoaniline (1.70 g, 5.71 mmol), PdOAc2 (0.064 g, 0.285 mmol), sodium bicarbonate (1.198 g, 14.27 mmol), ethyl acrylate (0.651 ml, 5.99 mmol) and DMF (1.902 ml). The reaction was heated in microwave for 1 hour at 80° C. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.860 g of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate. m/z (ESI) 270.1 (M+H)+.
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([O:42]CC)=O)[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]>>[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([NH:7][CH3:6])=[O:42])[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)c(F)c1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)c(F)c1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(3,4-difluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 12).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([CH2:15][N+:16]([O-:18])=[O:17])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.Cl[CH2:20][NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].Cl>CN(C)C=O>[Cl:7][C:8]1[C:9]([CH:15]([N+:16]([O-:18])=[O:17])[CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: O=[N+]([O-])Cc1ncc(Cl)cc1Cl
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(Cl)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Temperature: 0 °C
Yield: 70.3 %

Procedure:
To 6.57 g of potassium tert-butoxide in 100 ml of N,N-dimethylformamide, 10.10 g of 3,5-dichloro-2-(nitromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 30 minutes. Then, to the reaction mixture, 11.59 g of N-chloromethyl-2-(trifluoromethyl)benzamide in 50 ml of N,N-dimethylformamide was added dropwise with stirring under cooing with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was carefully poured into 100 ml of ice-water, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 14.00 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=O)[CH2:23][NH2:24])=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:24][CH2:23][CH2:22][NH:21][C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:26])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN)c3Cl)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(NCCN)c3Cl)c2n1
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a suspension of 8-[2,6-dichloro-3-glycylaminobenzyloxy]-2-methylquinoline (2.14 g) in tetrahydrofuran (21 ml) was dropwise added 2M boranemethylsulfide complex in tetrahydrofuran (5.48 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 15 minutes at the same temperature and refluxed for 6 hours. After cooling, the mixture was adjusted to pH 1 with 1N hydrochloric acid and refluxed for 30 minutes. The mixture was neutralized with saturated sodium bicarbonate solution and extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform) to give 8-[3-[N-(2-aminoethyl)amino]-2,6-dichlorobenzyloxy]-2-methylquinoline (525 mg) as colorless amorphous.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:56][C:55]([O:57][C:58]4[C:63]([F:64])=[CH:62][CH:61]=[C:60]([O:65][CH2:66][CH3:67])[C:59]=4[F:68])=[CH:54][C:53]3=[O:69])CC(C)C)=N2)CO1>C(#N)C>[CH2:66]([O:65][C:60]1[C:59]([F:68])=[C:58]([C:63]([F:64])=[CH:62][CH:61]=1)[O:57][C:55]1[CH2:56][N:2]([CH:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:53](=[O:69])[CH:54]=1)[CH3:67]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(N)CC2CCOCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(F)c(OC2=CC(=O)N(C(CC3CCOCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
A suspension of 2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride salt (766 mg, 2.0 mmol) in acetonitrile (15 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and the resulting mixture stirred at 60° C. for 15 min. After this time N,N-diisopropylethylamine (0.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 705 mg, 1.93 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (4 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 6 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (148 mg, 14%): HR-ES-MS (m/z) calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2520; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.07 (br. s., 3H), 1.13-1.31 (m, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.55-1.74 (m, 3H), 1.75-1.88 (m, 1H), 3.09-3.31 (m, 2H), 3.82 (br. s., 2H), 3.90 (s, 2H), 4.14 (q, J=6.9 Hz, 2H), 4.32 (d, J=18.6 Hz, 1H), 4.66 (br. s., 1H), 4.64 (d, J=18.6 Hz, 1H), 4.91 (dd, J=10.8, 4.4 Hz, 1H), 5.06 (s, 1H), 6.45 (d, J=1.8 Hz, 1H), 7.17 (td, J=9.4, 4.9 Hz, 1H), 7.27 (td, J=9.4, 1.3 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:12][CH:13]1[CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: FC1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)CC1
Yield: 99 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-fluoropiperidine hydrochloride gave 4-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (280 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 4.86 (dtt, J=47.9, 7.1, 3.6 Hz, 1H), 3.77 (s, 3H), 3.37 (d, J=9.4 Hz, 2H), 3.20-3.12 (m, 2H), 2.16-2.06 (m, 1H), 2.07-1.92 (m, 3H)
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:8].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH2:44])[NH:42][N:43]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH:44][C:7]([C:9]3[S:13][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[CH:11][CH:10]=3)=[O:8])[NH:42][N:43]=2)[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at 20° C. for 20 h. The temperature was increased to 60° C. and the reaction mixture was stirred for 20 h and then allowed to cool. The reaction mixture was diluted with acetone (10 ml) and quenched with damp solid sodium sulphite. The mixture was stirred for 30 mins, and then a solution of 10% methanol in DCM (10 mL) was added and the mixture stirred for a further 30 mins. The suspension was filtered and the solid washed with 10% methanol in DCM (20 mL); the combined filtrates were evaporated to give a yellow foam. The crude product was purified by silica column chromatography, eluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated to dryness to afford the crude product. This was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate (0.272 g, 50.2%) as a white dry film. 1H NMR (500.13 MHz, DMSO-d6) δ 1.46 (9H, s), 2.89-2.90 (6H, m), 3.22 (4H, t), 3.52 (4H, t), 3.75 (6H, s), 6.18 (1H, d), 6.27 (1H, s), 6.34 (1H, t), 6.42-6.42 (2H, m), 7.72 (1H, d), 9.81 (1H, s), 11.71 (1H, s); MS: m/z 542 (MH+)
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH:37]1([C@H:40]([NH2:42])[CH3:41])[CH2:39][CH2:38]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:42][C@@H:40]([CH:37]2[CH2:39][CH2:38]2)[CH3:41])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: C[C@@H](N)C1CC1
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 48.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.06 g, 2.49 mmol) and (R)-1-cyclopropyl-ethylamine HCl (202 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 314 mg of crude (R)-[4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-ethyl)-amine.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.45 g, 1.32 mmol) (from Example 16, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.6 mmol) and methyl iodide (0.75 g, 5.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.3 g, 84%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N+:19]([O-:35])=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccccc1)COC3
Reaction time: 2 h
Yield: 99.5 %

Procedure:
(11S)-11-[(Benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (0.92 g, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with MCPBA (0.81 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of 5% Na2CO3 solution and the layers were separated. The aqueous portion was extracted with an additional 10 mL of CH2Cl2. The combined organic layers were washed successively with H2O (20 mL) and brine (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.96 g of (11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a light-brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:7]=[O:8])[CH3:2]
Reactant: CC(C)=CCBr
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCC=C(C)C

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 1-bromo-3-methyl-2-butene in DMF using K2CO3 as base. MS (ISN): 233.1 [M−H]−.