Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClCCl.[CH3:43][NH:44][CH3:45]>O1CCCC1>[Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=[O:25])[N:44]([CH3:45])[CH3:43])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.065 g, 51%). 1H NMR (400 MHz, DMF-d6) δ 7.58 (app q, J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt, J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2N3O3 requires 506.0885).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1nccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1nccc(N(CC(=O)N(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3,4-Dichloro-N-(2-isopropyl-pyrimidin-4-yl)-benzenesulfonamide (80 mg, example 14) was dissolved in DMF (1 mL) and treated with cesium carbonate (113 mg). To the mixture was added 2-chloro-N,N-dimethylacetamide (37 mg) and the resulting suspension was allowed to stir at room temperature for 48 hours and then at 80° C. for 24 hours. The mixture was diluted with ethyl acetate, washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using DCM/MeOH/NH4OH 9:1:0.1 as an eluant. The desired product was obtained as a colorless glass (28 mg). MS (ESI): 431.3 (MH+).
Reaction SMILES: O[CH:2]1[CH2:8][CH:7]2[N:9](C(OC(C)(C)C)=O)[CH:3]1[CH2:4][O:5][CH2:6]2.C(N(S(F)(F)[F:23])CC)C.Cl.O1CCOCC1>>[F:23][CH:2]1[CH2:8][CH:7]2[NH:9][CH:3]1[CH2:4][O:5][CH2:6]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)C2
Agent: Cl
Solvent: C1COCCO1
Product: FC1CC2COCC1N2

Procedure:
Compound 51a was prepared from tert-butyl 6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate G8 by treatment with DAST (diethylaminosulfur trifluoride) followed by HCl/dioxane to remove the N-Boc protection.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (2.0 g, 9.66 mmol, 1.0 equiv; commercially available from Peakdale Molecular, UK) in ethanol (50 mL) was added palladium on activated charcoal 5% (0.10 g, 0.048 mmol, 0.5 equiv) and the reaction vessel filled with hydrogen (2.5 bar). After stirring at rt for 18 h, the reaction mixture was filtered over celite, concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.19 g (11%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 3.97 (s, 3H), 7.89 (d, J=4.9 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 52.67, 118.22, 156.45, 160.62, 161.18, 162.31. MS (ISP): 172.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)(=O)C.[Pt]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:11][CH2:10][NH:13][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=Cc1ccc(O)cc1
Agent: [Pt]
Solvent: CC(=O)O
Product: Oc1ccc(CNCCNCc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
24.16 g of a bisazomethine prepared from 2 mols of p-hydroxybenzaldehyde and 1 mol of ethylenediamine and with a melting point of 215°-216° C. (decomposition) are hydrogenated in 150 ml of glacial acetic acid with 0.5 g of 10% platinum/charcoal at 25° C. in a hydrogenation flask. After 24 hours no further H2 is taken up. The catalyst is filtered off and the filtrate is concentrated in a rotary evaporator. The residue is crystalline and is stirred with 90 ml of isopropanol at 60° C.; the crystals do not dissolve. They are filtered off at room temperature, washed with isopropanol, and dried at 80° C. in vacuo. Yield 30.65 g (86.8% of theory) of the diacetate of N,N'-bis-(4-hydroxybenzyl)-1,2-diaminoethan with a melting point of 152°-155° C. The NMR spectrum confirms the structure of the diacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30]>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Product: CC(C)OCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 2-(2-bromo-ethoxy)-propane, the title product was prepared in the same manner as described for example 1a (69%). Pink, viscous oil. MS: m/e=411(M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[O:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)=[N:43][N:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([C:42]5[O:41][C:40]([CH3:39])=[N:44][N:43]=5)[CH:50]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1nnc(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)o1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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+]
Product: Cc1nnc(-c2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazole (96 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 90 mg (72% yield) of the title compound as a oil. Purity 90%.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22]Br>CN(C=O)C.O>[CH3:1][C:2]1[N:11]([CH2:20][O:21][CH3:22])[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCBr
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(C)nc2ccc3ccc(C)cc3c2c1=O
Reaction time: 0.58 h

Procedure:
To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5 mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich) portion wise and the mixture was stirred 35 minutes. Bromomethyl methyl ether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and the solution was stirred at room temperature overnight. The solution was then diluted with water (100 ml) and extracted twice with methylene chloride (100, 40 ml). The combined methylene chloride extracts were washed with a small volume of water, dried (K2CO3), and concentrated in vacuo. The residue was purified by silica gel (4 0 g) chromatography eluting with ethyl acetate:methylene chloride (0 to 1:19) to give 3,9-dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one and the corresponding O-alkylated material in a 4:1 ratio as determined by NMR (0.79 g). 1H NMR (DMSO-d6, 300 MHz) for major isomer δ: 2.57 (s, 3H, C9 -CH3), 2.68 (s 3.38 (s, 3H, OCH3), 5.62 (s, 2H, NCH2O), 7.51 (dd, J=8,2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz, 1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculated for C16H16N2O2 : C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H, 10.43.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]([C:12](=O)[CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:18][C:19]([NH2:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN1CCOCC1>C(O)(C)C>[NH2:18][C:19]1[NH:26][C:12]([CH3:13])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C=C(N)N
Reactant: COC(=O)C(=Cc1ccc(C)cc1)C(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)OC)C1c1ccc(C)cc1
Yield: 84.7 %

Procedure:
A mixture of (E and Z) methyl 2-(4-methylbenzylidene)-3-oxobutanoate (887 mg, 4.06 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (677 mg, 4.06 mmol), and N-methylmorpholine (447 μl, 4.06 mmol) in Isopropanol (7682 μl) was refluxed overnight. The reaction was then concentrated and purified with column chromatography (0-100% EtOAc/Hexane) to afford 3-ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.1349 g, 3.44 mmol, 85% yield) as pale yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 (d, J=8.0 Hz, 2 H), 7.01 (d, J=7.8 Hz, 2 H), 5.90 (br. s., 2 H), 5.64 (s, 1 H), 4.86 (s, 1 H), 4.07 (q, J=7.1 Hz, 2 H), 3.64 (s, 3 H), 2.32 (s, 3 H), 2.27 (s, 3 H), 1.23 (t, 3 H); LCMS (m/z) ES+=331 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>>[CH3:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]1[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)[CH:24]=1
Reactant: CN(C)C(=O)c1cccc(CCl)c1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: CN(C)C(=O)c1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-chloromethyl-N,N-dimethyl-benzamide [CAS 442910-26-1]. MS (ES+) 436.3
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>CO>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:13]([F:27])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(C(N)=O)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Reaction time: 1 h
Yield: 112.8 %

Procedure:
To a heterogeneous mixture of ethyl 3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate (305 mg, 0.80 mmol) in MeOH (8 mL) was added aqueous 1 M NaOH (1.70 mL, 1.70 mmol). After one hour of stirring, the mixture was acidified with aqueous 1N HCl (5 mL). The reaction was extracted with EtOAc before the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (317 mg) which was used without further purification. HRMS (ESI+), 352.0745 (M+H)+ calcd., 352.0752 (M+H)+ found.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CO.[Pd]>[CH3:24][N:8]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a suspension of 5% Pd/C (4.60 g, 2.16 mmol) in ethanol (40 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)pyrrolidine-1-carboxylate (7.2 g, 21.6 mmol) in methanol (20 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with methanol (60 mL). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate (4.3 g, 99%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M165) (250 mg, 0.468 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (154 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[C:14]([CH:20]=O)[C:13]=2[O:22][CH3:23])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[NH4+:25].II>C1COCC1>[Cl:1][C:2]1[N:3]([C:12]2[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[C:14]([C:20]#[N:25])[C:13]=2[O:22][CH3:23])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1c(C=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C#N)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carbaldehyde (98 mg, 0.278 mmol) in THF (1.5 mL) is added ammonium hydroxide (30% aq. solution, 1.5 mL), followed by iodine (92 mg, 0.362 mmol), which caused a dark brown colour to appear. The resulting reaction mixture was stirred for 1 h and then quenched with NaHCO3 solution (5 mL) and Na2S2O3 solution (5 mL). This caused the reaction to change from dark brown to a clear pale yellow mixture. After stirring for 10 min the reaction was extracted with DCM (20 mL×2), dried (MgSO4) and concentrated under reduced pressure to afford the desired pro duct 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carbonitrile (82 mg, 0.235 mmol, 85%) as a yellow foam that crushed into a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[CH2:10]1.[OH:20][C:21]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:22]=1>>[C:21]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH2:10][C:11]2=[O:19])(=[O:20])[CH3:22]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccc(F)cc2F)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(F)cc1F
Yield: 90 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(2,4-difluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one to obtain the title compound (90%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[CH2:12]([NH:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([N:19]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1F
Yield: 66.7 %

Procedure:
A solution of 1,2-difluoro-4-nitro-benzene (0.96 g, 6.0 mmole) and benzyl methylamine (0.79 g, 6.6 mmole) in 4 mL of anhydrous DMF is heated with K2CO3 (0.41 g, 3.0 mmole) at 80° C. for 16 hours. After removal of the solvent, the residue is purified on flash chromatography with EtOAc/Hexanes (0-15%), yielding yellow oil 1.05 g (4.0 mmole) 67% of benzyl-(2-fluoro-4-nitro-phenyl)-methylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (144 mg, 0.46 mmol) in anhydrous THF (5.6 mL), was added 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 259A (161 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (31 mg, 0.25 mmol). The mixture was stirred at rt for 15 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (134 mg, 55%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.28-7.54 (m, 5H), 6.89 (s, 1H), 3.99 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[CH3:19]O>>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1CBr
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OC)c(CBr)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (1.359 ml) was added dropwise to a solution of the product from step (i) (4.02 g) in MeOH (50 mL), the resulting suspension was stirred at 0° C. for 10 min then warmed to rt for 18 h. The solvent was evaporated and the residue was diluted with EtOAc washed with sat. NaHCO3 and sat. brine. The organic phase was dried, filtered and evaporated. The crude product was purified by chromatography, to give the subtitle compound as a yellow oil, 1.47 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In methanol/toluene (1:10, 55 ml) was dissolved 4-hydroxy-3-nitrophenylacetic acid (2.0 g, 10.1 mmol). Trimethylsilyldiazomethane (2.0M hexane solution, 5.0 ml) was added dropwise to the resulting solution. After stirring at room temperature for 50 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate. The ethyl acetate extract was then washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.15 g, 100%) was obtained as a yellow solid (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][C:8]([CH3:16])([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:13](=[CH2:14])[C:8]([CH3:16])([CH3:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)C(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(Cl)C(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 38.6 %

Procedure:
To a suspension of PCl5(270 g, 1.3 mol) in CH2Cl2(1000 mL) was added dropwise methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0° C., following by addition of approximately 30 drops of dry DMF. The mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and slowly poured into ice water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2(500 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was distilled under reduced pressure to give methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%). 1 H NMR (400 MHz, CDCl3) δ 5.33(s, 1 H), 3.73(s, 3 H), 1.44(s, 6 H).