Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (350 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (196 mg), potassium carbonate (260 mg) and N,N-dimethylformamide (4 ml) was stirred at 50° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (400 mg, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)=[O:6].OP([O-])(O)=O.[K+].O.[C-:24]#[N:25].[K+]>CN(C)C=O>[OH:14][CH:13]([C:11]1[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:15])[Cl:16])=[O:6])[S:9][CH:10]=1)[C:24]#[N:25]
Reactant: O=Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: [C-]#N
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
To a mixture of 1.0 g. of 2-(β,β,β-trichloroethoxycarbonyl)amino-4-formylthiazole, 0.87 g. of KH2PO4, 6 ml. of water and 4 ml. of dimethylformamide is added 0.33 g. of KCN at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of ethyl acetate gives α-hydroxy-[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]-acetonitrile 1.127 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13](I)[CH2:14][CH3:15]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CCCI
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Product: CCCn1ccc2cc([N+](=O)[O-])ccc21
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield from 5-nitroindole and propyl iodide using a procedure similar to that in Description 2.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C(O)c1ccc(C(=O)c2cccc(Cl)c2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.114 g (0.720 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.188 g (0.7 mmol) of 4-(3-chlorobenzoyl)benzoic acid and 0.40 ml (2.9 mmol) of triethylamine in 30 ml of dichloromethane, 0.18 g (1.1 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1). The resulting purified product was washed with hexane to yield the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH3:41][NH:42][CH3:43].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[CH2:26][CH:27]([N:42]([CH3:43])[CH3:41])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC(N(C)C)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) was added to a mixture of dimethylamine (2M in THF, 1.07 mL, 2.14 mmol), and sodium cyanoborohydride (1.0 M in THF, 857 μL, 0.857 mmol) in ethanol (1.1 mL). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (59.5 mg, 43% yield) as a TFA salt. LC-MS (M+H)+ 496.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.90-7.99 (1 H, m), 7.32-7.39 (1 H, m), 7.19-7.25 (1 H, m), 7.09-7.17 (4 H, m), 6.91-7.04 (2 H, m), 4.99 (1 H, br. s.), 4.70 (1 H, ddd, J=15.2, 5.3, 2.4 Hz), 4.03 (1 H, dd, J=14.2, 12.1 Hz), 3.86-3.97 (3 H, m), 3.39-3.55 (1 H, m), 3.03 (1 H, dd, J=13.9, 5.6 Hz), 2.74-2.88 (6 H, m), 2.52 (1 H, br, s.), 2.17-2.33 (1 H, m), 1.97-2.13 (1 H, m), 1.37-1.51 (1 H, m).
Reaction SMILES: C([O:3][C:4]([CH:6]=[CH:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[N:20]2[CH:21]=[N:22][CH:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH:6]=[CH:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[N:20]2[CH:21]=[N:22][CH:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=CC=CCCCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CC=CCCCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6 g 5-(9-ethoxycarbonylnona-6,8-dienyl)imidazo[1,5-a]pyridine in 30 ml of methanol is added 6 ml of 1N sodium hydroxide. The reaction is allowed to stir at room temperature for 3 hours. The methanol is evaporated under reduced pressure and the residue diluted with 15 ml water and the solution adjusted to pH 7 with 1N hydrochloric acid. The solution is extracted with 2×150 ml of ethyl acetate. The combined ethyl acetate extracts are dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield 5-(9-carboxynona-6,8-dienyl)imidazo[1,5-a]pyridine melting at 120°-122°.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].[CH3:38][N:39]([CH3:51])[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[C:43](OCC)=[O:44]>O1CCCC1>[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH2:36][C:43](=[O:44])[C:42]1[CH:48]=[CH:49][CH:50]=[C:40]([N:39]([CH3:38])[CH3:51])[CH:41]=1
Reactant: CNC(=O)c1cccnc1C
Reactant: CCOC(=O)c1cccc(N(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1cccnc1CC(=O)c1cccc(N(C)C)c1
Reaction time: 2 h

Procedure:
263 ml. of 1.6 M.n-butyl lithium in hexane (420 mmol.) were slowly added to a solution of 58.7 ml. (420 mmol.) of diisopropylamine in 200 ml. of dry tetrahydrofuran stirred at -10° C. under nitrogen. To the resulting solution of lithium diisopropylamide, a solution of 30 g. (200 mmol.) of 2-methylnicotinic acid N-methylamide (Compound XII) in 200 ml. of dry tetrahydrofuran was slowly added at -20°--30° C. The resulting red reaction mixture was stirred under nitrogen at -20°--30° C. for an additional two hours. Then, a solution of 38.6 g. (200 mmol.) of ethyl 3-dimethylaminobenzoate in 100 ml. of dry tetrahydrofuran was slowly added at -20°--30° C. with stirring under nitrogen. Stirring under nitrogen was continued for 1 hour at the same temperature. The reaction mixture was then quenched with 250 ml. of saturated sodium chloride solution and extracted three times with ethyl acetate. The ethyl acetate phases were combined, washed four times with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to a thick oil (55.6 g.) which was dissolved in a small amount of isopropanol and chromatographed on silica gel using 5% isopropanol/chloroform as the eluant. The last major fraction to be eluted (approx. 24 g.) was rechromatographed on silic gel using 2% isopropanol/chloroform as the eluant. The largest fraction contained the crude product (17.2 g.).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][NH:6][C:7]([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)NOC(C)(C)C)ccc2c1NC(C)(C)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NOC(C)(C)C)ccc2c1NC(C)(C)CC2
Yield: 53 %

Procedure:
A solution of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,8-trimethylquinoline (114 mg, 0.39 mmol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (11 mg) at rt for 7 h. Filtration over Celite afforded 60 mg (60%) of 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline. The title compound was prepared by General Method 12 (EXAMPLE 147) from 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline (60 mg, 0.206 mmol) to afford 30 mg (77%) of 7-amino-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline as a light reddish oil. Data for 7-amino-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline: 1 H NMR (400 MHz, CDCl3) 6.70 (d, J=7.9, 1H), 6.09 (d, J=7.9, 1H), 3.30 (bs, 3H), 2.71 (t, J=6.7, 2H), 1.89 (s, 3H), 1.65 (t, J=6.7, 2H), 1.21 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31](O)=[O:32])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:32])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.69 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.78 g (4.1 mill), and stirred at 0° C. for 30 min. 2-adamantyl acetic acid 0.80 g (4.1 mill) and WSC 1.11 g (5.79 mill) were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 23 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 50 ml solution of lithium aluminum hydride 0.47 g (12 mill) and refluxed for 2 hours. The reaction mixture was cooled, added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19][CH3:20])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.O>CN(C)C=O.C1(C)C=CC(S([O-])=O)=CC=1.[Na+]>[Cl:1][C:2]1[C:3]([CH2:19][CH3:20])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=2)=[CH:13][CH:12]=1
Reactant: CCc1nccc(NC(=O)Cc2ccc(O)cc2)c1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2)c1Cl
Temperature: 80 °C
Reaction time: 0.83 h
Yield: 60.6 %

Procedure:
0.59 g (2 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-hydroxyphenylacetamide, 0.32 g (2.2 mmol) of potassium carbonate, 0.35 g (2.2 mmol) of 2-chloro-5-nitropyridine and 0.01 g of sodium 4-toluenesulfinate were dissolved in 5 ml of N,N-dimethylformamide, and the solution was stirred for 50 minutes at 80° C. After completion of the reaction, the reaction solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.5 g of the desired product as a milky white powder (melting point: 128° to 131° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13](Br)=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1.[CH3:47][CH2:48][C:49]1[CH:54]=[N:53][CH:52]=[CH:51][C:50]=1[CH3:55]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C-:13]([N+:53]2[CH:52]=[CH:51][C:50]([CH3:55])=[C:49]([CH2:48][CH3:47])[CH:54]=2)[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)=[N:11]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1
Reactant: CCc1cnccc1C
Solvent: CCO
Product: CCc1c[n+](-[c-]2c(NC(=O)c3cccc(NC(=O)COc4ccc(C(C)(C)CC)cc4C(C)(C)CC)c3)nn(-c3c(Cl)cc(Cl)cc3Cl)c2=O)ccc1C
Yield: 94.9 %

Procedure:
10 g Of 1-(2,4,6-trichlorophenyl)-3-{3-[(2,4-di-tert-amylphenoxy)acetamido]benzamido]-4-bromo-5-pyrazolone and 6.4 g of β-collidine were refluxed in 100 ml of ethanol for 5 hours. After cooling, the resulting crystals were washed with water and dried, and recrystallized from ethanol to give 10 g of Compound 3 having a melting point of 162° to 165°C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([OH:15])[CH3:14].CC(C)([O-])C.[K+].F[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([O:15][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[CH3:14]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc2ccccc2c1CC(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
1-(2-Methyl-naphthalen-1-yl)-propan-2-ol (1.2 g, 6.0 mmol) was dissolved in freshly distilled THF (15 mL) in a round bottom flask fitted with a reflux condenser. Potassium tert-butoxide (739 mg, 6.60 mmol) was added and the reaction was stirred at room temperature for 30 minutes. 2-fluoronitrobenzene (0.70 mL, 6.60 mmol) was added via syringe. The reaction was stirred at vigorous reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then was concentrated. The residue was diluted with saturated aqueous NaHCO3 and was extracted three times with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 20% CH2Cl2-hexanes) to give 2-methyl-1-[2-(2-nitro-phenoxy)-propyl]-naphthalene (1.51 g, 4.72 mmol) in 79% yield as an oil that solidified on standing. 1H NMR (300 MHz) CDCl3 δ 8.03 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.67 (m, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.29 (m, 2H), 6.90 (m, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.93 (m, 1H), 3.67 (dd, J=7.5, 14.5 Hz, 1H), 3.46 (dd, J=5.7, 14.4 Hz, 1H), 2.56 (s, 3H), 1.46 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][CH2:28][OH:29].[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:31])[C@:4]1([OH:30])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOS(C)(=O)=O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 1.5 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione in 25 ml of pyridine is cooled to 0°C and 0.6 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to 2.0 g of crude mesylate.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:3]=1.Cl.[CH3:26][C:27]1[N:28]=[C:29]([NH:32][C:33]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]2)=[O:34])[S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:4]3[N:3]=[C:2]([N:38]4[CH2:39][CH2:40][CH2:41][C@@H:36]([NH:35][C:33]([NH:32][C:29]5[S:30][CH:31]=[C:27]([CH3:26])[N:28]=5)=[O:34])[CH2:37]4)[CH:10]=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: Cc1csc(NC(=O)N[C@@H]2CCCNC2)n1
Reactant: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1csc(NC(=O)N[C@@H]2CCCN(c3ccc(C(N)=O)c(Nc4ccc(N5CCN(C)CC5)cc4)n3)C2)n1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
A mixture of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide (60 mg, 0.173 mmol), (R)-1-(4-methylthiazol-2-yl)-3-(piperidin-3-yl)urea hydrochloride (96 mg, 0.347 mmol), and DIEA (0.182 mL, 1.041 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 120° C. overnight. The reaction mixture was quenched with water, resulting in the formation of light brown precipitate. The solid was filtered, washed with water, and dried under vacuum. The residue was purified by MPLC chromatography (ISCO, 7% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 22 mg of (R)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-6-(3-(3-(4-methylthiazol-2-yl)ureido)piperidin-1-yl)nicotinamide as a yellow solid. LCMS: (M+H)+=550.08; 1H NMR (400 MHz, CDCl3) δ ppm 10.62 (1H, s), 7.47 (2H, d, J=9.23 Hz), 7.33 (1H, d, J=8.79 Hz), 6.85 (2H, d, J=9.23 Hz), 6.28 (1H, s), 5.91 (1H, d, J=8.79 Hz), 5.69 (2H, br. s.), 4.00 (1H, d, J=7.47 Hz), 3.65-3.79 (2H, m), 3.55-3.64 (1H, m), 3.40-3.50 (1H, m), 3.07-3.14 (4H, m), 2.52-2.58 (4H, m), 2.33 (3H, s), 2.19 (3H, s), 1.87-1.98 (1H, m), 1.55-1.82 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH3:25]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 85 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (93 mg, 85%), which was obtained as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[O:31])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 82 (0.4 g, 0.69 mmol) was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.19 g, 1.07 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 0.22 g, 51%).