Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C[N:17]([CH:19](OC)OC)C.Cl.[C:25]([NH:29]N)([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([N:29]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=[N:17]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)NN
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (19.8 g, 94.20 mmol) and DMFDMA (13.76 mL, 103.61 mmol) in toluene (150 mL) was stirred at 100° C. for 14 hr, and concentrated under reduced pressure. The residue was dissolved in ethanol (150 ml), tert-butylhydrazine hydrochloride (11.74 g, 94.20 mmol) and TEA (14.44 mL, 103.61 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 3 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (18.67 g, 64.3 mmol, 68.3%) as a white powder.
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>C(O)C.O=[Pt]=O>[Cl:15][C:10]1[CH:9]=[C:8]([S:5]([N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:22]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=2)[CH3:21])[CH:1]([CH3:2])[CH3:3])(=[O:6])=[O:7])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(C)N(CCCC=O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCCN(C(C)C)S(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Reaction time: 7 h

Procedure:
The aldehyde prepared in the preceding paragraph (8.90 g, 0.027 m) and N-methyl-homoveratrylamine (5.29 g, 0.027 m) in absolute ethanol (100 ml) containing PtO2 (0.6 g) was shaken under hydrogen (7 hours) and the reaction filtered and stripped to provide the crude product (13.32 g) as a dark greenish gum. This material was chromatographed, after removal of a small amount of insoluble solid, on dry column silica gel (500 g) with 30% methanol/70% ethyl acetate to provide the title compound (7.26 g) as a clear white gum.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[C:29](Cl)(=O)[O:30]C1C=CC=CC=1.[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1>C1COCC1>[CH3:39][N:40]([CH3:46])[C@@H:41]1[CH2:45][CH2:44][N:43]([C:29]([NH:21][C:17]2[CH:16]=[C:15]([O:14][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:20]=[CH:19][N:18]=2)=[O:30])[CH2:42]1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])c4ccccc34)ccn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (200 mg, 0.71 mmol) and Et3N (0.20 mL, 1.42 mmol) in dry THF was added phenyl carbonochloridate (98 μL, 0.78 mmol) and the reaction mixture maintained at RT for 1 hr. An aliquot of (R)—N,N-dimethylpyrrolidin-3-amine (270 μL, 2.13 mmol) was added to this mixture and after 15 hr at RT a second aliquot of (R)—N,N-dimethylpyrrolidin-3-amine (100 μL, 0.79 mmol) was added and the mixture was maintained at RT for a further 1 hr. The resulting mixture was partitioned between aq. NH4Cl (10 mL) and DCM (10 mL) and the aqueous layer was separated and extracted with DCM (3×10 mL) The combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution and then, 10% [2% NH3 (7M in MeOH) in MeOH] in DCM, isocratic elution and finally, 30% MeOH in DCM, isocratic elution) to afford (R)-3-(dimethylamino)-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide, Intermediate K1, as a yellow/brown solid (250 mg, 81%); Rt 1.54 min (Method 2); m/z 422 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[N:7][O+:8]([O-])[N:9]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].[N-]=[N+]=[N-].[Na+]>C(O)CO>[F:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: COC(=O)c1cc2n[o+]([O-])nc2c(F)c1Nc1ccccc1C
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: OCCO
Product: COC(=O)c1cc2nonc2c(F)c1Nc1ccccc1C
Temperature: 145 °C

Procedure:
A solution comprised of methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo[1,2,5]oxadiazole-5-carboxylate 2-oxide and sodium azide (1.38 equiv.) in ethylene glycol is heated to 140-150° C. for 30 minutes to obtain, after column chromatography, the desired product.
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:26])([F:25])[C:15]([NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:16]>>[CH:7]1([N:6]2[C:2]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:18]([NH:17][C:15](=[O:16])[C:14]([F:25])([F:13])[F:26])[CH2:19][CH2:20]3)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=[N:5]2)[CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1cnn(C2CC2)c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Yield: 61 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.105 g, 61%). 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 6.55-6.38 (m, 1H), 4.30-4.15 (m, 1H), 3.65-3.53 (m, 1H), 3.55-3.25 (m, 4H), 2.25-2.05 (m, 6H), 1.35-1.05 (m, 4H).
Reaction SMILES: [NH2:1][NH2:2].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=S)[NH:9][CH3:10])=[C:6](F)[CH:5]=1>CS(C)=O.C(OCC)(=O)C.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:7]([C:8]([NH:9][CH3:10])=[N:1][NH:2]2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: CNC(=S)c1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CNc1n[nH]c2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
Anhydrous hydrazine (0.25 mL, 8.1 mmol) was added to a solution of 4-bromo-2-fluoro-N-methylbenzothioamide (200 mg, 0.8 mmol) in dimethylsulfoxide (2.5 mL). The reaction was heated to 100° C. and stirred for 2 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous was extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (20-100% ethyl acetate/heptanes) gave the title compound (98 mg, 54%) as a white solid. +ESI (M+H+1) 228.0; 1H NMR (400 MHz, CD3OD, δ): 7.52 (d, J=8.58 Hz, 1H), 7.43 (s, 1H), 7.04 (d, J=8.39 Hz, 1H), 2.94 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[C:9]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A mixture of 5-amino-1-pentanol (619 mg, 6.00 mmol), 2-chloro-1,3-dinitrobenzene (1.01 g, 4.99 mmol), triethylamine (0.837 mL, 6.01 mmol) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added 5-amino-1-pentanol (520 mg, 5.04 mmol) at room temperature and the resultant mixture was stirred at room temperature for 0.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (1.30 g, 4.82 mmol, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:15][N:14]=1>>[FH:1].[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:19]2[CH:20]=[C:21]([NH:22][C:2]3[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:23]=[CH:24][CH:25]=2)=[CH:17][N:18]=1
Reactant: Nc1cccc(-c2cnc(N)nc2)c1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Product: F
Product: Nc1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Yield: 79 %

Procedure:
N-(3-(2-aminopyrimid-5-yl)phenyl)-2-nitro-4-iodoaniline hydrofluoride (6l) was prepared analogously from 1c (Example 1) and 2l (Example 7). Yield: 79%. Mp 236-238° C.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C=C.I[C:36]1[CH:41]=[CH:40][N:39]=[C:38]2[NH:42][C:43](=[O:45])[O:44][C:37]=12>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[C:11]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[NH:42][C:43](=[O:45])[O:44][C:37]=23)[S:10][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reactant: O=c1[nH]c2nccc(I)c2o1
Product: O=c1[nH]c2nccc(-c3cc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)c2o1

Procedure:
The title compound was prepared from 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole and 7-iodo[1,3]oxazolo[4,5-b]pyridin-2(3H)-one using procedures analogous to those described in Example 8-A, Steps 2 and 3. LC/MS (AA) ES+ 429, 431. 1H NMR (400 MHz, d6 DMSO) δ: 8.03 (d, J=5.77 Hz, 1H), 7.83 (s, 1H), 7.59 (d, J=2.01 Hz, 1H), 7.43-7.39 (m, 2H), 7.36 (d, J=8.29 Hz, 1H), 7.06 (s, 2H).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH3:18].O1C2C=CC(O)=CC=2OC1.[F:45][C:46]1[CH:47]=[C:48]([OH:53])[CH:49]=[CH:50][C:51]=1[F:52]>>[CH2:17]([O:19][C:20](=[O:34])[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([Br:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([C:49]2[CH:50]=[C:51]([F:52])[C:46]([F:45])=[CH:47][C:48]=2[OH:53])([OH:32])[C:23]1=[O:33])[CH3:18]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl(4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate and 1,3-benzodioxol-5-ol with 3,4-difluorophenol, the title compound was obtained as a white solid (42%); MS (ES+) m/z 424 (M−17), 426 (M−17), 464 (M+23), 466 (M+23).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH:31]([NH:34][CH3:35])([CH3:33])[CH3:32]>>[CH:31]([N:34]([CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNC(C)C
Product: CC(C)N(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isopropyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 13H), 2.88 (s, 3H), 1.40 (d, 6.3 Hz, 3H), 1.36 (d, 6.3 Hz, 3H); MS (DCI) m/z 408 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](OC2C=CC=CC=2)=[N:17][C:18]#[N:19])=[CH:11][CH:10]=1>COCCOC>[C:18]([N:17]=[C:16]([O:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[NH:8][C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=1)#[N:19]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(N)nc1
Solvent: COCCOC
Product: N#CN=C(Nc1ccc(N)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.6 %

Procedure:
To a stirred mixture of the crude 2,5-diaminopyridine from Step 1 (0.0719 mol) and 100 ml of ethylene glycol dimethylether, under nitrogen, was added diphenylcyanocarbonimidate (17.1 g, 0.0718 mol) in one portion. This mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was triturated three times with Et2O. The solid residue (17.5 g) was stored under nitrogen until it was chromatographed in two portions: 5.0 g was chromatographed over 1000 ml of silica gel (230-400 mesh) by gravity elution with 5% MeOH/CHCl3 at a rate of 21 ml/minute to give 3.02 g of product; the other 12.5 g was chromatographed over 1000 ml of silica gel in the same manner (a poorer separation resulted at this loading) to give 7.31 g of product. The two lots were combined and crystallized from CH3CN to give 8.32 g (45.8%), m.p. 191°-192.5° C. of the titled product as amber needles. (An additional 0.98 g (5.4%) of dark amber needles was also obtained.)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](OCC)=[O:19])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].[Li+].[BH4-].CO.C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][OH:19])[N:6]2[CH2:13][C:14]([F:16])([F:17])[F:15].[OH:19][CH2:18][C:5]1[N:6]([CH2:13][C:14]([F:17])([F:15])[F:16])[C:7]2[C:3]([CH:4]=1)=[CH:2][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc2c(c1)cc(CO)n2CC(F)(F)F
Product: N#Cc1ccc2c(cc(CO)n2CC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %
Yield: 6 %

Procedure:
To an ice-cold solution of ethyl 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.45 g, 1.36 mmol) in THF (12 mL), under N2, was added LiBH4 (2 M THF solution, 2.04 mL, 4.08 mmol). The mixture was stirred at rt for 8 h. Additional LiBH4 (2M THF solution, 3 mL, 6 mmol) was added and stirred at rt for 60 h. The mixture was cooled in an ice bath and quenched by sequential dropwise addition of water and 1N HCl (exothermic). The mixture was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% EtOAc-hexanes gradient) to afford a mixture of the title compounds. A second flash chromatography (0-2% MeOH—CH2Cl2 gradient) afforded 4-chloro-2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 10) as a white solid (0.25 g, 63% yield) (MS (ES) m/z 289 (M+1)) and 2-(hydroxymethyl)-1-(2,2,2-trifluoroethyl)-1H-indole-5-carbonitrile (Example 11) (0.021 g, 6% yield) (MS (ES) m/z 255 (M+1)).
Reaction SMILES: [CH3:1][C:2](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](O)=[O:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)(Cl)Cl>[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([N:4]([CH2:3][C:2]([CH3:1])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:26]
Reactant: CC(=Cc1ccccc1)CNCCN1CCCCC1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=O)N(CCN2CCCCC2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
(2-Methyl-3-phenyl-allyl)-(2-piperidin-1-yl-ethyl)-amine, 0.5 g (1.9 mmol), was dissolved in 10 ml of anhydrous methanol under nitrogen. The solution was cooled to 0° C. To this mixture was added 3,4,5-trimethoxybenzoic acid 0.49 g (2.3 mmol), 0.2 ml of triethylamine, and TBTU 1.2 g (3.8 mmol). The reaction was stirred for 18 hours at room temperature. The reaction mixture was then diluted with chloroform, extracted with 2×10 ml of water, 2×10 ml sodium bicarbonate, and washed 2×10 ml of brine. The organic layer was dried over sodium sulfate and was concentrated. The compound was then purified on silica gel using 1.2% methanol in chloroform to give 102 mg of product as an off white HCl salt. Yield: 12%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) and p-N,N-dimethylaminopyridine (61 mg, 0.5 mmol) in pyridine (5 mL) was added ethyl chloroformate (0.11 mL, 1.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 h. After evaporation the residue was extracted with ethyl acetate/water and the organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO2, heptane/ethyl acetate=100:0 to 70:30) afforded the title compound (260 mg, 73%) as a white solid. MS: m/e=355.0 [M+H]+.
Reaction SMILES: ClCCl.C[O:5][C:6]1[C:15]2[C:10](=[C:11]([CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.B(Br)(Br)Br>O>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][CH:7]=[C:6]2[OH:5])[CH3:17]
Reactant: CCc1cccc2c(OC)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1cccc2c(O)cccc12
Temperature: 0 °C
Yield: 75 %

Procedure:
Anhydrous dichloromethane (20 mL) was added to 8 (870 mg, 4.6 mmol). After cooling to 0° C., BBr3 (boron tribromide 1.0M in dichloromethane) (14 mL, 14 mmol) was added dropwise. The reaction mixture was heated to reflux for 5 h. After cooling, a large amount of water was slowly added and the mixture was extracted three times with dichloromethane. The organic layer was evaporated and the residue was purified on MPLC to afford compound 9c, 75% yield; MS-ESI− (m/z, %): 171 (M+−1, 100), 172 (M+, 45); 1H NMR δ 1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 5.19 (1H, s, OH), 6.82 (1H, d, J=7.8 Hz, H-2), 7.31-7.45 (3H, m, H-3, 6, 7), 7.65 (1H, d, J=8.7 Hz, H-4), 8.06 (1H, d, J=8.1 Hz, H-8).
Reaction SMILES: [CH:1](S(C)(=O)=O)=[CH2:2].BrBr.N12CCCN=C1CCCCC2.[OH:20][C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>ClCCl>[O:20]1[CH:2]=[CH:1][C:30]2[C:29](=[O:31])[C:28]3[C:23]([C:22](=[O:32])[C:21]1=2)=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: C=CS(C)(=O)=O
Agent: BrBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2occc21
Yield: 24.6 %

Procedure:
To the solution of 5 grams (47.2 mmoles) of methyl vinyl sulfone in 100 mL of dichloromethane, 7.9 grams (49.5 mmoles) of bromine was added. The mixture was refluxed for 6 hours, and then evaporated to sticky residue. To the residue solution in 150 mL of tetrahydrofuran cooled in ice bath, 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 8.2 grams (47.2 mmoles) of 2-hydroxy-1,4-naphthoquinone and 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 6 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 2.3 grams of product (overall yield 25%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.17 (d, J=2, 1H), 7.86-7.91 (m, 2H), 8.09-8.13 (m, 2H), 8.32 (d, J=2.1H). Mass (M+H) is 199.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([F:17])[C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]1.[Cl:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>ClCCl>[Cl:25][C:26]1[C:31]([C:32]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:4]2[CH:5]=[C:6]([F:17])[C:7]([N:8]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]3)=[C:2]([F:1])[CH:3]=2)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl

Procedure:
A mixture of 3′,5′-difluoro-4′-[3-(trifluoromethyl)-1H-pyrazol-1-yl][1,1′-biphenyl]-2-amine (i.e. the product of Step D; 0.17 g, 0.52 mmol), 2-chloro-3-pyridinecarbonyl chloride (0.092 g, 0.52 mmol) and triethylamine (0.050 g, 0.52 mmol) in dichloromethane (5 mL) was stirred for 16 h at room temperature. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes. The resulting solid was triturated with 1-chlorobutane and hexanes to yield the title compound (0.090 g), a compound of the present invention.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH2:11])=[N:8][CH:9]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:19](=[O:21])[CH3:20])=[N:8][CH:9]=1
Reactant: NCc1ccc(F)cn1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
In a round-bottomed flask, (5-fluoropyridin-2-yl)methylamine dihydrochloride (800 mg, 4.0 mmol) was suspended in THF (15 ml). The suspension was cooled to 0° C. and triethylamine (1.75 ml, 12.6 mmol) was added followed by dropwise addition of acetyl chloride (0.30 ml, 4.22 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 654 mg (97%) of N-(5-fluoro-pyridin-2-ylmethyl)-acetamide as a light brown oil which was used without further purification.