Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]3[N:21]([C:29]4[C:30]5[C@H:37]([CH:38]([CH3:40])[CH3:39])[CH2:36][CH2:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:22][C:23]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:16]=23)C(=O)OC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[CH:38]([C@H:37]1[C:30]2[C:29]([N:21]3[C:17]4[C:16](=[C:15]([CH2:14][NH:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH:20]=[CH:19][CH:18]=4)[C:23]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:22]3)=[N:34][CH:33]=[N:32][C:31]=2[CH2:35][CH2:36]1)([CH3:40])[CH3:39]
Reactant: CC(C)[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CN(C(=O)OC(C)(C)C)C5CCCC5)cccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC5CCCC5)cccc43)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-tert-butyl cyclopentyl((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)carbamate (0.0156 g, 0.0286 mmol) in DCM (2 mL) was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 1 hour and concentrated to yield (S)—N-((1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine trihydrochloride as a solid. LCMS (APCI+) m/z 446.3 [M+H]+; Rt=3.28 min.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[N:37]1([C:41](=O)[CH2:42]Cl)[CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:41][CH2:42][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 19.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azetidin-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([Li])(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[C:26](/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[C:41]#[N:42])=[N:27]\S(C(C)(C)C)=O)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].Cl.CO>C1COCC1>[Br:17][C:18]1[CH:19]=[C:20]([C:26]2([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[C:34]3[C:35](=[C:36]([F:40])[CH:37]=[CH:38][CH:39]=3)[C:41]([NH2:42])=[N:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: COc1ccc(/C(=N\S(=O)C(C)(C)C)c2cccc(F)c2C#N)cc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1Br
Reaction time: 2.5 h
Yield: 89.3 %

Procedure:
A solution of 4-bromo-2-trifluoromethylpyridine (1.76 g, 7.80 mmol) in THF (2 mL) was added dropwise at −100° C. to t-butyllithium (9.17 mL, 15.59 mmol) in THF (15 mL) followed by the addition of (E)-N-((3-bromo-4-methoxyphenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (3.1 g, 7.09 mmol) in THF (10 mL). The reaction mixture was left on a thawing cooling bath for 1 hour and then allowed to reach room temperature and stirred for 2.5 hours. Hydrochloric acid in methanol (1.25 M, 28.4 mL, 35.4 mmol) was added and the reaction was stirred for 1 hour. Silica powder was added and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% 0.1M NH3 in methanol in DCM) to afford the title compound (3.04 g, 89%).
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20](=[O:22])[CH3:21]>O1CCOCC1>[C:1]1([N:7]2[C:19]([C:20](=[O:22])[CH3:21])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC=NNc1ccccc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccnn1-c1ccccc1
Yield: 34.7 %

Procedure:
To a mixture of 2-(phenylhydrazono)ethanal (3.10 g) (Journal of Chemical Society, Perkin Trans. 1, 1981, 503-513.), potassium carbonate (4.40 g) and dioxane (20.0 mL) was added 1-chloropropan-2-one (2.10 g) at room temperature, and the mixture was heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (1.35 g).
Reaction SMILES: [CH3:1][S:2][CH3:3].[Na].[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:9]([NH:11][C:12]1([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]2C[O:23]2)[C:13]1=[O:25])=[O:10]>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:9]([NH:11][C:12]1([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH:22]([OH:23])[CH2:1][S:2][CH3:3])[C:13]1=[O:25])=[O:10]
Reactant: CSC
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC2CO2)c2ccccc21
Agent: [Na]
Solvent: CCO
Product: CSCC(O)CN1C(=O)C(CCC(=O)O)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
12 ml of an aqueous 15% sodium methyl sulfide solution was added to 24 ml of an ethanol solution of 1.635 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(2-oxiranylmethyl)-2-oxo-1H-indol-3-yl]propionate. The mixture was stirred at 50° C. for 3 hours. The reaction mixture was concentrated, made acidic with aqueous 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried, filtered and then concentrated. The residue was purified by silica gel column chromatography [chloroform-methanol (10:1)] and recrystallized from ethyl acetate-hexane to afford 1.52 g of 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylthio-2-hydroxypropyl)-2-oxo-1H-indol-3-yl]propionic acid as colorless needles. Melting point: 168.5° to 169.5° C., IR (Nujol) (cm-1): 3400, 3300, 1710, 1650, 1615, FAB-MS (m/z): 499 & 497 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1>[Pd].CO.C(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1
Reactant: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NCCc1ccc(O)cc1-c1ccccc1
Reaction time: 12 h
Yield: 71.4 %

Procedure:
Palladium on carbon (10%, 5 mg) was added to 8a (120 mg, 0.35 mmol) in degassed MeOH (3.5 mL) and the solution was placed under an atmosphere of H2. After 12 h, the solution was diluted with DCM and filtered through Celite. The eluent was concentrated to afford a yellow solid, which was purified by column chromatography (SiO2, 100:5, DCM:MeOH) to afford phenol 9a (64 mg, 0.25 mmol, 79%) as a pale yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.25-7.14 (m, 5H), 7.11-7.05 (m, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H), 5.61 (t, J=5.5 Hz, 1H), 3.12-3.02 (m, 2H), 2.55 (t, J=7.1 Hz, 2H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 155.2, 143.4, 141.6, 130.8, 129.1, 128.4, 127.2, 127.2, 117.4, 115.0, 41.1, 31.8, 23.2; HRMS m/z: [M+Na+] for C16H17NO2Na, calcd, 278.1151. found, 278.1155.
Reaction SMILES: Br[C:2]1[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.C([Sn](CCCC)(CCCC)[C:42]1[O:43][CH:44]=[CH:45][N:46]=1)CCC.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[N:3]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:2]([C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncco3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (102.9 mg, 0.177 mmol) synthesized in Example (13c) was dissolved in toluene (5 mL), and 2-(tri-n-butylstannyl)oxazole (133.7 mg, 0.373 mmol) and tetrakis(triphenylphosphine) palladium (20.5 mg, 0.0177 mmol) was added, followed by heating to reflux for 18 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added thereto, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=35%-55%) to afford t-butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-5-(1,3-oxazol-2-yl)-1H-pyrrole-1-carboxylate.
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]2=[O:22].BrCCCCC.Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>>[F:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[C:18](=[O:21])[C:17]2=[O:22]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 1A, and making tnon-critical variations to replace 4-bromoindole with 7-fluoroisatin, and 1-bromopentane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (34%): MS (ES+) m/z 336.2 (M+23).
Reaction SMILES: O[CH:2]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH:2]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)OCC(O)CNC(=O)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OCC(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.28 g of racemic benzyl (2-hydroxy-3-isopropoxypropyl)carbamate (4.79 mmol, 1 equivalent), 0.85 g of phthalimide (5.75 mmol, 1.2 equivalents) and 1.88 g of triphenylphosphine (7.2 mmol, 1.5 equivalent) were initially charged in 20 ml of dry tetrahydrofuran. 1.42 ml of diisopropyl azodicarboxylate (7.2 mmol, 1.5 equivalent) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 2.3 g (66% pure; 78% of theory) of the title compound (contaminated with diisopropyl hydrazine-1,2-dicarboxylate).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][S:8][CH2:9]Cl.C(N(CC)CC)C>>[C:1]([O:6][CH2:7][S:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CSCOC(=O)C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting isobutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 64° C./12 mm Hg, n20 1.4470.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)[CH3:15]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2)[CH3:15]
Reactant: CCc1ccccc1B(O)O
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1cccc2[nH]c(C(=O)O)cc12

Procedure:
To a mixture of 0.28 g of 4-bromo-indole-2-carboxylic acid and 0.069 g of tetrakistriphenylphosphinepalladium in 11 ml of toluene and 2 ml of 2M soda is added a solution of 0.300 g of 2-ethylphenylboronic acid in 3 ml of ethanol. This mixture is refluxed for 16 h, filtered and the aqueous phase acidified with 2N HCl and extracted with ethyl acetate. Concentration of the organic phase gives the product as a brownish powder, m.p. 230-233°, sufficiently pure for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NC2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (150 mg, 0.37 mmol) was dissolved in methylene chloride (3 ml) at 0° C., and triethyl amine (0.05 ml, 1.11 mmol) and cyclopropyl amine (0.03 ml, 0.56 mmol) were slowly added thereto. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and filtrated with magnesium sulfate. The crude solution was evaporated and dried under a reduced pressure, to obtain 5-(4-chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, which are not further purified. The resulting product was dissolved in benzene (3 ml), and phosphorus pentachloride (85 mg, 0.41 mmol) was added thereto at room temperature. The solution was stirred for 20 minutes, hydroazoic acid (1.0 ml, 2.0 M solution in benzene) was added thereto and maintained room temperature for overnight. For completion of the reaction, reaction solution was refluxed for 10 minutes and purified by reverse phase preparative HPLC, to obtain the title compound (83 mg, 50%) as white solid.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C=O.[C:36]([BH3-])#N.[Na+].O>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][N:30]([CH3:36])[CH2:29][CH2:28]5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:10]([F:33])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC(n2cc(-c3ccc4ncc(Cc5c(F)cc6ncccc6c5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,7-Difluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 245, 40 mg, 0.090 mmol) was dissolved in MeOH (1.5 mL) with formaldehyde (0.034 mL, 0.449 mmol) and sodium cyanoborohydride (33.2 mg, 0.449 mmol). The RM was stirred at rt for 2 h. Water was added and it was extracted with EtOAc twice. Combined organic layers were washed with brine and dried over Na2SO4, filtered and the solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound (tR 0.8 min (conditions 2), MH+=460).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.N1[CH2:41][CH:40](C2C=CC3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)[CH2:39]1.C(NC(=O)CCl)(C)C>>[CH:40]([NH:30][C:28](=[O:29])[CH2:27][N:25]1[CH2:24][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:26]1)([CH3:41])[CH3:39]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: CC(C)NC(=O)CCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CN1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure of 319, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) and N-isopropyl-2-chloroacetamide gave 470 isolated as a yellow solid (91 mg, 26%). LCMS: RT=3.31 min, [M+H]+=467. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1 H, d, J=8.18 Hz), 8.05 (1 H, s), 7.40 (1 H, d, J=8.06 Hz), 7.17 (1 H, dd, J=8.24, 1.83 Hz), 6.99 (1 H, d, J=1.78 Hz), 5.83-5.73 (1 H, m), 4.35-4.29 (2 H, m), 3.86-3.80 (1 H, m), 3.69-3.58 (3 H, m), 3.41-3.35 (2 H, m), 3.18 (2 H, d, J=6.73 Hz), 3.00 (2 H, s), 1.50 (6H, d, J=6.59 Hz), 1.03 (6 H, d, J=6.59 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1([CH2:38][OH:39])[CH2:37][CH2:36]1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:39][CH2:38][C:35]1([NH:34][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: NC1(CO)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added (1-aminocyclopropyl)methanol (59 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 25% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-(hydroxymethyl)cyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 8.1%) as a yellow solid. MS: (M+H)+=363; 1H NMR (300 MHz, DMSO): δ 13.36 (s, 1H), 12.81 (s, 1H), 9.16 (s, 1H), 8.75 (s, 1H), 8.40-8.38 (m, 2H), 7.43 (s, 1H), 7.16 (d, 1H, J=8.7 Hz), 4.89 (brs, 1H), 3.59 (brs, 2H), 2.54 (s, 3H), 0.92-0.83 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([O:25][CH3:26])=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[C:13]([O:25][CH3:26])=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a solution of ethyl 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxyphenyl)propanoate (450 mg) in methanol (4.0 mL) and THF (8.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature 15 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (275 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO.Cl>O>[Br:8][C:6]1[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:2]([O:22][CH3:21])[CH:7]=1
Reactant: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Yield: 95.3 %

Procedure:
A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800 mL), and the pH adjusted to 2 by the addition of conc. HCl. The resulting mixture was extracted with CH2Cl2 (3×150 mL). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated to give a nearly colorless oil (20.5 g) which slowly solidified upon standing. This was recrystallized from methanol (125 mL)/water (40 mL) to give the desired acid 16 (11.6 g), m.p. 134-135° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.10 g, 0.40 mmol), 2-chloro-5-fluoro-pyrimidine (0.053 g, 0.40 mmol) and triethylamine (0.11 mL, 0.81 mmol) in DMF (0.5 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2:1-20 IPA:89-70 hexane) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):345.29