Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:37])([F:36])[C:24](=[O:35])[CH2:25][C:26]([CH3:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:27]>C1COCC1>[F:37][C:23]([F:22])([F:36])[C:24]([CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:35])[CH2:25][C:26]([CH3:27])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:34]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccccn1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1cc2ccccc2[nH]1)C(F)(F)F)c1ccccn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a solution of 42.4 mg (0.324 mmol, 1.5 eq.) of 2-methylindole in 2 mL of THF, 389 μL (0.972 mmol, 4.5 eq.) of n-butyl lithium (2.5 M solution in hexanes) and 648 μL (0.648 mmol, 3.0 eq.) of potassium tert-butoxide (1.0 M solution in THF) were added dropwise at −75° C. The resulting mixture was allowed to warm to −20° C. over 30 minutes. The reaction mixture was cooled to −75° C. and a solution of 50 mg (0.216 mmol) of 1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-one in 1 mL of THF was added at this temperature. The resulting mixture was stirred at this temperature for 30 minutes and then quenched with saturated NH4Cl solution. The product was extracted into ether and the ethereal layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 22 mg (28%) of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][C:11](=[O:15])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(O)C#Cc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 30 h
Yield: 30 %

Procedure:
PtCl2 (5 mol %) was added to a solution of 1-(3,4-dichlorophenyl)hex-5-en-1-yn-3-ol (2.98 g; 12.36 mmol) in toluene (65 mL) and the resulting mixture was stirred at 80° C. for 30 h until the reaction was complete by TLC. The toluene was concentrated at 45-50° C. using a rotary evaporator, and the residue was purified by flash chromatography (9:1→2:1 heptane/EtOAc) to give the desired product (895 mg; 30%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.68 (t, 1 H) 1.25-1.30 (m, 1 H) 1.90-1.99 (m, 1 H) 2.36-2.41 (d, 1 H) 2.59-2.64 (d, 1 H) 2.80-2.89 (m, 2 H) 7.00 (d, 1H) 7.25 (s, 1H) 7.37 (d, 1 H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)OCCO2
Yield: 30.3 %

Procedure:
A solution of 1,4-benzodioxan-6-amine (2.00 g, 13.2 mmol), bis-(2-choroethyl)amine hydrochloride (3.54 g, 19.8 mmol) and potassium carbonate (1.83 g, 13.2 mmol) in of 20 mL chlorobenzene is heated to reflux for 24 hours. The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (8% methanol/methylene chloride on silica) provides 0.88 g (30%) of the desired 1-(1,4-benzodioxan-6-yl) piperazine as a white solid (m.p. 138° C., TLC Rf 0.37 with 10% methanol/methylene chloride).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:28]=[C:29]([Br:32])[C:30]=1[OH:31])[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=O)[NH2:13].O.Cl>C1COCC1.CO>[NH2:13][C@H:12]([CH2:11][C:10]1[CH:28]=[C:29]([Br:32])[C:30]([OH:31])=[C:8]([Br:7])[CH:9]=1)[CH2:14][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1
Reactant: N[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N1CCC(N2CCCCC2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N[C@H](Cc1cc(Br)c(O)c(Br)c1)CN1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 400 ml of THF were added in batches, with stirring and at room temperature, 14.4 g (20 mmol) of 1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine within 30 minutes. The reaction mixture was kept for 30 minutes at room temperature and refluxed for 2 hours and then neutralised by the careful addition of 1 ml of water and 5.1 ml of concentrated aqueous hydrochloric acid. After the addition of 100 ml of methanol the solid precipitate was suction filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 5.4 g (57% of theory) of the desired product was obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[O:19][CH:20]=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[O:19][CH:20]=[CH:21][N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3ncco3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ncco3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A degassed mixture of 1-benzyl-5-chloro-2-(1,3-oxazol-2-yl)-1H-pyrrolo[3,2-b]pyridine (0.55 g, 1.8 mmol, from Step 3), di-tert-butyl hydrazine-1,2-dicarboxylate (0.50 g, 2.2 mmol, Aldrich), Cs2CO3 (0.70 g, 2.2 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.18 g, 0.24 mmol, Aldrich) in toluene (16.8 mL) was heated to 110° C. for 4 hours. Upon cooling, the reaction was partitioned between water and EtOAc. The aqueous layer was extracted with an additional two portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with 25% then 40% EtOAc in hexanes afforded purified product. Yield: (0.59 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])[N:9]([CH3:32])[C:6]2=[CH:7][N:8]=1.Br[C:34]1[N:35]=[C:36]([C@H:44]2[CH2:49][CH2:48][C@H:47]([N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[N:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=12>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:34]4[N:35]=[C:36]([C@H:44]5[CH2:45][CH2:46][C@H:47]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)[CH2:48][CH2:49]5)[N:37]5[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[C:38]=45)=[CH:17][C:16]=3[O:30][CH3:31])=[O:13])[N:9]([CH3:32])[C:6]2=[CH:7][N:8]=1
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc2cc(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n(C)c2cn1
Product: COc1cc2cc(C(=O)Nc3ccc(-c4nc([C@H]5CC[C@H](N6CCN(C)CC6)CC5)n5ccnc(C)c45)cc3OC)n(C)c2cn1

Procedure:
5-Methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (22 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (20 mg) were reacted according to the procedure described in example 4 step 4c and purified by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) to give 5-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (19 mg).
Reaction SMILES: C([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)=[O:21])[CH:11]=2)=[CH:6][C:5]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])C.C(O)(=O)C.Cl>O>[OH:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)=[O:21])[CH:11]=2)=[CH:6][C:5]=1[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31]
Reactant: CCOc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(O)c(NS(=O)(=O)c4ccccc4)c3)cc3[nH]ncc23)cs1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
N-(6-{6-(Ethyloxy)-5-[(phenylsulfonyl)amino]-3-pyridinyl}-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (24 mg) was weighed to a microwave vial and acetic acid (0.25 ml) and concentrated HCl (0.25 ml) were added. The reaction was heated under microwave irradiation for 10 min at 100° C. The reaction was cooled to RT and then heated again under microwave irradiation for 10 min at 100° C. Water was added to the reaction and the resultant precipitate was collected by filtration. The precipitate was dissolved into MeOH:DCM then evaporated to dryness. The residue was then dissolved in DMSO:MeOH (0.8 ml, 1:1, v/v) and purified by MDAP (method F) to give the title compound (6.5 mg).
Reaction SMILES: C(NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:67]=[CH:66][C:38]([C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[C:50]4[C:54](=[CH:55][CH:56]=3)[C:53](=[O:57])[N:52]([C@@H:58]([CH:63]([CH3:65])[CH3:64])[C:59]([O:61]C)=[O:60])[CH2:51]4)=[CH:44][CH:43]=2)=[O:40])=[CH:37][CH:36]=1>>[CH3:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:48]3[CH:49]=[C:50]4[C:54](=[CH:55][CH:56]=3)[C:53](=[O:57])[N:52]([C@@H:58]([CH:63]([CH3:64])[CH3:65])[C:59]([OH:61])=[O:60])[CH2:51]4)=[CH:46][CH:47]=2)=[O:40])=[CH:66][CH:67]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(OC)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Product: COc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)cc1
Yield: 79 %

Procedure:
The compound of example 311 was prepared analogous to compound of example 305 by hydrolysis of compound of example 310.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([OH:9])[CH:8]=1)[CH3:2].[CH:11](OCC)(OCC)[O:12]CC.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[C:4]=1[CH:11]=[O:12])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCc1cc(O)cc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCc1cc(O)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
To a suspension of 5-ethyl-benzene-1,3-diol (2.17 g, 15.72 mmol) and triethyl orthoformate (23.26 g, 157 mmol) in benzene (40 mL) was added AlCl3 (6.30 g, 47.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. After cooling to room temperature, the mixture was poured onto ice and acidified with HCl. The mixture was extracted with EtOAc and the organic extracts was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-ethyl-4,6-dihydroxy-benzaldehyde (1.0 g, 38%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.08 (s, 1H), 6.25 (s, 1H), 6.00 (s, 1H), 5.80 (s, 1H), 2.90 (m, 2H), 1.30 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[N:62]=[C:61]([N:63]2[CH2:68][CH2:67][O:66][CH2:65][CH2:64]2)[CH:60]=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:58]=[CH:59][CH:60]=[C:61]([N:63]3[CH2:64][CH2:65][O:66][CH2:67][CH2:68]3)[N:62]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1cccc(N2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(N2CCOCC2)n1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 45 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-(6-isocyanatopyridin-2-yl)morpholine as the starting materials in 45% yield. LCMS for C34H39ClN9O3 (M+H)+: m/z=656.2.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[N:16][NH:15][C:14]1=[S:18].[Cl:19][C:20]1[CH:47]=[CH:46][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=[C:29]3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH:35]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([C:29]2[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=2)[CH:35]=[C:26]([C:24]([C:23]2[CH:46]=[CH:47][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:17]2[N:13]([CH3:12])[C:14]([SH:18])=[N:15][N:16]=2)[CH:27]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: Cn1cn[nH]c1=S
Reactant: O=C(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25 ml) under N2 flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one (0.0024 mol) described in International Publication WO98/40383, was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.38 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH2Cl2/CH3OH/NH4OH97/3/0.1). The pure fractions were collected and the solvent was evaporated. A part of the residue (0.049 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.018 g (1%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, melting point: 193° C. (intermediate 13).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][N:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:13][CH2:12]1
Reactant: CN1CCC(O)CC1
Reactant: O=Cc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(C=O)c2)CC1
Reaction time: 3 h
Yield: 51.9 %

Procedure:
To a stirred solution of 3-hydroxybenzaldehyde (8 g, 65 mmol), 1-methyl-4-piperidinol (7.5 g, 65 mmol), triphenylphosphine (13.1 g, 65 mmol) and THF (100 ml) was added diethylazodicarboxylate (11.4 g, 65 mmol) in THF (20 ml) over a 35 minute period. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 5 days. The reaction mixture was concentrated in vacuo, and partitioned between CHCl3 (300 ml) and 3N HCl (300 ml). The aqueous layer was concentrated in vacuo, the residue was treated with 10% K2CO3 and extracted with CHCl3 (2×100 ml). The solvent was removed in vacuo to afford 7.4 g of crude 3-(1-methyl-4-piperidinyloxy)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][S-:22].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:22][CH3:21])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: C[S-]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(C=O)c2)cc1C(N)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
Under a solution of 2-aminocarbonylamino-5-(3-formylphenyl)pyrrole-3-carboxamide (Compound No. 14-2, 50 mg, 0.18 mmol) in trifluoroacetic acid (4 mL) was added to a solution of sodium methanethiolate (14 mg, 0.20 mmol) in dichloromethane (2 mL) and the mixture was stirred for 10 minutes. Moreover, borane-pyridine complex (41 μL, 0.41 mmol) was added thereto and the whole was stirred for 10 minutes. The reaction solution was concentrated in vacuo. Saturated aqueous sodium hydrogencarbonate (3 mL) and water (2 mL) were added to the residue, extracted with ethyl acetate (10 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the target compound (22 mg) as a colorless solid (Yield 39%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:34])[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[Cl:33][C:25]1[CH:24]=[C:23]([C:21]2[O:20][N:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[N:11]([CH3:34])[CH:10]=[C:9]4[C@@H:7]3[CH2:8][C@H:6]3[C:4]([OH:5])=[O:3])[N:22]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c([C@@H]5C[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
To a solution of trans-ethyl-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D64) (20 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 60° C. for 4 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford trans-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylic acid (E39) (4 mg). δH (DMSO-d6, 400 MHz): 1.31 (1H, m), 1.35 (6H, d), 1.42 (1H, m), 1.72 (1H, m), 2.48 (1H, m), 3.60 (3H, s), 4.88 (1H, m), 7.21 (2H, m), 7.45 (2H, m), 7.82 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 12.27 (1H, br s). MS (ES): C24H22ClN3O4 requires 451; found 452.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+].CO[CH2:28][CH2:29]OC>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:28]=[CH2:29])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (6 g, 17.7 mmol) in DME (100 mL) was added Pd(Ph3)4 (1.0 g, 0.9 mmol) under argon atmosphere and the mixture was stirred for 30 min at ambient temperature. After addition of vinyl boronic anhydride pyridine complex (4.3 g, 17.7 mmol), water (25 mL) and K2CO3 (2.45 g, 17.7 mmol) the reaction was heated under reflux for 7 h. The reaction mixture was concentrated in vacuo to half of the volume, quenched by addition of saturated aqueous NaHCO3 and extracted with EtOAc. After drying (Na2SO4) the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (eluent: hexane/EtOAc 9:1 to 4:1) to afford the title compound as a colorless oil. 1H-NMR (500 MHz, DMSO): δ (ppm) 7.62 (d, 1H), 7.45 (m, 1H, —NH), 7.35 (d, 1H), 6.68 (dd, 1H), 5.82 (d, 1H), 5.32 (d, 1H), 4.18 (d, 2H), 1.39 (s, 9H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][CH2:28][CH2:29]Cl>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:28][Cl:27])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Yield: 60 %

Procedure:
6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 60% yield using the method described in example 85A, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 1,2-dichloroethane in dimethylformamide. The title compound was isolated as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=CC=C(F)[C:3]=1[C:9]1[C:13](C#N)=[C:12](/C(/C(=O)C(F)(F)F)=C/N(C)C)[O:11][N:10]=1.ClC1C=C([NH:34][NH2:35])C=CC=1.CCN(C(C)C)C(C)C>C(O)C>[NH:34]1[CH:7]=[CH:2][C:3]([C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[N:35]1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C(\C(=O)C(F)(F)F)c1onc(-c2c(F)cccc2Cl)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1cc(-c2ccon2)n[nH]1
Yield: 10.6 %

Procedure:
To a solution of 0.1 g (0.2579 mmol) (Z)-3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carbonitrile in dry ethanol, 0.0462 g (0.2579 mmol) 3-Chlorophenylhydrazine and 0.78 mL (0.2579 mmol) DIPEA were added. The reaction mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo and was dried in high vacuum. Purification was achieved by using pTLC, and 0.0037 g (yield of theory: 3.0%) of the pyrazolyl-isoxazole derivative were obtained. Result of LC/MS MH+: 466.9; 1H NMR (DMSO-d6; CCl4): 7.73-7.97 (6H, m, CH-arom.), 8.04 (1H, s, CH-arom.), 8.81 (1H, s, CH-pyraz.)