Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1cccc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 3 c], (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 3 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:51]=[CH:50][C:39]([O:40][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N:44]1([CH2:43][CH2:42][CH2:41][O:40][C:39]2[CH:50]=[CH:51][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:37][CH:38]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Reactant: CC1(C)OB(c2ccc(OCCCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccc(OCCCN4CCOCC4)cc3)c2)c1)NOC1CCCCO1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (4.6 g) and 4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-morpholine (3.9 g) are dissolved in DME (200 mL). Under an inert gas atmosphere are added are added (Ph3P)3PdCl2 (1.4 g) and 2M Na2CO3-solution (31 mL). The mixture is heated to 100° C. for 2 h. After filtration and extraction, the crude product from the organic phase is purified by silica gel flash chromatography. 4.7 g of the title compound are obtained as brownish oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:15](=[O:24])[NH:16]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:25]/[C:26]2[NH:27][CH:28]=[CH:29][C:30]=2[O:31][CH3:32])/[C:15](=[O:24])[NH:16]3)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc(O)cc3)c21
Yield: 0 %

Procedure:
Using Method S above, 4-hydroxyphenyl boronic acid (85.0 mg, 0.62 mmol) (see Gilman, supra) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 6) using DPPFPdCl2 (17 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.42 mL, 0.84 mmol) and DME (15 mL) at reflux for 1 day to give (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (yield: 11 0 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:14][C:13]([C:6]1[CH:7]=[C:8]([CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:9]([OH:11])=[O:10])=[O:15])[CH:17]=[CH2:16]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C=CCBr
Product: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (5 g) was converted to the mono allyl ester using one equivalent of allyl bromide (2 ml) using a similar method to that described in example 1. The requited acid (2.7 g) was extracted from the organic phase with aqueous NaHCO3. The organic layer contained the di-allyl ester (2.7 g). The mono acid, 3-allyloxycarbonyl-5-nitrobenzoic acid, was obtained as a white solid. Nmr (CDCl3): 4.87 (d, 2H); 5.3-5.5 (q, 2H); 5.97-6.15 (m, 1H); 9.01 (t, 3H.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].[CH3:17]O>>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:14]([O:15][CH3:17])([CH3:16])[CH2:12][CH2:13]2
Reactant: C=CC(C)=O
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CO
Product: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 3 h

Procedure:
A solution ob 304.4g. (2.0 mol) of trimethylhydroquinone in 1.2 liters of methanol and 300 ml. of trimethyl orthoformate was degassed, placed under N 2 and cooled in an ice bath to 3° centigrade. To the flask was added 5.0 ml. of concentrated aqueous sulfuric acid followed, dropwise over 3.0 hours, by 340 ml. (about 4.0 mol) of methyl vinyl ketone. The suspension was stirred without cooling for 44 hours. The mixture was worked up by extracting with diethyl ether, and washing with water, and saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was removed on a rotary evaporator at 30 to 50° centigrade to give (±)-6-hydroxy-2-methoxy-2,5,7,8-tetra-methylchroman as a light tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][C:5]=1[CH2:6][CH:7]([CH2:10][CH2:11][CH:12]=C)[C:8]#[N:9])([O-:3])=[O:2].I([O-])(=O)(=O)=[O:26].[Na+].ClCCl.[OH2:34]>C(#N)C.C(Cl)(Cl)(Cl)Cl.[Ru](Cl)(Cl)Cl>[C:8]([CH:7]([CH2:6][C:5]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:10][CH2:11][C:12]([OH:26])=[O:34])#[N:9]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: C=CCCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(CCC(=O)O)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2-(2-nitro-5-phenoxy-benzyl)-hex-5-enenitrile (1.07 g, 3.31 mmol) was dissolved in a mixture of acetonitrile (10 mL) and carbon tetrachloride (10 mL). In a separate vial sodium periodate (2.84 g, 13.28 mmol) was dissolved in water (15 mL) and this solution was added to the reaction mixture followed by ruthenium trichloride (0.021 g, 0.100 mmol). The reaction mixture was stirred vigorously for 16 h, and the next morning the reaction mixture was added to a separatory funnel with dichloromethane. The organic layer washed 3 times with 1N HCl and one time with saturated brine solution. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to yield a residue.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[S:16][CH2:17][CH:18]=[CH:19][CH2:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl.[OH:25][NH2:26]>N1C=CC=CC=1>[OH:25][N:26]=[CH:20][CH:19]1[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[S:16][CH2:17][CH2:18]1
Reactant: OCC=CCSc1cc2ccccc2n1-c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: ON=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84.7 %

Procedure:
A solution of the product of the above (2) (3.71 g) in pyridine (75 ml) is heated at 110° C. for 70 minutes. After cooling, methanol (25 ml) and hydroxyamine hydrochloride (2.2 g) are added thereto. The mixture is stirred at room temperature for 50 minutes and evaporated. The residue is acidified with ice-cooled 3 N-hydrochloric acid and extracted with chloroform. The extract is evaporated to give oily residue. The residue is chromatographed on a column of silica gel and eluted with benzene. The eluate is evaporated to give 4-hydroxyiminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (3.28 g). The product is dissolved into tetrahydrofuran (55 ml) and lithium aluminium hydride (1.4 g) is added thereto at room temperature. The mixture is refluxed for 1 hour. Ethyl acetate, an 10% aqueous solution of sodium hydroxide and water are successively added thereto. The precipitate is collected by filtration, washed with ethyl acetate and chloroform, and added to the filtrate. The organic layer is separated, washed with water, dried and evaporated to give the free base of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=O)[N:19]([CH2:23][O:24]CC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](C=O)[CH:39]=1.Cl>C1(C)C=CC=CC=1.CO>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:20]=[C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:14]=3)[NH:19][C:23]2=[O:24])[CH:39]=1
Reactant: O=Cc1cccnc1
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(-c2cnc3c(c2)C(=Cc2cccnc2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of 5-(3,4,5-trimethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (157 mg, 0.365 mmol) in toluene (2 mL) was added triethylamine (56 μl, 0.365 mmol), molecular sieves 4 Å (100 mg), and 3-pyridinecarboxaldehyde (38 μl, 0.401 mmol). The resulting mixture was stirred overnight at room temperature, after which it was filtered and partitioned between DCM and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40-70% EtOAc:Hexanes to yield the SEM-protected precursor as a mixture of cis and trans isomers (101 mg, 53%). 41 mg (0.079 mmol) of this material was dissolved in MeOH (1.5 ml), 6 N HCl (3 ml) was added, and the mixture was stirred for 3 hours at 45° C. The reaction was quenched with 1 N NaOH (15 ml), neutralized by the addition of saturated NaHCO3 and extracted with DCM. Silica gel chromatography eluting with 0-5% MeOH:DCM yielded the title compound (22 mg, 72%) as a cis/trans-mixture. 1H NMR (CDCl3, 300 MHz): δ 9.15 (d, J=4.8 Hz, 1H), 9.11 (bs, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.98 (d, J=1.1, 1H), 8.69 (dd, J=0.9, 2.9 Hz, 1H), 8.66 (dd, J=0.9, 2.8 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.95 (m, 1H), 7.93 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.44 (m, 1H), 6.75 (s, 2H), 6.59 (s, 2H), 3.97 (s, 6H), 3.91 (s, 3H), 3.90 (s, 6H), 3.86 (s, 3H).
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[Cl:27][C:28]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:32]([Cl:40])[CH:31]=[CH:30][C:29]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOCC.O>[Cl:40][C:32]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=1[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)c(CN2CCCC2)c1Cl
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CN(C[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
To a mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)amino]-methyl}cyclobutyl methanesulfonate (1.59 g, 5.42 mmol), intermediate 23, 2,4-dichloro-3-(pyrrolidin-1-ylmethyl)phenol (2 g, 8.13 mmol), and Cs2CO3 (2.65 g, 8.13 mmol) in DMSO (30 mL) was heated at 90-95° C. for 2 h under vigorous stirring in a flow of argon, and then cooled. Water (20 mL) and ether (50 mL) were added, and the layers were separated. The water layer was subjected to extraction with ether (2×50 mL). The combined organic layers were washed with water (30 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel, 63/100 μm, 50 g, CHCl3/hexane 20:80→100:0, CHCl3/MeOH 100:0→80:20) to furnish the title compound (1.7 g, 70%). LC/MS data: 443.1, 444.1, 445.1 (M+H) (calculated for C22H32Cl2N2O3 443.42). 1H NMR-data (DMSO-d6): 7.35 (d, 1H, J=9 Hz, Ar—H); 6.86 (d, 1H, J=9 Hz, Ar—H); 4.81-4.90 (m, 1H); 3.82 (brs, 2H, CH2); 3.33 (d, 2H, J=8 Hz, CH2); 2.78 (s, 3H, NCH3); 2.50-2.62 (m, 5H); 2.22-2.30 (m, 2H); 2.11-2.21 (m, 2H), 1.58-1.72 (m, 4H); 1.40 (brs, 9H, Boc).
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:23]>C(O)C>[CH3:13][O:14][C:15]1[C:16]([OH:23])=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1cccc(O)c1OC
Reactant: C=O
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)c(O)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g of 35% formalin. To the solution was dropwise added under chilling with ice a solution of 2.35 g of methyl 1-piperazinecarbodithioate in 5 ml of ethanol. The mixture was then stirred for 30 min. at room temperature. The mixture was refluxed overnight under heating after addition of a solution of 1.54 g of 2,3-dimethoxyphenol in 5 ml of ethanol under chilling with ice. The reaction mixture was cooled to room temperature. The solvent was distilledoff under reduced pressure, and the residue was purified by silica gel column chromatography. The eluate was treated with 10 ml of ethanol to obtain a crystalline product. The product was collected by filtration and washed with ethanol to give 1.76 g of the desired compound as a pale yellow crystalline product, m.p. 113° C. (decomp.), yield 51.5%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(CC)CC)C.C(C1[C:33]([OH:34])=[C:32](C(C)(C)C)[CH:31]=C(C)C=1)(C)(C)C.C(Cl)(=O)C=C>O.C(OCC)C>[C:33]([O:1][CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:34])[CH:32]=[CH2:31]
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=CC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 9-hydroxymethylanthracene (20.8 g, 0.1 mol) and triethylamine (11.1 g, 0.11 mol), containing 0.05 g of 2,6-di-tert.butyl-p-cresol, in 200 ml of freshly distilled diethyl ether was cooled with stirring to 0° C., and the temperature of the mixture was kept at about this level while acryloyl chloride (9.32 g, 0.103 mol) was added. The mixture was then warmed to refluxing temperature and heated to reflux for 2 hours. After the mixture had been cooled, 200 ml. of water was added, and the two layers were separated. The organic layer was washed twice with 50 ml portions of cold 10% sulphuric acid and then with a saturated aqueous solution of sodium bicarbonate, while the aqueous acid layer was extracted further with dichloromethane, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate. Finally, the two organic solutions were mixed, dried over anhydrous magnesium sulphate, and the solvents distilled off. There remained 11.1 g of the title compound as a yellow, semicrystalline oil. It solidified on standing and then had m.pt. 120°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:32]1[CH2:38][O:37][CH2:36][CH2:35][NH:34][CH2:33]1.Cl.O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([N:34]3[CH2:33][CH2:32][CH2:38][O:37][CH2:36][CH2:35]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: C1CNCCOC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CCCOCC3)c2CC1
Temperature: 80 °C

Procedure:
To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester, in a sealed tube in 4 mL ethanol, was added 0.2 mL (1.12 mmol) DIPEA followed by 47 mg (0.34 mmol) homomorpholine hydrochloride, and the reaction was heated at 80° C. for 16 hours. 5 mL of H2O was added and the mixture was extracted with EtOAc (2×10 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 10:0 to 6:4).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:16][CH2:17][CH2:18][N:19]([CH2:27][CH2:28]Cl)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O>[OH2:15].[ClH:16].[ClH:16].[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[CH2:27][CH2:28][N:1]([C:2]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:6]=3)([CH3:3])[CH3:4])[CH2:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(N(CCCl)CCCl)cc1
Reactant: CC(=O)NCc1ccc(C(C)(C)N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NCc1ccc(C(C)(C)N2CCN(c3ccc(F)cc3)CC2)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of N-(4-(1-amino-1-methylethyl)phenylmethyl)-acetamide (1.55 g) and N,N-di(2-chloroethyl)-4-fluoroaniline (1.5 g) in dimethyl sulfoxide (30 ml) were added potassium carbonate (3.12 g) and potassium iodide (2.50 g) and the mixture was stirred at 80° C. for 24 hr. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel chromatography (developing solvent; ethyl acetate:hexane=3:1) and treated with 1M hydrochloric acid-ether in ethanol to give the title compound (0.33 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=O)[CH:11]=1)[O:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=[C:17]([C:18](=[O:19])[CH3:20])[C:16]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=1)[O:8][C:7]([CH3:14])=[CH:6][C:5]2=[O:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cc(F)cc(C=O)c2o1
Product: CCOC(=O)C(=Cc1cc(F)cc2c(=O)cc(C)oc12)C(C)=O

Procedure:
The title compound is prepared in analogy to example 25 (stage 25a) starting from 6-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde (2.18 g, 10.62 mmol) and ethyl acetoacetate (1.33 g, 10.62 mmol). 3.30 g (98% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:11][CH3:10])=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (positive ion) m/z=202.0, 204.0 (M+H)+. Step C
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 65.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 μl, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 52 mg (64% yield) of the title compound. Purity 93%.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1)[NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1C[CH2:28][CH:27]([NH:30][C:31]2[N:32]=[CH:33][C:34]3[CH2:40][CH2:39][NH:38][CH2:37][C:35]=3[N:36]=2)[CH2:26]C1.Cl.ClC1C=C(C(C2[O:56][CH:55]=NC=2)N)C=CC=1Cl>>[Si:1]([O:8][CH2:9][CH2:10][CH:11]([NH:12][C:55]([N:38]1[CH2:39][CH2:40][C:34]2[CH:33]=[N:32][C:31]([NH:30][CH:27]([CH3:26])[CH3:28])=[N:36][C:35]=2[CH2:37]1)=[O:56])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[C:15]([F:23])[CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Reactant: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCO[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Yield: 28.1 %

Procedure:
Condensation of 278 and 72 was carried out in accord with the procedure described in step 6 of example 1 except 278 was used in place of 28 and 72 was used in place of 22. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:5) to afford 0.123 g (28.1%) of N-(3-(tert-butyldimethylsilyloxy)-1-(3-fluoro-4-(trifluoromethyl)phenyl)propyl)-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (280).