Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
A solution of 6-bromo-2-pyridinecarboxaldehyde (512 mg, 2.75 mmol) and 4-(triflouromethyl)benzeneboronic acid (522 mg, 2.75 mmol) in DME (46 mL) was treated a slurry of Na2CO3 (875 mg, 8.26 mmol) in water (23 mL) followed by Pd(PPh3)4 (64 mg, 0.06 mmol). The resulting mixture was then heated to reflux, under nitrogen over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt, was reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (100 mL), dried (MgSO4), filtered and reduced to give a yellow solid residue. Purification by SPE (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a yellow foam (565 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:27][C:26]2[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=2[O:18]1>CN(C)C=O>[O:27]1[C:26]2[CH:25]=[CH:24][C:21]([CH2:22][O:10][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=3)=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: N#Cc1ccc(O)cc1F
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccc3c(c2)OCO3)cc1F

Procedure:
A mixture of 2-fluoro-4-hydroxybenzonitrile (S. M. Kelly, Helv.Chim.Acta. 1984, Volume 67, P.1572-1579) (30 g), potassium carbonate (45.36 g) and 3,4-methylenedioxybenzyl chloride (42.65 g) in dimethylformamide (500 ml) was stirred at 90° C. for 2 hours. The reaction mixture was filtered and the filtrate evaporated. The residue was stirred with ethyl acetate (500 ml) and filtered affording the title compound (32.1 g) as a cream coloured solid, m.p. 139-140° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.C(O)(C)C>C(O)CCCC>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH:16]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCCCCO
Solvent: CC(C)O
Product: COC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 2,6-dichloropurine (17 g, 90 mmol) in 300 ml of 1-pentanol are added 37.8 g (250 mmol) of methyl-3-aminobenzoate and stirred for 8 hours at 75° C. After cooling to RT, 200 ml of isopropanol is added and the mixture is stirred for 1 h. After filtration, the precipitate is taken up into MeOH/H2O and treated with NaHCO3 to pH >8. After filtration, the product ist washed with H2O and MeOH and dried to obtain 25.4 g (93% yield) of 3-(2-chloro-9H-purin-6-yl-amino)-benzoic acid methyl ester, Rf=0.5; (CH2Cl2/MeOH (9/1)); m.p. 242° C.; ESI-MS: 304 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+−C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([CH:15](Br)[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[O:17])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:26]([NH2:28])=O>O>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[N:28]=[CH:26][O:17][C:16]=4[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1Cl)C(Br)c1cc2c(s1)-c1ncccc1OCC2
Reactant: NC=O
Solvent: O
Product: Clc1ccccc1-c1ocnc1-c1cc2c(s1)-c1ncccc1OCC2
Yield: 17.5 %

Procedure:
6,7-Dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl-(2-chlorophenyl)-2-bromoethanone from Example 37 (65.0 mg, 0.150 mmol) was suspended in formamide (2 mL, 50 mmol). The reaction was microwaved on 300 watts at 130° C. for 20 minutes. Water was added and the product was extracted with ethylacetate. The organic layer was washed with water twice and brine, dried over MgSO4, and evaporated to dryness. The crude product was purified on silica gel column, eluting with 25% of ethylacetate in hexane to give 129 (yield 10 mg, 18%). MS (ESI+) 381.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[C:10](=[O:15])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1ccc(Cl)cc1Cl
Product: CN(C)C=C1CCCC(c2ccc(Cl)cc2Cl)C1=O

Procedure:
2-(2,4-dichloro-phenyl)-cyclohexanone (101 mg, 0.42 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (105 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 298.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[Na+].NN>[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)[O-]
Agent: [Ni]
Agent: NN
Agent: [Na+]
Product: COc1cc(N)c(N)cc1C(=O)O

Procedure:
reacting the sodium 2-methoxy-4-amino-5-nitrobenzoate with hydrazine in the presence of Raney nickel to form 2-methoxy-4,5-diaminobenzoic acid;
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:6]=[CH:7][CH:8]=1>Br.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Agent: Br
Solvent: CCOC(C)=O
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
3-(3-Methoxy-phenyl)-1-methyl-azepan-2-one (as described in Step A above) (1.067 g, 4.58 mmol) was refluxed in 48% HBr (5 mL) for 1 h. The reaction was diluted with EtOAc, washed with H2O, brine, dried (MgSO4), and concentrated to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([Br:18])=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:19]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Br:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:19][C:9]=3[CH2:10][O:11]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)COc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)COc1cc(Br)ccc1-2
Temperature: 25 °C

Procedure:
The solution of 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid methyl ester (160 mg, 0.5 mmol) and sodium hydroxide (1.0 N, 1 ml, 1 mmol) in THF/MeOH (2 ml/2 ml) was heated at 50° C. for 3 hours. The mixture was cooled to 25° C. and was acidified with 2 N HCl (0.6 ml). The solvents were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid as brown powder.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@@H:8]1[C:20]([O:22]C)=[O:21].[ClH:36]>CO.O.ClCCl.CO>[ClH:36].[ClH:36].[OH:3][CH:4]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@@H:8]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CN(CCSC(C)(C)C)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC(C)(C)C)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
1 cm3 of 5N aqueous sodium hydroxide solution was added, with stirring and under an inert atmosphere, to a solution of 0.26 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(tert-butylthio)ethyl]piperidine-3-carboxylate in 5 cm3 of methanol. After heating the solution to a temperature in the region of 60° C. and then cooling to room temperature, the reaction mass was evaporated under reduced pressure (2.8 kPa) at a temperature in the region of 60° C. The residue obtained was taken up in 5 cm3 of distilled water and then 5 cm3 of concentrated hydrochloric acid (d=1.18) were added. The mixture was evaporated under reduced pressure (2.8 kPa) at a temperature in the region of 60° C. The residue obtained was taken up in 4 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. The white precipitate obtained was filtered off and washed with 2 times 2 cm3 of this same mixture. The filtrate was concentrated under reduced pressure (2.8 kPa) at a temperature in the region of 40° C. The product obtained was dried under reduced pressure (16 Pa) at a temperature in the region of 60° C. 0.29 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(tert-butylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a solid with a beige color melting with softening in the region of 169° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[CH:11]=1.CC(C)=O>O1CCCC1.[Cl-].[Na+].O>[CH3:24][N:23]([CH3:25])[C:20]1[CH:19]=[CH:18][C:17]([S:16][C:12]2[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(Sc2ccc(N(C)C)cc2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CN(C)c1ccc(Sc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of lithium aluminium hydride (61 mg, 1.1 mmol) in dry tetrahydrofuran (2 mL) at 0° C., under an argon atmosphere, was added a solution of 3-(4-dimethylamino-phenylsulfanyl)-benzoic acid methyl ester (287 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) in a dropwise manner. The mixture was stirred at room temperature for 1 hour and then cooled to 0° C. Acetone (2 mL) was added dropwise followed by brine (8 mL) to give a slurry that was filtered through a pad of celite, which was washed with ethyl acetate (3×10 mL). The organic layer was washed with brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound (255 mg, 98%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:5].C(N(CC)CC)C.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:46]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:47])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[CH3:5]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1

Procedure:
(R)-2-(2′-Ethylaminomethyl-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-propionic acid methyl ester (0.10 mmol) in CH2Cl2 was treated with triethylamine (0.03 mL, 0.20 mmol) and benzyl isocyanate (0.02 mL, 0.20 mmol) at room temperature for 2 hours. The mixture was worked up with CH2Cl2 and H2O to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[C:13]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:43][C:44]1[C:49]([NH2:50])=[C:48]2[O:51][CH2:52][O:53][C:47]2=[CH:46][CH:45]=1>C1(C)C=CC=CC=1>[Cl:43][C:44]1[C:49]([NH:50][C:15]2[C:14]3[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]=3[O:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:18]=[CH:17][N:16]=2)=[C:48]2[O:51][CH2:52][O:53][C:47]2=[CH:46][CH:45]=1
Reactant: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(=O)[nH]cnc3c2)CC1
Reactant: Nc1c(Cl)ccc2c1OCO2
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A first portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.19 g) in toluene (3 ml) was added to a stirred mixture of phosphoryl chloride (0.059 ml), diisopropylethylamine (0.13 ml) and toluene (3 ml) that was heated to 80° C. and the resultant mixture was heated to 80° C. for 6 hours. The mixture was allowed to cool to ambient temperature and was stirred overnight. The mixture was re-heated to 80° C. and a solution of 6-chloro-2,3-methylenedioxyaniline (0.088 g) in toluene (2 ml) was added. The resultant mixture was stirred and heated to 80° C. for 1.5 hours. The mixture was cooled to ambient temperature and the solvent was decanted from the oily gum that had been deposited. The oily gum was suspended in DMF (3 ml), a second portion of 7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (0.088 g) was added and the reaction mixture was heated to 100° C. for 9 hours. The mixture was allowed to cool to ambient temperature and partitioned between ethyl acetate and a 2M aqueous hydrochloric acid solution (10 ml). The aqueous solution was basified by the addition of 10M aqueous sodium hydroxide solution (10 ml) and extracted with methylene chloride. The organic solution was dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.008 g); NMR Spectrum: (DMSOd6) 1.85-1.95 (m, 2H), 2.1-2.2 (m, 2H), 2.2 (s, 3H), 2.2-2.4 (m, 4H), 2.4-2.6 (m, 4H), 2.87 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.9 (m, 2H), 4.2 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 6.85 (s, 1H), 6.9 (s, 1H), 6.95 (d, 1H), 7.05 (d, 1H), 8.35 (s, 1H), 9.2 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>CCOCC.O>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cc3)ccc21
Yield: 47.1 %

Procedure:
A suspension of 15.8 g (48 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzoic acid (Example 6) in 160 ml of absolute ether was added dropwise to a suspension of 1.9 g (49 millimoles) of lithium aluminum hydride in 150 ml of absolute ether. Thereafter, the mixture was stirred under reflux for 3 hours, after which 50 ml of ethyl acetate, 200 ml of water and 150 ml of 2N HCl were added dropwise in succession, and the phases were separated. The aqueous phase was extracted once again with ether, and the combined ether extracts were washed with water, dried over Na2SO4 and evaporated down. The oil which remained (17 g) was stirred with heptane, and the resulting crystals were filtered off under suction and dried. 7.2 g (48%) of the title compound of melting point 115°-117° C. were obtained in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32](=[O:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32]([OH:34])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (0.1350 g, 0.221 mmol) in THF (5.00 mL) was treated with sodium borohydride (0.042 g, 1.107 mmol) at 0° C. and the resulting mixture was stirred for 10 min before being allowed to warm to room temperature for 1 h. The resulting suspension was quenched with 1 N aqueous NaOH, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated to give 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol, which was used directly without further purification.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@H:7]([CH2:13][P:14](/[CH:18]=[CH:19]/[C:20]1[C:21]([CH:37]([CH3:39])[CH3:38])=[N:22][C:23]2[C:28]([C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)([O:16][CH3:17])=[O:15])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(C)C.CC(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH:37]([CH3:39])[CH3:38])[C:20]=2/[CH:19]=[CH:18]/[P:14]([O:16][CH3:17])([CH2:13][C@@H:7]([OH:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:15])=[CH:35][CH:34]=1
Reactant: COC(=O)C[C@@H](CP(=O)(/C=C/c1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)CP(=O)(/C=C/c1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of (S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoic acid, methyl ester (1.136 gm, 1.57 mmol) in THF (14 ml) was treated with HOAc (450 ul, 472 mg, 7.9 mmol) and tetra-n-butylammonium fluoride (1.0M in THF, 5.40 ml, 5.40 mmol). After stirring at room temperature for 18 hours, the solution was poured into saturated NaHCO3 and extracted with EtOAc. The EtOAc extract was washed with brine, dried (Na2SO4), filtered, and stripped to give an oil which was subsequently chromatographed (flash, Merck SiO2, 1:1 acetone:hexane). (S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (709 mg, 93%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:44]([NH2:48])(=[O:47])[CH:45]=[CH2:46]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([O:40][CH2:46][CH2:45][C:44]([NH2:48])=[O:47])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(N)=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(OCCC(N)=O)CC1

Procedure:
In a manner similar to the method described in example 177, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone (example 101) was reacted with acrylamide (Promega) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O4 [(M+H)+] 694.2922, observed 694.2918.