Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ClC(Cl)C(O)=O.[C:22]([O:30][CH2:31][C@@H:32]1[O:36][C@H:35]([N:37]2[CH:44]=[C:43]([F:45])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[C@@H:34]([OH:46])[CH2:33]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C(O)=O.[BH4-].[Na+]>C1C=CC=CC=1.CS(C)=O.N1C=CC=CC=1.C(OCC)(=O)C.CO>[C:22]([O:30][CH2:31][C@@H:32]1[O:36][C@H:35]([N:37]2[CH:44]=[C:43]([F:45])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[C@H:34]([OH:46])[CH2:33]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OC[C@H]1C[C@H](O)[C@@H](n2cc(F)c(=O)[nH]c2=O)O1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Agent: O=C(O)C(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(=O)[nH]c2=O)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Dicyclohexylcarbodiimide (DCC, 3.53 g, 17.1 mmol) and dichloroacetic acid (0.235 mL, 2.56 mmol) were added to a solution of 14 (2.00 g, 5.71 mmol) in anhydrous benzene (50 mL), DMSO (35 mL) and pyridine (0.46 mL). The resulting solution was stirred at room temperature under argon during 4 h and diluted with ethyl acetate (300 mL). Oxalic acid (1.54 g, 17.1 mmol) dissolved in methanol (4.6 mL) was added and the reaction mixture was stirred at room temperature during 1 h and then filtered to eliminate precipitated dicyclohexylurea (DCU). The filtrate was washed with brine (3×300 mL), with a saturated aqueous sodium hydrogen carbonate solution (2□ 300 mL) and fmally with water (3×200 mL) before being dried over sodium sulphate and evaporated under reduced pressure. The resulting residue was co-evaporated several times with absolute ethanol and dissolved in a mixture of absolute ethanol (31 mL) and anhydrous benzene (15 mL). The resulting solution as then cooled to 0° C. and sodium borohydride (NaBH4, 0.32 g, 8.56 mmol) was added. The reaction mixture was stirred at room temperature under argon during 1 h and diluted with ethyl acetate (300 mL) filtered. The filtrate was washed with a saturated aqueous sodium chloride solution (3×300 mL) and with water (2□ 200 mL) before being dried over sodium sulphate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-6%) in chloroform] to. give pure 15 (1.10 g, 55%), as a white foam: mp 171-172□C; UV (ethanol): λmax228 nm (ε14700) 270 nm (ε9100), λmin248 nm (ε5000); 1H NMR (DMSO-d6): δ11.8 (br s, 1H, NH), 8.0-7.5 (m, 6H, C6H5CO and H-6), 5.90 (dd, 1H, H-1′, J1′-2′=4.1 Hz and J1′-F5=1.8 Hz), 5,5 (br s, 1H, OH-2′), 4.7 (br q, 1H, H-4′J=11.7 Hz and J=7.0 Hz), 4.4-4.3 (m, 3H, H-2′, H-5′ and H-5″), 2.4 (m, 1H, H-3′), 1.9-1.8 (m, 1H, H-3″); MS (maxtrix GT): FAB>0 m/z 701 (2M+H)+, 351 (M+H)+, 221 (S)+, 131 (BH2)+, 105 (C6H5CO)+; FAB<0 m/z 1049 (3M-H)−, 699 (2M−H)−, 349 (M−H)−; 129 (B)−, 121 (C6H5CO2)−; [α]D20=−101 (c, 0.70 DMSO).
Reaction SMILES: COC[O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[P:16]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]=1[O:32]COC)[C:17]([CH3:20])([CH3:19])[CH3:18].C(Cl)(=O)C>C(OCC)(=O)C.CO>[OH:32][C:22]1[C:23]([C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=1[P:16]([C:6]1[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=1[OH:4])[C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: COCOc1c(P(c2cc(C)cc(C(C)(C)C)c2OCOC)C(C)(C)C)cc(C)cc1C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: Cc1cc(P(c2cc(C)cc(C(C)(C)C)c2O)C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an ethyl acetate/methanol=1/1 solution (60 mL) of bis(2-methoxymethoxy-3-tert-butyl-5-methylphenyl)(tert-butyl)phosphine (1.01 g, 2 mmol) was added acetyl chloride (0.79 g, 10.0 mmol) at room temperature, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure to quantitatively obtain bis(2-hydroxy-3-tert-butyl-5-methylphenyl)(tert-butyl)phosphine as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.C(Cl)Cl.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[CH3:18][S:19]([O:7][CH2:6][C:3]1([C:1]#[N:2])[CH2:5][CH2:4]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(CO)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(C#N)CC1

Procedure:
A mixture of 1-cyanocycloprop-1-ylmethanol (4.31 g, 44.4 mmol), obtained as in the proceeding paragraph, triethylamine (9.04 mL, 64.8 mmol) and methylene chloride (78 mL) was cooled under argon to between 0° and 5° C. and methanesulfonyl chloride (4.67 mL, 59.9 mmol) was added slowly. The mixture was cooled 3 hours with stirring at 0° to 5° C., then diluted with water and extracted with methylene chloride. The extract was washed with 5% sodium bicarbonate, dried (MgSO4) and concentrated to dryness to give 1-cyano-cycloprop-1-ylmethyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (102 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.66 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.51-7.60 (m, 7H), 8.55 (s, 1H), 8.66 (s, 1H), 9.26 (s, 1H); LC-MS (ESI) m/z 547 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[CH3:32][O:31][C:27]1[CH:26]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[C:28]=1[O:29][CH3:30])[C:23]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1)=[O:24]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OC1CCN(CCc2c[nH]c3ccccc23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)OC2CCN(CCc3c[nH]c4ccccc34)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
A mixture of 3 g. (0.013 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of 3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodium carbonate in 40 ml. of chloroform was stirred under anhydrous conditions for 24 hours. Then 0.3 g. of additional acid chloride was added and the mixture stirred another 24 hours. The mixture was treated with 50 ml. of water, stirred for 1 hour and the chloroform layer separated and dried over magnesium sulfate. Evaporation of the chloroform on a rotating evaporator gave an oil which would not crystallize.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([Cl:21])[C:18](I)=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.CN(C=O)C>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]([Cl:21])=[CH:16][C:14]=2[N:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CSc1nc2cc(I)c(Cl)cc2[nH]1)OCC
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(CSc1nc2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1)OCC
Temperature: 120 °C

Procedure:
A mixture of (6-Chloro-5-iodo-1H-benzoimidazol-2-ylsulfanylmethyl)-phosphonic acid diethyl ester (Intermediate 1, 0.4 g, 1.0 mmol), phenyl acetylene (0.26 mL, 2.0 mmol), PdCl(PPh3)2 (0.34 g, 0.050 mmol), CuI (0.018 g, 0.1 mmol), Et3N (0.96 mL, 6.94 mmol), and 10.0 mL of DMF was heated to 120° C. for 10 minutes using a microwave reactor. HPLC indicated the reaction was complete. The crude mixture was diluted with 40 mL EtOAc and washed with 3×40 mL H2O. The organic fractions were separated, combined, dried over MgSO4, and concentrated in vacuo to afford an oil. This oil was purified by MPLC to afford title compound 1-1 as clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].O=S(Cl)Cl.COC(=O)C=CC1C=CC(OC)=C(OC)C=1.[H-].C([Al+]CC(C)C)C(C)C>CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][CH2:8][OH:9]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: COC(=O)C=Cc1ccc(OC)c(OC)c1
Agent: [H-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C=CCO)cc1OC
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 0.42 g (2.0 mmol) of 3,4-dimethoxycinnamic acid in 50 ml MeOH was added SOCl2 (50 μl) and the mixture was stirred at 60° C. for 5 h. Methanol was taken to dryness and the obtained 3,4-dimethoxycinnamic acid methyl ester was reduced with 1M THF solution of diisobutylaluminum hydride (8.0 mmol) in absolute THF (50 ml) at 20° C. for 1 h. Water was added, the mixture was extracted with EtOAc, dried with MgSO4 and distilled in vacuo (Kugelrohr apparatus (Aldrich), 0.1 mm Hg, T. oven 185–190° C.) giving an off-white solid, yield 0.36 g (92%), m.p. 70–71° C. The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:28])[C:25](O)=[O:26])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(OC(C)C)(C)C>>[F:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:28])[C:25]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[O:26])[CH2:22][CH2:23]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC(C)OC(C)C
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(trifluoromethyl)-aniline and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 109-111° C. (diisopropylether)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[C:24]([O:36]CC2C=CC=CC=2)[CH:23]=1)[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:36][C:24]1[CH:23]=[C:22]([CH2:21][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])[CH:27]=[CH:26][C:25]=1[OH:28]
Reactant: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a solution of (1R,2R)-2-acetyloxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (7) (2.0 g, 3.4 mmol) in 20 mL of methanol, 10% Pd—C (100 mg) pre-mixed with 10 mL of methanol was added under nitrogen atmosphere. The nitrogen was exchanged with hydrogen and the mixture stirred under the hydrogen atmosphere at room temperature for 4 h. After filtration and washing with methanol, the filtrate was concentrated to provide 1.4 g (100% yield) of the title compound (8). 1H NMR (400 MHz, CDCl3): δ 1.14 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 2.06 (s, 3H), 2.92 (dd, J=12.8, 6.4 Hz, 1H), 2.96 (dd, J=12.8, 6.4 Hz, 1H), 4.46 (dd, J=12.4, 6.4 Hz, 1H), 4.95 (m, 2H), 5.05 (d, J=8.8 Hz, 1H, NH), 6.65 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.73 (d, J=8.0 Hz, 1H). MS (ESI) m/z 434.1 (M+Na)+ and 410.1 (M−H)−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>C1COCC1>[CH2:14]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-phenylethanol (9.09 g; 72.9 mmol) dissolved in THF (75 ml) and cooled to 0° C. is added NaH (60%; 3.5 g; 87 mmol) in portions over 10 minutes. The mixture is allowed to warm to room temperature, stirred for 45 minutes and cooled. Allyl bromide (6.3 ml; 73 mmol) is added and the mixture is brought to room temperature and stirred vigorously. The reaction mixture is heated at 45° C. for 3 hours, quenched with MeOH, diluted with Et2O, washed with H2O 3x and brine, dried (MgSO4) and concentrated to dryness. The resultant yellow oil is purified by column chromatography using 10% ether/petroleum ether to give 2-allyloxyethylbenzene as a clear oil which is used directly in Step B.
Reaction SMILES: [Li+].CCC[CH2-].[CH2:6]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[CH2:7][CH3:8].[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].CO>[Cl:14][C:15]1[N:16]=[N:17][C:18]([C:11]2[S:10][C:9]([CH2:6][CH2:7][CH3:8])=[N:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CCCc1nccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [CH2-]CCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1ncc(-c2ccc(Cl)nn2)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
N-butyllithium (2.5M in Hexanes, 1.3 mL, 3.3 mmol) was added dropwise over 2 min to a −78° C. solution of 2-propylthiazole (380 mg, 3 mmol) in THF (8 mL). After stirring for 45 min at −78° C., a solution of zinc chloride (0.5M in THF, 7 ML, 3.5 mmol) was added. The solution was stirred for 1 h, during which it warmed to rt. Tetrakis-triphenylphosphine (172 mg, 0.15 mmol) and 3,6-dichloropyridazine were added and the reaction was heated to 68° C. for 16 h. After cooling to rt, methanol (3 mL) and 2N HCl (2 mL) were added. The pH was adjusted to ˜8 with Na2CO3 and the mixture was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was washed with water (2×10 mL) and brine (20 mL) and was dried over Na2SO4. Concentration of the solution in vacuo followed by SiO2 flash chromatography yielded the product as an off-white solid (200 mg, 28%). 1H-NMR (CDCl3): δ 8.16 (1H, s), 7.77 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=8.8 Hz), 3.04 (2H, t, J=7.6 Hz), 1.89 (2H, sextet, J=7.6 Hz), 1.06 (2H, t, J=7.6 Hz). ESI-MS (m/z): Calcd. for C10H10ClN3S: 239.0/241.0; found: 240.2/242.2 (M+H; M+2+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:37][C@H:38]2[NH:42][C:41](=[O:43])[CH2:40][CH2:39]2)(=O)=O)=CC=1>CN(C=O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:37][C@H:38]5[NH:42][C:41](=[O:43])[CH2:40][CH2:39]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CCC(=O)N1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (600 mg, 1.95 mmol), (prepared as described for the starting material in Example 107), in DMF (20 ml) was added powdered potassuim carbonate (540 mg, 3.9 mmol) and (5S)-5-(p-toluene-sulphonylmethyl)-2-pyrrolidinone (580 mg, 2.16 mmol). The reaction was then heated at 100° C. for 4 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). The product was evaporated, triturated with ether, and filtered to give (5S)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (240 mg, 31%) as a white solid.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[N:12]=[CH:11][C:10]=1[C:23]#[N:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+]>CN(C)C=O>[C:23]([C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:9]=1[CH:8]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:24]
Reactant: CCOC(=O)C(Cl)Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.75 h
Yield: 54 %

Procedure:
To a stirred, slightly warmed solution of 1.4 grams (0.003 mole) of ethyl 2-chloro-3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]propionate in 25 mL of N,N-dimethylformamide was added in one portion 0.1 gram (0.004 mole) of sodium hydride. Upon completion of the addition the reaction mixture was warmed to about 60° C., where it was stirred for 1.75 hours. The reaction mixture was then allowed to cool to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was again warmed to about 60° C., where it was stirred for two hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue remaining was stirred with water for about 40 minutes, giving a solid that was collected by filtration. The solid was recrystallized from ethanol and water, yielding 0.6 gram of ethyl 3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]-acrylate, m.p. 131°-134° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].CN(C)C=O.C(Cl)(=O)C([Cl:40])=O>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([Cl:40])=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23].[Cl:29][C:30]1[N:31]=[C:32](Cl)[C:33]2[CH2:39][N:38]([CH3:40])[CH2:37][CH:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:34]=2[N:35]=1.CCN(C(C)C)C(C)C>C(#N)C.CO>[Cl:29][C:30]1[N:31]=[C:32]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:7]=2[N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[C:33]2[CH2:39][N:38]([CH3:40])[CH2:37][CH:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:34]=2[N:35]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCN)n1
Reactant: CN1Cc2c(Cl)nc(Cl)nc2C(c2ccc(F)cc2)C1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCNc2nc(Cl)nc3c2CN(C)CC3c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-1-amine, 2 TFA (46.6 mg, 0.090 mmol), 2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (20 mg, 0.064 mmol) and DIEA (55.9 μL, 0.320 mmol) in acetonitrile (320 μL) and 2 drops of MeOH was stirred at rt overnight. The crude product was purified by Prep-HPLC to obtain 2-chloro-8-(4-fluorophenyl)-6-methyl-N-(4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine, 2 TFA (43.6 mg, 82% yield). LC-MS (M+H)+=567.2. 1H NMR (500 MHz, methanol-d4) δ 9.00 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.03-7.95 (m, 2H), 7.21-7.12 (m, 2H), 7.04-6.96 (m, 2H), 4.39 (t, J=6.3 Hz, 2H), 4.00 (s, 1H), 3.60-3.52 (m, 2H), 3.42-3.23 (m, 2H), 2.94 (dd, J=11.7, 5.4 Hz, 1H), 2.68 (dd, J=11.7, 6.0 Hz, 1H), 2.48-2.39 (m, 6H), 1.99 (t, J=6.8 Hz, 2H), 1.84 (td, J=7.2, 3.4 Hz, 2H).