Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:61]1[CH2:66][CH2:65][CH:64]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH2:63][CH2:62]1.[Li+].[Cl-]>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:61]2[CH2:66][CH2:65][CH:64]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)[CH2:63][CH2:62]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC(N2CCOCC2)CC1
Reaction time: 0.25 h

Procedure:
5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1 eq.) and BOP (1.25 eq.) were suspended in DMF (5 mL) at rt and TEA (2.4 eq.) was added. After 15 mins, to the homogenous reaction mixture was added 4-piperidin-4-yl-morpholine (1.25 eq.) all at once. After stirring for 2 days, the reaction was added to a mixture of chloroform-isopropanol (5:1) and 5% aq. LiCl. The organic layer was separated, washed with 5% aq. LiCl (2×), 1 M aq. NaOH (3×), brine, dried and concentrated. The residue was purified to give the titled compound;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:6]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5]=[CH2:6]
Reactant: COC(=O)C(C)(C)C(C)OS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: C=CC(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 130 %

Procedure:
A solution of 2,2-dimethyl-3-(toluene-4-sulfonyloxy)butyric acid methyl ester (18.06 g, 0.06 mol) in DBU (15 ml) was heated at 140-160° for 3.5 h. The mixture was allowed to cool to room temperature and was then diluted with ether. The mixture was washed with HCl (1 M), sodium bicarbonate, then brine. The ethereal layer was dried and partially evaporated to give a concentrated solution of 2,2-dimethyl-but-3-enoic acid methyl ester (10 g). (Savu and Katzenellenbogen, J Org. Chem, 46:239-250 (1981)). Further evaporation was avoided due to the volatility of the product (bp 102°). (Tsaconas et al., Aust. J Chem., 53:435-437 (2000)).
Reaction SMILES: CS(C)=O.[C:5](Cl)([C:7](Cl)=[O:8])=[O:6].[CH2:11]([O:18][CH2:19][CH2:20][CH:21]([CH2:24][CH:25]=[CH2:26])[CH2:22]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(O)CO>C(Cl)Cl.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:7][CH2:5][O:6][CH:22]1[CH:21]([CH2:20][CH2:19][O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:24][CH:25]=[CH2:26]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCC(CO)CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(CCOCc1ccccc1)C1OCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Dry DMSO (19.36 mL, 273.6 mmol) in dry CH2Cl2 (35 mL) was added dropwise to a stirred solution of 2 M (COCl)2 (68.40 mL, 136.8 mmol) at −78° C. during 15 min. The alcohol 12 (24 g, 109.44 mmol), prepared according to Example 11 , in dry dichloromethane (50 mL) was then added during 10 min, resulting in a slightly cloudy solution. This was stirred for 30 min at −78° C. and a solution of triethyl amine (79 mL, 547.2 mmol) in dichloromethane (50 mL) was then added dropwise during 15 min. The mixture was stirred for 30 min at −78° C. and 30 min at 0° C. The reaction was quenched by adding water (25 mL) with rapid stirring. The resulting slurry was immediately poured into ether (300 mL) and washed with 20% KHSO4 (2×200 mL). The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were washed with brine solution (2×100 mL), dried over MgSO4, filtered, and concentrated to afford crude aldehyde 13 (22 g) which was immediately used for protection. A stirred solution of crude 13 (22 g, 101.25 mmol), ethylene glycol (9.4 g, 151.87 mmol), and p-toluenesulfonic acid monohydrate (1 g) in dry benzene (200 mL), contained in a 500 mL round-bottom flask fitted with a Dean Stark trap, was heated at reflux for 12 h. The mixture was cooled to room temperature, the benzene layer was separated, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were dried over MgSO4 and filtered. The residue obtained on concentration was purified by column chromatography on silica gel, using ether/hexane (1:1) as eluant, to give acetal 14 (21 g, 73.5%) as an oil. IR (KBr) νmax 3066, 3030, 2927, 2881, 1642, 1457, 1400, 1365, 1208, 1156, 1100, 1028, 946, 739, 628 cm−1; 1HNMR (CDCl3) δ 1.62-1.66 (m, 1 H), 1.79-1.91 (m, 2 H), 2.08-2.11 (m, 1 H), 2.25-2.28 (m, 1 H), 3.54 (t, J=6.9 Hz, 2 H), 3.78-3.90 (m, 4 H), 4.47 (s, 2 H), 4.80 (d, J=3.8 Hz, 1 H), 4.97-5.04 (m, 2 H), 5.77-5.82 (m, 1 H), 7.23-7.34 (m, 5 H); 13CNMR (CDCl3) δ 28.55, 33.78, 38.33, 64.77, 64.86, 68.40, 72.59, 106.00, 116.04, 127.29, 127.45, 128.16, 136.66, 138.62; mass spectrum (EI), m/z (rel intensity) 262 (M+. 1.6), 171 (4.4), 156 (3.2), 149 (9), 128 (3.3), 114 (2.6), 109 (7), 105 (4.1), 99 (3.6), 92 (3.7), 91 (31), 81 (3.7), 77 (5), 73 (100), 67 (4), 65 (6).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22](=[O:55])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:37][CH:36]=1)(=[O:32])=[O:31])[CH3:20]>C1COCC1.CCOC(C)=O>[CH2:19]([O:21][C:22](=[O:55])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:39][CH:40]=1)(=[O:31])=[O:32])[CH3:20]
Reactant: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC(O)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Tetrabutylammonium fluoride (0.6 mL of a 1.0 M solution in THF, 0.6 mmol) was added to a solution of the silylether 10 (159 mg, 0.29 mmol) in THF (3.0 mL) at 23° C. The reaction was stirred for 16 h, diluted with EtOAc and washed with water. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 2:1 hex/EtOAc) afforded 118.6 mg (94%) of the alcohol 11 as a light yellow, viscous oil.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([Cl:36])[N:25]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CN(C=O)C.O>[Cl:36][C:26]1[CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:29]=[C:24]([N:7]2[C:6]3[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:22])[N:25]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2[nH]c(C(F)F)nc12
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2CCOCC2)n1
Temperature: 100 °C
Yield: 48.7 %

Procedure:
A mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 64) (3.13 g, 10 mmol), 4-(2,6-dichloro-4-pyrimidinyl)morpholine (2.64 g, 11 mmol), and powdered K2CO3 (5 g, 40 mmol) in 30 mL DMF was heated at 100° C. for 8 hrs. The mixture was cooled and diluted with water to give a precipitate which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (19:1) gave tert-butyl 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-ylcarbamate (2.49 g, 44% yield): mp (i-Pr2O) 233-236° C.; 1H NMR (CDCl3) δ 8.30 (s, 1H), 7.57 (t, JHF=53.8 Hz, 1H), 6.64 (m, 1H), 6.63 (d, J=1.8 Hz, 1H), 6.43 (s, 1H), 4.01 (s, 3H), 3.88-3.85 (m, 4H), 3.82-3.77 (m, 4H), 1.52 (s, 9H); Anal. Calcd. for C22H25ClF2N6O4: C, 51.7; H, 4.9; N, 16.45. Found: C, 52.0; H, 4.9; N, 16.6%.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH2:19][CH3:20])([CH2:16][CH:17]=[CH2:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5].C=O.[C:24]([BH3-])#N.[Na+]>C1COCC1.C(#N)C.O.C(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]([CH2:19][CH3:20])([CH2:16][CH:17]=[CH2:18])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:13][CH2:14][OH:15])[CH3:24])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CCC(CC)(C(=O)c1ccc(NCCO)cc1)N(C)C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: C=CCC(CC)(C(=O)c1ccc(N(C)CCO)cc1)N(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
In a 300 ml sulfonation under argon atmosphere, 2.90 g (10 mmol) of 2-dimethylamino-2-ethyl-1-[4-(2-hydroxy-ethylamino)-phenyl]-pent-4-en-1-one are dissolved in 55 ml THF and 137 ml acetonitrile. 4.5 ml (60 mmol) of a 37% aqueous formaldehyde solution are added over 10 min. at 25° C., followed by 2.21 g (30 mmol) of sodium cyanoborohydride. After 10 min at 25° C., the mixture is stirred at 50° C. for 4 h, cooled to room temperature and diluted with 100 ml water. The yellow semi-solid is redissolved in methylene chloride, washed with 20 ml of aq. sat. NaHCO3 and water, the organic phase dried with brine and sodium sulfate, and evaporated under vacuum to give 2.3 g (75%) of the title compound as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[C:19]([CH3:25])[C:9]=1[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11].Cl>O1CCCC1>[OH:11][CH:10]([C:9]1[C:19]([CH3:25])=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:8]=1[OH:7])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)CCCCC(=O)O)c(O)c1C
Temperature: 0 °C

Procedure:
To a well stirred suspension of lithium aluminum hydride (2 parts) in dry tetrahydrofuran (50 volume parts) was added a solution of 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the free form) in dry tetrahydrofuran (10 volume parts) at room temperature. After being stirred under reflux for 2 hours, the mixture was cooled to 0° C., acidified with cold dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to column chromatography on silica gel and eluted with carbon tetrachloride-acetone (5:1). From the 1st fraction, 6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-3 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.45 part) was obtained as colorless needles melting at 165°-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH2:18]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CN1CCCC1=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:29][CH:28]([OH:30])[CH2:27][O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: CCCCCCCCOCC1CO1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Product: CCCCCCCCOCC(O)COc1ccc(-n2nc3ccccc3n2)c(O)c1

Procedure:
A mixture of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole (7.0 grams, 0.031 mole), 3-n-octyloxy-1,2-epoxypropane (10.7 grams, 0.046 moles), N-methyl-2-pyrrolidone (40 ml) and ethyltriphenylphosphonium bromide (0.2 gram) was heated for four hours at 135°-150° C. The solvent and excess epoxide were then removed by distillation. The resulting residue was dissolved in methylene chloride, washed with hydrochloric acid, water and sodium chloride solution before passing through a silica gel column. The product was obtained as a yellow oil which crystallized on standing. Recrystallization from heptane gave the above named product with a melting point of 51°-55° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Cl)(=O)[C:2]1[CH:7]=CC=C[CH:3]=1.C(C1C2C(=CC=CC=2)C=CN=1)(C)C.O[CH2:33][NH:34][C:35](=[O:39])[CH:36]([Cl:38])[Cl:37].[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH:2]([C:1]1[C:13]2[C:12](=[C:17]([CH2:33][NH:34][C:35](=[O:39])[CH:36]([Cl:38])[Cl:37])[CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][N:9]=1)([CH3:3])[CH3:7]
Reactant: O=C(NCO)C(Cl)Cl
Reactant: O=C(NCCc1ccccc1Cl)c1ccccc1
Agent: CC(C)c1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1nccc2c(CNC(=O)C(Cl)Cl)cccc12

Procedure:
(a-2-2) Ten grams of 1-(1-benzoyloxy-1-methylethyl)-isoquinoline was dissolved in 100 ml of ethanol, and 2 g of 10% palladium-carbon was dissolved. The mixture was stirred in a stream of hydrogen at room temperature and atmospheric pressure for 24 hours. The reaction mixture was filtered through Celite, and the solvent was distilled off. Distillation under reduced pressure afforded 4.0 g of 1-isopropylisoquinoline. (b) A mixture of 9.4 g of 1-isopropylisoquinoline and 12 g of N-hydroxymethyl dichloroacetamide was dissolved in 94 g of conc. sulfuric acid and 9.5 g of 20% fuming sulfuric acid, and the solution was heated for 3 hours. The reaction mixture was poured into water, made weakly alkaline with an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-benzene to afford 20 g of 1-isopropyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 150.7° to 151.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCOCC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (5.6 g, 13.7 mmol), morpholine (12 mL, 137 mmol), copper(I) iodide (1.1 g, 5.4 mmol), N,N-dimethylglycine hydrochloride (1.5 g, 10.9 mmol) and potassium carbonate (5.7 g, 41.1 mmol) in dimethyl sulfoxide (35 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (4.5 g, 80%) as a yellow solid which was used for next step without further purification: LC/MS m/e calcd for C23H27ClN2O3 (M+H)+: 415.94, observed: 415.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@H:14]1[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]1.C12CC(C=C1)C(=O)N2>>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][C:17]([CH2:19][OH:20])=[CH:16][CH2:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: N[C@@H]1CC=C(CO)C1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=C1NC2C=CC1C2
Product: Nc1nc(Cl)c(NC=O)c(N[C@@H]2CC=C(CO)C2)n1

Procedure:
By the method of Example 7, N-2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.56 g, 52.4 mmol) was reacted with (4R)-4-amino-1-cyclopentene-1-methanol (1.4 g, 52.4 mmol), available from (−)-2-azabicyclo[2.2.1]hept-5-en-3-one (Chiroscience) by methods described in Examples 1-4 and 42 of U.S. Pat. No. 5,049,671. Crystallization from ethyl acetate—methanol gave title compound as white crystals, m.p. 148-150° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6)δ: 8.97 and 8.55 (s and d with J=11.3 Hz, total 1, NHCHO), 8.12 and 7.80 (s and d with J=11.5 Hz, total 1, CHO), 7.00 and 7.78 (both d, J=7.4 Hz, total 1, NH), 6.60 and 6.40 (both 8, total 2, NH2), 5.48 (s, 1, ═CH), 4.74 (t, J=5.5 Hz, 1, OH), 4.74-4.60 (m, 1, NCH), 4.0-3.90 (m, 2, CH2O), 2.75-2.55 and 2.40-2.15 (both m, 2 each, 2CH2); [α]58920−4.4°, [α]57820−5.2°, [α]54620−4.8°, [α]43620−20.0°, [α]36520−60.4° (c 0.25, methanol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([OH:12])=[CH:6][CH:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[N:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([O:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[N:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
Under nitrogen, to a solution of 2,3-dimethyl-5-hydroxyindole (643 mg, 4 mmol), in DMF (10 ml) was added potassium carbonate (690 mg, 5 mmol). After stirring for 15 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol), (prepared as described for the starting material in Example 1), was added. The mixture was heated at 90° C. for 2 hours followed by 30 minutes at 95° C. After cooling, the mixture was poured onto water (100 ml) cooled at 5° C. The precipitate was filtered, washed with water, followed by ether and dried under vacuum to give 7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (1.4 g, 95%).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[Li+].[CH3:9][CH:10]([N-]C(C)C)[CH3:11].C(Br)C=C>C1COCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:11][CH:10]=[CH2:9].[CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: CC(=O)CC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2,4-pentanedione (4.11 mL, 39.9 mmol) was dissolved in anhydrous THF (120 mL) and cooled to 0° C. using an ice-water bath. To the stirred THF solution, 2.2 equivalent of 2.0 M LDA (44 mL, 87.8 mmol) was slowly added. After addition was complete, the mixture was stirred at 0° C. for 20 min under argon atmosphere. Allyl bromide (3.46 mL, 39.9 mmol) was then added to the resulting pale red solution at 0° C. under argon. After removing of ice-water bath, the resulting reaction was allowed to stir for 20 min at room temperature before being quenched by saturated aqueous 1 M of HCl (aq). The reaction mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with brine, water (3×50 mL), dried over MgSO4. After filtration, the solution was concentrated, and the residue was purified by chromatography using 9:1 ratio of n-hexane:EtOAc. The product, 3, was isolated as a pale yellow oil, 1.21 g (22% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[N:10]([CH2:33][CH:34]=[CH2:35])[C:11]1[C:20](Br)=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C].[C]>C(#N)C.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]([N:10]1[C:11]2[C:20](=[C:19]3[O:18][C:17]([CH:22]([CH3:24])[CH3:23])=[C:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:15](=[O:32])[C:14]3=[CH:13][CH:12]=2)[C:34]([CH3:35])=[CH:33]1)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cn(C(=O)OCc2ccccc2)c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12

Procedure:
A mixture of allyl-[8-bromo-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl]carbamic acid benzyl ester (0.094 g, 0.166 mmol), tetrakis(triphenylphosphine)palladium (0) (0.01 g, 0.0086 mmol, 5 mol %) and cesium carbonate (0.27 g, 0.83 mmol, 5 eq.) in acetonitrile (4 ml) and methylene chloride (1 ml) is irradiated in a microwave instrument at 100° C. for 20 min. The mixture is filtered through Celite filter aid, and the pad of Celite is washed with methylene chloride, followed by ethyl acetate. The combined filtrates are evaporated in vacuo, and the residue is purified by flash chromatography (15% ethyl acetate in cyclohexane) to afford a yellow solid. LC-MS analysis suggests, that the product is a mixture of carbon-carbon double bond isomers in a 1.7:1 ratio.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:61](O)(=[O:64])[CH2:62][OH:63]>C1COCC1.CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:62](=[O:63])[CH2:61][OH:64])[CH3:2]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 48 (50 mg, 127 μmol) in THF (2 mL) and DMF (2 mL), EDC hydrochloride (27 mg, 139 μmol), HOBt (19 mg, 139 μmol), DIPEA (25 mg, 190 μmol) and glycolic acid (11 mg, 139 μmol) is added. The mixture is stirred at rt for 1 h before it is concentrated and separated by prep. HPLC to give the title compound (32 mg) as a colourless oil; LC-MS: tR=1.05 min, [M+H]+=453.08; 1H NMR (CDCl): δ1.00 (d, J=6.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.89-2.00 (m, 1H), 2.37 (s, 3H), 2.47 (s, 3H), 2.63 (d, J=7.0 Hz, 2H), 2.73 (q, J=7.5 Hz, 2H), 3.75-3.83 (m, 2H), 3.93-3.99 (m, 2H), 4.23 (s, 2H), 7.03-7.15 (m, 1H), 7.94 (s, 2H), 8.09 (s, 1H), 8.55 (s, 1H).