Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([Cl:20])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
Reactant: COc1ccc(B(O)O)cc1Cl
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(N)nc(N)c3n2)cc1Cl
Yield: 38.7 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (464 mg, 2.37 mmole), K2CO3 (1332 mg, 9.64 mmole), 3-chloro-4-methoxyphenyl boronic acid (907 mg, 4.86 mmole) in 1,4-dioxane (35.5 ml) and water (7 ml) was purged with a stream of nitrogen for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.24 mmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 4 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel flash chromatography, using methanol and 1% Et3N in CH2Cl2 as eluent, gradually increasing the methanol concentrations from 5% to 10%, to afford the pure title compound (277 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 302 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([Cl:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[N:5]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Temperature: 85 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
To a solution of 4-amino-2,6-dichloropyridine (1.0 g, 6.1 mmol), 5-chloro-2-methoxy-phenylboronic acid (1.4 g, 7.3 mmol) and palladium acetate (137 mg, 0.61 mmol) in ethylene glycol dimethyl ether (50 ml), degassed with argon, was added a solution of cesium fluoride (3.8 g, 24.4 mmol) in water (10 ml) followed by triphenylphosphine (320 mg, 1.22 mmol). After stirring at 85° C. for 12 hours, the mixture was filtered through a pad of celite under suction. The filtrate was dried over sodium sulfate and purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4 followed by 2:5) to provide 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine (720 mg, 44% yield). 1H NMR (acetone-d6) δ 3.91 (s, 3H, CH3), 5.92 (s, 2H, NH2), 6.60 (d, 1H, J=1.8 Hz, Ar), 7.14 (d, 1H, J=8.8 Hz, Ar), 7.33 (d, 1H, J=1.9 Hz, Ar), 7.37 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.90 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23](Cl)=[O:24])=[N:21][CH:22]=4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][NH2:27]>ClCCl>[CH3:26][NH:27][C:23]([C:20]1[CH:19]=[N:18][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[CH:22][N:21]=1)=[O:24]
Reactant: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 123, step 1 (1.59 mmol) in dry dichloromethane (10 ml) was treated with methylamine (5 ml, 10 mmol, 2M solution in THF) and stirred at room temperature for 18 hours. The mixture was reduced in vacuo and the resulting crude material was applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The basic fractions were then reduced and the crude product purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.2:1.8:98 and then 0.4:3.6:96) to afford the title compound (E125). 1H NMR (CDCl3) δ 8.91 (1H, d, 1.3 Hz), 8.26 (1H, d, 1.3 Hz), 7.61 (1H, br quartet, 4.8 Hz), 7.15 (1H, m), 6.92 (2H, m), 3.03 (3H, d, 5.1 Hz), 2.93 (4H, m), 2.79 (1H, m), 2.47 (4H, m), 2.08 (2H, m), 1.91 (2H, m), 1.70-1.62 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5]2[CH:8]=[C:9](Br)[CH:10]=[CH:11][C:4]=2[O:3]1.BrCCBr.[CH2:18]([O:25][C:26]([N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:29][CH:30]=[O:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:13])[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:30]([OH:31])[CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: O=CCN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc(C(O)CN(CCCCCCOCCCCc3ccccc3)C(=O)OCc3ccccc3)ccc2O1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To 0.166 g (6.83 mmol) Mg in 1 ml THF is added dropwise a few drops of a solution comprising 1.51 g (6.21 mmol) 2,2-dimethyl-6-bromobenzo-1,3-dioxane in 20 ml THF and a catalytic amount of 1,2-dibromoethane. Once the reaction has started, the remaining 2,2-dimethyl-6-bromobenzo-1,3-dioxane solution was added while maintaining the temperature at 40° C. Upon completion of the addition (15 min), the reaction is allowed to stand a further 30 min at 40° C. The mixture is then cooled to −7° C. and a solution of 2.64 g (6.21 mmol) N-benzyloxycarbonyl-N-2-oxoethyl-6-(4-phenylbutoxy)hexylamine in 5 ml THF is added thereto. After allowing the reaction to stand at 0° C. for 1 hr, the temperature of the reaction mixture is allowed to increase to room temperature, 30 ml of a saturated NH4Cl solution is added and the mixture stirred for 15 min. Finally, 30 ml AcOEt is added, the EtOAc phase is separated, washed with 30 ml H2O, dried on anhydrous Na2SO4 concentrated to dryness and the residue purified by column chromatography on silica gel (gradient CH2Cl2 to CH2Cl2/EtOAc 4:1), to give 1.50 g (40.9%) N-[2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethyl]-N-benzyloxycarbonyl-6-(4-phenylbutoxy)hexylamine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH2:30]([Sn](CCCC)(CCCC)C(C)=C)[CH2:31][CH2:32]C.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Cu](I)I>[C:31]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:32])=[CH2:30]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: I[Cu]I
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Example 9; 100 mg, 0.186 mmol), Tributyl-isopropenyl-stannane (CAS: 100073-15-2; 74 mg, 0.223 mmol), Tris(dibenzylideneacetone)dipalladium chloroform complex (15.4 mg, 0.0149 mmol), Triphenylarsine (27 mg, 0.0856 mmol), Copper iodide (3.2 mg, 0.0167 mmol) in N,N-Dimethylformamide (1 ml) was heated at 90° C. for 75 minutes. The mixture was cooled to room temperature and DMF was evaporated under high vacuum. The residue was dissolved in Ethyl acetate and 4mL of a 30% Potassium fluoride solution were added. The mixture was stirred for 30 minutes. Then the aqueous phase was separated and extracted 2 times with Ethyl acetate. The organic phases were combined, washed with water, dried with Na2SO4 ,filtered and evaporated to dryness. The so obtained residue was chromatographed over SiO2 (Heptane/EtOAc 0% to 30% over 15 minutes) to provide the title compound (59 mg, 70% as a yellow solid).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH2:19][CH2:20]Cl)[CH2:16][CH2:17]Cl.Cl.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(O)CCC>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:20][CH2:19][N:15]([CH3:14])[CH2:16][CH2:17]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCO
Product: CC(=O)N1CCc2ccc(N3CCN(C)CC3)cc21
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A stirred mixture of 1-acetyl-6-amino-2,3-dihydro-1H-indole (D10, 37.8 g, 0.22 mole), mechlorethamine hydrochloride (46 g, 0.24 mole) and anhydrous potassium carbonate (80 g, 0.58 mole) in 1-butanol (1800 ml) was heated at reflux for 8 h, then additional mechlorethamine hydrochloride (25 g, 0.13 mole) and potassium carbonate (41 g, 0.30 mole) were added and reflux continued for 3 h. The reaction mixture was allowed to cool and then washed with water (1000 ml). The aqueous wash was extracted with ethyl acetate, and the extract combined with the 1-butanol solution and concentrated in vacuo. The brown oily residue (60 g) was chromatographed on silica gel eluting with 0-8% MeOH/DCM to give an orange oil, which was trituated with ether to afford the title compound as a beige solid (12.2 g, 22%).
Reaction SMILES: Br[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:21]#[N:22])[CH2:4][C@@H:3]1[OH:23].O1C=CCCC1.C(=O)([O-])[O-].[Ca+2].[Br-].[Li+]>C1C=CC=CC=1.CC(N(C)C)=O.C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:21]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:20])[C@H:5]([CH2:4][C@H:3]([OH:23])[CH:2]=[CH:19]1)[CH2:6][CH2:7]3)#[N:22]
Reactant: C[C@]12C[C@H](Br)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: C[C@]12C=C[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Yield: 11 %

Procedure:
p-Toluenesulphonic acid (10 mg.) was added to a stirred solution of 2β-bromo-17β-cyano-3α-hydroxy-5α-androstane (2.65 g.,) and dihydropyran (10 ml.) in dry benzene (200 ml.). After 45 minutes at room temperature the solution was washed with aqueous 10% sodium bicarbonate (25 ml.) and water prior to being dried (MgSO4), filtered and evaporated to give crude 2β-bromo-17β-cyano-3α-(tetrahydropyran-2'ξ-yloxy)-5α-androstane. A mixture of calcium carbonate (15 g.), anhydrous lithium bromide (22.5 g.) and the tetrahydropyranyl derivative in dimethylacetamide (100 ml.) was stirred and heated on an oil bath (110°) for 6 hours. After cooling, the reaction mixture was diluted with chloroform and washed with water before drying (MgSO4) filtration and evaporation to a residue which was dissolved in methanol (100 ml.) and aqueous 2N hydrochloric acid (2 ml.). After 21/2 hours at room temperature and methanol was removed by evaporation and the residue dissolved in chloroform (25 ml.). This solution was washed with aqueous 10% sodium bicarbonate (25 ml.) and water (25 ml.) before drying (MgSO4), filtration and evaporation to a gum (2.55 g.). A sample (1.0 g.), after preparative TLC eluting with acetone/petrol (1:2,), afforded title compound (230 mg.,) as a white froth; [α]D 0°, (c 0.3). A sample was recrystallised from ether/petrol (x2); m.p. 129°-133°; [α]P 4°, c 0.5.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]=2[CH:11]=1.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[Br:1][CH2:9][C:10]1[CH:23]=[CH:22][C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]=2[CH:11]=1
Reactant: Cc1ccc2oc3ccccc3c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2oc2ccc(CBr)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
Benzoyl peroxide (4.6 g, 19 mmol) and N-bromosuccinimide (67.6 g, 380 mmol) were added to a mixture of 2-methyl-9H-xanthen-9-one (79.9 g, 380 mmol) and carbon tetrachloride (800 ml) with heating under reflux, and the mixture was stirred for 4 hours. After spontaneous cooling to room temperature, water was added to the reaction mixture, and the reaction product was extracted with chloroform. The extract was washed with saturated sodium bicarbonate aqueous solution, water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethyl acetate to give the title compound (78.3 g, 271 mmol, 71%) as yellow crystals.
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[CH:8][CH2:7][CH:6]=[C:5]1[O:12]C)([CH3:3])[CH3:2].Cl>CO>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[CH:8][CH2:7][CH2:6][C:5]1=[O:12])([CH3:3])[CH3:2]
Reactant: COC1=CCC=C(OC)C1C(C)C
Agent: Cl
Solvent: CO
Product: COC1=CCCC(=O)C1C(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92.9 %

Procedure:
To a solution of 6-isopropyl-1,5dimethoxy-cyclohexa-1,4-diene (7 g) in methanol (50 mL) was added 2.5% hydrochloric acid (10 mL) drop wise at 0° C. The reaction mixture was stirred for 45 minutes, then diluted with ice-cold water (30 mL). The product was extracted with ether (3×70 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo yielded the title compound as a light yellow oil (6 g, 93%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Tl+].[Sn:6](I)(I)(I)I.[Sn](Br)(Br)(Br)Br>C(OC(=O)C)(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[Sn+4:6].[C:1]([O-:4])(=[O:3])[CH3:2].[C:1]([O-:4])(=[O:3])[CH3:2].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: I[Sn](I)(I)I
Agent: Br[Sn](Br)(Br)Br
Agent: CC(=O)[O-]
Agent: [Tl+]
Solvent: CC(=O)OC(C)=O
Product: [Sn+4]

Procedure:
In order to produce tin-(IV)-acetate, expensive intermediate compounds first have to be prepared such as, for example, thallium acetate. The thallium acetate is reacted in acetic acid anhydride with tin-(IV)-iodide or tin-(IV)-bromide to obtain tin-(IV)-acetate. This procedure is exceedingly cumbersome and, from an economics point of view, requires substantial expenditure.
Reaction SMILES: [CH3:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[CH3:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Product: Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from 6-methyl-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:24][CH2:25][C:26](OC)=[O:27]>CO.C[O-].[Na+]>[Cl:24][CH2:25][C:26]([NH:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:27]
Reactant: COC(=O)CCl
Reactant: CCCCCCCCCCCCCCCCCCOCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOCCCNC(=O)CCl
Yield: 92 %

Procedure:
A four-necks-flask equipped with a stirrer, a temperature gage, a dehydrating pipe and a dropping funnel was charged with 327.6 g of 3-octadecyloxypropylamine obtained in the same manner as in Example 21, 900 g of methanol and 3.9 g of a methanol solution of 28% sodium methylate as a catalyst. 113.9 g of methyl chloroacetate was added to the mixture in one hour while the mixture was kept at 15 to 25° C. and the resulting mixture was reacted for 30 hours. After the reaction was completed, the precipitated crystal was filtered. The crystal was washed with 300 g of methanol and then dried to obtain 371.8 g of 2-chloro-N-(3-octadecyloxypropyl)-acetamide as a white powder.
Reaction SMILES: CC(C)([O-])C.[Na+].F[C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.N1C2C(=CC=CC=2)C=C1.C1(C)C=CC=CC=1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)ccn2)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Yield: 126 %

Procedure:
44.9 mg (0.2 mmol) of palladium acetate, 70 mg (0.2 mmol) of 2-(dicyclohexylphosphino)biphenyl, 1.3455 grams (14 mmol) of sodium t-butoxide, 1.1281 grams (5 mmol) of 2-(2,4-difluorophenyl)-4-chloropyridine, and 0.7029 grams (6 mmol) of indole were mixed with 60 ml of toluene and refluxed for 48 hours. Next a double portion of the catalyst package and one more portion of indole was added to the mixture to reflux for 72 hours. The reaction contents were cooled to room temperature, diluted with dichloromethane and preabsorbed onto silica and chromatographed using methylene chloride eluent to isolate 0.978 grams of yellow solid in 63% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[CH2:45][O:44][C@H:43]4[C@@H:38]([O:39][CH:40]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:41][CH2:42]4)[CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[CH2:45][O:44][C@H:43]4[C@@H:38]([O:39][CH:40]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:41][CH2:42]4)[CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(-c4ccc(C(=O)O)cc4)cc3)c(Cl)cc21
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 4′-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxylate (474 mg, 0.651 mmol) in THF (5.2 mL) under nitrogen was added a 2.5N aqueous solution of NaOH (5.2 mL, 10.4 mmol). The mixture was allowed to stir at 40° C. for 24 hours. The mixture was then cooled to room temperature and diluted with water (40 mL). The mixture was acidified with 1N aqueous HCl and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a yellow solid. LC-MS: calculated for C38H40ClN3O7Si 713.23, observed m/e: 714.21 (M+H)+ (Rt 2.85/4 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]([C@@H:8]2[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@H:10]([CH2:15][OH:16])[O:9]2)[C:4]2=[N:17][C:18]([Br:23])=[C:19]([C:20]([NH2:22])=[O:21])[C:3]=12>N1C=CC=CC=1>[C:20]([O:16][CH2:15][C@H:10]1[C@H:11]([OH:14])[C@@H:12]([OH:13])[C@@H:8]([N:5]2[C:4]3=[N:17][C:18]([Br:23])=[C:19]([C:20](=[O:21])[NH2:22])[C:3]3=[C:2]([NH2:1])[N:7]=[CH:6]2)[O:9]1)(=[O:21])[CH:19]([CH3:3])[CH3:18]
Reactant: NC(=O)c1c(Br)nc2n([C@H]3O[C@@H](CO)[C@@H](O)[C@@H]3O)cnc(N)c1-2
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@@H]1O[C@H](n2cnc(N)c3c(C(N)=O)c(Br)nc2-3)[C@H](O)[C@H]1O
Temperature: -40 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
The compound of formula 1a (452 mg, 1.16 mmol) obtained in step 3 of Example 1 was dissolved in pyridine (5.8 mL) and then temperature was lowered to −40° C. Isobutyryl anhydride (193 μl, 1.16 mmol) was added to the above solution slowly by using a syringe pump for 1 hour. The reaction mixture was stirred at −40° C. for 6 hours and then the temperature was raised to room temperature, followed by extraction with water (20 mL) and ethyl acetate (20 mL) three times. The ethyl acetate extract was washed with saturated sodium_bicarbonate solution and brine and then dried over magnesium sulfate, followed by concentration. Flash chromatography was performed to give the target compound of formula 1b (215 mg, 0.47 mmol, 40%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(CNc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c4)cc3c2c(=O)[nH]1
Yield: 101.1 %

Procedure:
A solution of diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate (2.3 g, 4.1 mmol) in ethanol (25 ml) and 0.2 N NaOH (100 ml) was stirred under nitrogen at room temperature for 3 hours. The solution was adjusted to pH 7 with 1N HCl and reduced in volume under vacuum to remove the ethanol. The product was precipitated by acidifying the solution with 1N HCl to pH 3 with stirring under nitrogen. The suspension was stirred 15 minutes, filtered under nitrogen, washed with water, pressed with a sheet of latex to remove excess water, and dried under high vacuum to give N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzo-yl)-L-glutamic acid as a white solid (2.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.82-2.12 (m, 2H, glu CH2), 2.29 (t, J=7 Hz, 2H, glu CH2), 2.43 (s, 3H, C3—CH3), 4.32-4.42 (m 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9—CH2), 6.39 (dd, J=15,2 Hz, 1H, Ar), 6.53 (dd, J=9.2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH), 7.47 (dd, J=9.9 Hz, 1H, Ar), 7.59(d, J=9 Hz, 1H, Ar), 7.61(dd, J=8, 2 Hz, 1H, Ar), 7.73 (t, J=7 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.42 (br s, 2H, CO2H's), 12.53 (s, 1H, NH). Anal. Calculated for C26H23FN4O6.3/2-H2O.1/3 NaCl: C, 56.49; H. 4.74; N, 10.14; Cl, 2.12; Na, 1.37. Found: C, 56.48; H, 4.64; N, 10.20; Cl, 2.01; Na, 1.30.