Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:8]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28](F)=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH:12]1[CH3:38])(=[O:10])[CH3:9].O>CS(C)=O.C(O)(=O)C>[C:8]([N:11]1[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH3:38])(=[O:10])[CH3:9]
Reactant: COc1cc(F)cc2nc(-c3ccc(N4CC(C)N(C(C)=O)C(C)C4)cc3)[nH]c(=O)c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxy-ethanol (1.00 g, 13.4 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.50 g, 12.5 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.57 g, 1.34 mmol) and the reaction mixture was stirred at 85° C. for 24 hours. Water was added. The mixture was acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol in dichloromethane). The resulting mixture was purified by preparative HPLC to obtain the title compound as a white solid. Yield: 0.140 g (23.2%). MP 225-227° C. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.50 (bs, 1H), 4.23 (m, 2H), 4.14 (bs, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H), 2.99 (bs, 2H), 2.07 (s, 3H), 1.25 (bs, 6H). MS (ES) m/z: 481.11 (M++1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([F:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[C:9]([F:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:22][CH:23]=1)=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Br)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of oxalyl chloride (0.657 mL, 7.50 mmol) in DCM (10 mL) and of DMF (0.01 mL) were added to a suspension of 3-bromo-2-fluorobenzoic acid (1.095 g, 5 mmol) in DCM (10 mL) and the RM was stirred for at RT for 2 h. The solvent was evaporated off under reduced pressure. The residue was dissolved in DCE (10 mL), treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.744 mL, 5.50 mmol) and DIPEA (1.747 mL, 10.00 mmol) and the RM was stirred for at RT for 1 h. The RM was treated with an aq. NaHCO3 and extracted with DCM. The combined extracts were washed with water, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 100 g, n-hexane/EtOAc 2:1) to afford the title compound as beige crystals. UPLC-MS (Condition 2) tR=1.22 min, m/z=375.9/378.0 [M−H−]−.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH2:24][CH3:25])[CH:22]=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.Cl.CCOCC>S(Cl)(Cl)=O.CO>[CH2:24]([N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:29][CH:26]4[CH2:28][CH2:27]4)=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[CH:22]1)[CH3:25]
Reactant: NC1CC1
Reactant: O=S(=O)(O)Cl
Reactant: CCn1cncc1-c1ccnc(Nc2ccccc2)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCn1cncc1-c1ccnc(Nc2ccc(S(=O)(=O)NC3CC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Chlorosulphonic acid (250 μl, 3.6 mmol) was added dropwise to solution of 2-anilino-4-(1-ethylimidazol-5-yl)pyrimidine (Method 32; 250 mg, 0.9 mmol) in thionyl chloride (5 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclopropylamine (1 ml, 13.5 mmol) in MeOH (4ml) added. The mixture was stirred for 15 minutes and the volatiles were evaporated in vacuo. Water (20ml) was added and the resultant solid was washed with water (2×10 ml), ether (2×10 ml) and dried under vacuum at 60° C. for 18 hr. The resultant solid was dissolved in MeOH (4 ml) and treated with 1M HCl in ether (0.62 ml, 0.62 mmol). The solvent was evaporated in vacuo and the resultant solid triturated with ether, collected by filtration and dried under vacuum at 60° C. to yield the title compound (220 mg, 56%) as a golden solid. NMR: 0.34 (m, 2H), 0.52 (m, 2H), 1.52 (t, 3H), 2.21 (m, 1H), 4.77 (q, 2H), 7.43 (d, 1H), 7.74 (m, 3H), 7.93 (d, 2H), 8.54 (s, 1H), 8.72 (d, 1H), 9.41 (s, 1H), 10.20 (brs, 1H); m/z 385.
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][CH2:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:28]>C(OCC)(=O)C>[Br-:25].[O:28]=[C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH2:26][N+:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:12]2
Reactant: O=C(CBr)c1nccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCC1)C2)c1nccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
(R)-Quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (120 mg, 0.36 mmol) was dissolved in ethyl acetate (3.65 ml) and 2-bromo-1-(thiazol-2-yl)ethanone (83 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain (3R)-1-(2-oxo-2-(thiazol-2-yl)ethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (125 mg, 0.234 mmol, 64.0% yield) pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:41])[CH2:32][O:33][C:34]([N:36]6[CH:40]=[CH:39][N:38]=[CH:37]6)=[O:35])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:42])[C@H:20]4[O:43][C:44](=[O:46])[CH3:45])=[O:17])[CH2:15][C@@:7]3([OH:47])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:48]1(N)[C:53](F)=[C:52](F)[C:51](F)=[C:50](N)[C:49]=1F.Cl.Cl.N1C=C[CH:65]=[CH:64][CH:63]=1>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@@H:24]([CH:31]([CH3:41])[CH2:32][O:33][C:34]([NH:36][CH2:40][CH2:39][NH:38][C:37]6[C:53]7[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=7)[CH:65]=[CH:64][CH:63]=6)=[O:35])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:42])[C@H:20]4[O:43][C:44](=[O:46])[CH3:45])=[O:17])[CH2:15][C@@:7]3([OH:47])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)COC(=O)n3ccnc3)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@@H](C(C)COC(=O)NCCNc3cccc4ccccc34)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 48 h

Procedure:
To (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-{2-[(1H-imidazol-1-ylcarbonyl)oxy]-1-methylethyl}-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 143, 80 mg, 0.12 mmol) in pyridine (5 ml) was added 4-dimethylaminopyridine (16 mg, 0.13 mmol) followed by N-1-naphthyethylenediamine dihydrochloride salt (32 mg, 0.12 mmol). After stirring the reaction mixture for 48 h, the reaction mixture was concentrated in vacuo and purified by flash chromatography eluting with hexane ethyl acetate (2:1 and then 1:1) to give the pure title compound.
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.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[CH2:22][CH2:21][NH:20]1.[CH2:38](N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:38])=[C:4]([N:20]2[CH2:21][CH2:22][C:23]3[C:28](=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH:19]2[CH2:18][C:17]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:15]([O:14][CH3:13])[CH:16]=2)[N:3]=1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2c2nc(Cl)nc3c2ncn3C)cc1OC
Yield: 45.8 %

Procedure:
Using the procedure of Preparation D, 2.01 g of 2,6-dichloropurine, 3.76 g of 1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline hydrochloride and 4 g of triethylamine in 20 ml of methylene chloride gave 2.31 g of the titled product.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[S:26])[CH:21]=[CH:22][CH:23]=1>C1C=CC=CC=1.CCCCCC>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCC(=N)N
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
Following a procedure similar to that described in Example 42 and using 3.4 g. sodium in 350 ml. dry acetone, 24.7 g. heptanamidine hydrochloride, and 30.4 g. 3-(trifluoromethyl)phenyl isothiocyanate [b.p. 50°-52°C./0.05-0.08 mm.; prepared from 3-(trifluoromethyl)aniline] in 150 ml. dry acetone there was obtained 1-[3-(trifluoromethyl)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 105°-107°C. (from benzene-n-hexane); hydrochloride (34.4 g.), m.p. 154°-155°C. (from acetonitrile).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4].Cl.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:25][CH2:26]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3ccncc3)CC1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
Compound 24 (42.0 mg, 0.101 mmol) obtained in Example 24, and 4-chloropyridine.hydrochloride (22.6 mg, 0.151 mmol) were dissolved in ethanol (0.5 mL), and the mixture was stirred at 140° C. for 2 hours under microwave (CEM; Discover, 300 watts) irradiation after adding triethylamine (140 μL, 1.01 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography, and crystallized from diisopropylether to give the title compound (Compound 25) (17.0 mg, 40%).
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.[CH3:7][C@@H:8]1[CH2:13][C:12](=O)[CH2:11][C@H:10]([CH3:15])[O:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:7][C@@H:8]1[CH2:13][CH:12]([NH:6][C:5]2[NH:1][N:2]=[CH:3][N:4]=2)[CH2:11][C@H:10]([CH3:15])[O:9]1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Reactant: Nc1ncn[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CC(Nc2ncn[nH]2)C[C@H](C)O1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (1.6 g, 49%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH:19][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:14][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: NCCOc1ccc(Oc2cccc(Cl)c2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
With stirring, a solution of 13 g of ethyl chloroformate in 20 ml of toluene is added dropwise to a solution of 24.8 g of 2-[4-(3-chlorophenoxy)phenoxy]ethylamine and 16.8 g ethyl diisopropylamine in 150 ml of toluene, and the mixture is thereafter stirred for 15 hours at this temperature. After cooling to room temperature, the reaction mixture is washed in succession with water, 1N hydrochloric acid and, finally, with a solution of sodium chloride and dried over sodium sulfate. The solvent is removed by vacuum distillation and the crude product is further purified by chromatography over silica gel with a 1:3 mixture of diethyl ether/hexane, affording the pure ethyl 2-[4-(3-chlorophenoxy)phenoxy]ethylcarbamate of m.p. 45°-46° C. The product so obtained is identical with that obtained in Example 1A.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]2[CH2:50][CH2:49]2)[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]2[CH2:49][CH2:50]2)[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C2CC2)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C2CC2)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 155.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-2-cyclopropyl-1-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.63 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from dichloromethane and diisopropyl ether to give the title compound (1.3 g, 97%) as a colorless solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[NH2:13]C(N)=O.CN(C)C=O.N>CO.O>[NH:6]1[C:7]2[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2](=[O:3])[NH:13][C:5]1=[O:4]
Reactant: NC(N)=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)c2ccccc2[nH]1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
978 g of isatoic acid anhydride were added in portions with stirring at 150° C. to a mixture of 720 g of urea and 1 liter of dimethylformamide and the mixture was then heated at 180° C. until evolution of ammonia ceased. The mixture was cooled and one liter of water was immediately added thereto followed by the addition of one liter of methanol. The warm mixture was stirred for one hour and was then filtered. The product was rinsed with warm water and with methanol and was then added with stirring to 2-3 volumes of warm dimethylformamide. The mixture was filtered and the product was rinsed with methanol to obtain 747 g of quinazoline-2,4-dione.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:6][CH:7]=1.[CH:22]1[CH:27]=[CH:26][C:25]([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>CC#N>[Br-:1].[CH2:14]([O:13][C:11]([CH2:10][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:5]1[O:6][CH:7]=[C:3]([CH2:2][P+:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=2)[N:4]=1)=[O:12])[CH3:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CC(Cc1nc(CBr)co1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)CC(Cc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)co1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A solution of ethyl (±)-4-(4-bromomethyl-1,3-oxazol-2-yl)-3-phenylbutanoate (1.0 g, 2.84 mmole) and PPh3 (745 mg, 2.84 mmole) in dry CH3CN (10 mL) was heated at reflux under N2. After 3 hr, the mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with Et2O (10 mL) to give the title compound (1.66 g, 95%) as a white powder: MS (ES) m/e 535 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
(±) cis-2-Ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.2 g, 10.8 mmol), 4-benzyloxyphenol (2.17 g, 10.8 mmol), p-toluenesulfonic acid (40 mg) were dissolved in toluene (50 ml) and heated at 60° C. for 5 h, then 2 h at reflux under nitrogen. On cooling, the reaction mixture was diluted with diethyl ether (150 ml) and washed sequentially with 10% aq. sodium hydroxide, water and brine. After drying over sodium sulfate, solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (1.17 g) as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6](O)=[O:7])=[C:4]([Cl:12])[CH:3]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([Cl:15])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1c(Cl)cc(Br)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 103.1 %

Procedure:
A solution of 4-bromo-2,6-dichlorobenzoic acid (2 g, 7.4 mmol), and thionyl chloride (5.5 mL, 74 mmol) in dichloromethane (30 mL) was heated under refluxed for 5 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting mass was taken up in dichloromethane (20 mL) and concentrated under vacuum. The process was repeated 2-3 times to remove excess thionyl chloride. 4-Bromo-2,6-dichlorobenzoyl chloride (2.2 g, 100%) thus formed was used as such for the next step.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:74])[C@@H:22]([NH:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[CH2:45]([NH:44][C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:21](=[O:74])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (14R,18R)-18-(decylcarbamoyloxy)-13,21-dioxo-14-palmitamido-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid diethyl ester (1 eq) in DCM (0.1 M) was stirred at 0° C. Trimethylsilyl bromide (10 eq) was added and allowed to warm to room temperature. The reaction was then heated to 32° C. and stirred overnight. The reaction was then diluted with DCM and concentrated with a stream of nitrogen then purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM with 0.5% AcOH to afford (14R,18R)-18-(decylcarbamoyloxy)-13,21-dioxo-14-palmitamido-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid as a colorless oil. 1H NMR (DMSO-d6): δ 7.32 (t, 1H), 6.65 (t, 1H), 5.63 (t, 1H), 5.24 (t, 1H), 5.16 (t, 1H), 4.68 (m, 1H), 4.48 (m, 1H), 3.46-3.78 (m, 15H), 3.17 (m, 4H), 2.75-2.95 (m, 4H), 2.15-2.35 (m, 4H), 1.56 (m, 4H), 1.49 (m, 4H), 1.20-1.45 (m, 52H), 0.87 (t, 9H). LRMS [M+H]=1039.7.