Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[N+:43]([O-])=O.[BH4-].[Na+]>C1C=CC=CC=1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:43][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][C:2]=1[Br:1])[CH2:6][O:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:9]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(N)c2)cc1
Reaction time: 1 h

Procedure:
The solution of 10.8 g of tert-butyl 3-(4-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 250 ml of benzene is admixed with stirring at 10° C. with the solution of 4.08 g of nickel chloride hexahydrate in 150 ml of benzene. At approx. 5° C., the mixture is admixed with 2.0 g of sodium borohydride in small portions over 1 hour. The reaction mixture is stirred for a further 1 hour, poured onto water (500 ml) and extracted with tert-butyl methyl ether (2×500 ml). The organic phases are washed successively with water (500 ml) and brine (500 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.03.
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38](OC)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:36][C@@H:37]([CH2:42][O:43][CH2:44][CH3:45])[C:38]([NH:19][C:16]4[CH:15]=[CH:14][C:13]([S:12][CH3:11])=[CH:18][N:17]=4)=[O:39])=[C:30]3[CH:29]=[N:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CSc1ccc(N)nc1
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(SC)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2M Trimethylaluminium in hexane (0.457 mL, 0.91 mmol) was added to 5-(methylthio)pyridin-2-amine (CAS no. 77618-99-6) (0.111 g, 0.79 mmol) in toluene (22 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-ethoxypropanoate (Intermediate L2) (0.300 g, 0.79 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated at reflux for 16 hours. The mixture was allowed to cool to ambient temperature and left standing for 2 days. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL) then washed with saturated brine (50 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 0 to 3% MeOH in DCM to afford the product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: CCOc1ccc2[nH]c(=O)n(-c3ccccn3)c2c1
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc([N+](=O)[O-])cc1OC
Yield: 65.1 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 37 step A) starting from 1 g of 5- ethoxy-1,3-dihydro-3-(pyrid-2-yl)-2H-benzimidazol-2-one and 1.2 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. 1.2 g of the expected product are obtained after crystallization from iso ether. M.p.=175° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH:19](=[N:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[O:8][C:4]=2[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CN1CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc(Cl)c(N=Cc4ccccc4)cc3o2)CC1

Procedure:
A 30 mg portion of 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 20 ml of anhydrous toluene, and the solution was mixed with 1 ml of benzaldehyde and heated under reflux for 6 hours. The solvent was concentrated under a reduced pressure, the residual oily matter was mixed with hexane and then the thus formed precipitate was collected by filtration to obtain the title compound (24 mg) in white color.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccc1
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:28][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([S:10](=[O:11])(=[O:12])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:22])=[CH:21][CH:20]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: COc1cccc(N)c1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3cccc(OC)c3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 3-methoxyaniline (32 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-methoxyphenyl)-4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzamide as a white solid. Yield: 70 mg (63%). 1H-NMR: 10.44 (s, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.45 (t, J=2.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 6.72 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11]OS(C)(=O)=O)=[CH:8][C:6]=2[N:7]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][S:25][C:23](=[O:26])[CH3:24])=[CH:8][C:6]=2[N:7]=1
Reactant: CC([O-])=S
Reactant: Cc1nc(N2CCOCC2)c2sc(COS(C)(=O)=O)cc2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCc1cc2nc(C)nc(N3CCOCC3)c2s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of methanesulfonic acid 2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester (300 mg) in DMF (8 mL) was added potassium thioacetate (113 mg). The reaction was stirred at 60° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give thioacetic acid S-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl) ester as an off-white solid (210 mg).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=2)[CH2:24]1)=[O:12]
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Reactant: FC(F)(F)c1ccc(C2CCCNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (44 mg, 0.22 mmol) was dissolved in DCM (4 ml). 3-(4-Trifluoromethylphenyl)piperidine HCl (51 mg, 0.19 mmol) and triethylamine were added. The mixture was stirred for 1 h, 1 M HCl (2 ml) was added, and the phases were separated. The organic phase was absorbed on silica and the mixture purified by flash chromatography using heptane/EtOAc as eluent. The fractions containing the first eluting diastereomer were collected to yield 21 mg of A11.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH3:60])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (170 mg, 0.25 mmol) is dissolved and K2CO3 (0.65 g, mmol) is suspended in DMF (30 mL). To the vigorously stirred reaction mixture a solution of 1-bromotetradecane (0.1 mL, 0.45 mmol) in DMF (10 mL) is added dropwise at 50° C. during 30 mins and the mixture is heated for 1.5 h. After evaporation of solvent, the residue is dissolved in toluene:ethanol (1:1 by vol., ca. 5 mL) and purified by chromatography using a column (5×25 cm) of silica gel (Merck 60) which is washed with toluene. After the elution of the first 3 fractions, elution is continued using toluene:ethyl acetate (2:1 by vol.). The fifth compound eluted is collected, the solvent evaporated and the residue dried under high vacuum to afford product as violet crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]([NH:17]S(C(C)(C)C)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.O1CCOCC1>CO>[NH2:17][CH:11]([C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(N)c1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 2-(2,6-dimethoxyphenyl)-2-(1,1-dimethylethylsulfinamido)-acetate (4.215 g; 12.27 mmol) in anh. MeOH (120 ml) was treated dropwise with a solution of 4 M HCl in dioxane (6.30 ml; 25.20 mmol). The resulting heterogeneous mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. Concentration to dryness under reduced pressure afforded the chlorhydrate salt of ethyl 2-amino-2-(2,6-dimethoxyphenyl)acetate as a yellow oil. LC-MS (conditions D): tR=0.66 min.; [M+H]+: 240.40 g/mol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.O.Cl.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(CCCN3CCC4(CC3)OCCO4)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 51 g of 8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1,4-dioxa-8-azaspiro[4.5]decane hydrochloride, 100 ml of water, 100 ml of ethanol and 150 ml of 3N hydrochloric acid was heated at 75°-80° C. for 3 hrs and at ambient temperature overnight, with stirring. The mixture was cooled, basified with 3N sodium hydroxide solution and extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 37 g (96%) of product as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[O:27][CH:28]=2)[N:3]=1.Cl.[NH:37]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH3:38].C(N(CC)CC)C>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:4]3[N:3]=[C:2]([N:37]([CH3:38])[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:7]([C:8]#[N:9])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:5]=3[C:20]#[N:21])[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)c1nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
230 mg (about 0.45 mmol) of the crude product from Example 50A were dissolved in 3 ml of absolute THF, and 127 mg (0.91 mmol) of methyl sarcosinate hydrochloride and 138 mg (1.36 mmol) of triethylamine were added. The reaction mixture was stirred at RT for 10 h. After removal of the solvent on a rotary evaporator, the residue was purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gave the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:10][C:6]1[NH:5][C:4](=[O:9])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: COc1ccc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxy-2(1 h)-pyridone (1.00 g, 7.99 mmol, AstaTech, Inc) in DCM (26 mL) at 0° C. was slowly added bromine (0.819 mL, 15.98 mmol). After addition, the mixture was stirred at rt for 18 h. The mixture was then cooled to 0° C. and saturated aqueous NaHCO3 (4 mL) was slowly added. The mixture was then stirred at rt for 30 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (1×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was purified by silica gel flash column chromatography (solid loading, 0%-100% EtOAc/hexane) to give the title compound as a tan solid. MS (ESI, positive ion) m/z: 204, 206 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[H-].[Na+].Cl.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47]Cl>>[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CN(C)CCCl
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OCCN(C)C
Yield: 31 %

Procedure:
The same procedure as in Example 48 was repeated, using 360 mg (0.66 mmol) of Compound 47 obtained in Example 47 and 2 equivalents of sodium hydride (60% in oil), except that 2-dimethylaminoethyl chloride hydrochloride was used in place of methyl iodide and reaction temperature was 60° C. in place of room temperature, to give 127 mg (yield: 31%) of Compound 53 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0 mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g, 53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and crystals were filtered with hexane. The filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (300 ml), and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) to give the objective substance (7.5 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:22]([O:24][C:25]([CH3:27])=[CH2:26])=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1([C:8]([NH:10][C:22](=[O:23])[O:24][C:25]([CH3:27])=[CH2:26])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=C(C)OC(=O)Cl
Reactant: COC1(C(N)=O)CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(OC)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A −78° C. solution of 1-methoxycyclopentanecarboxamide (0.9 g, 6.29 mmol) in THF (40 mL), under Ar, was treated with LiHMDS (1M in THF, 8.17 mL, 8.17 mmol), stirred for 0.5 h, treated with a solution of isopropenyl chloroformate (0.824 mL, 7.54 mmol) in THF (5 mL), stirred at −78° C. for 15 min, warmed to RT and stirred for 1 h. The mixture was treated with satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methoxycyclopentanecarbonyl)carbamate (1.5 g, 105%) which was used without further purification. MS (ESI) m/z: 228.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[CH2:15]([O:17][CH2:18][CH2:19]O)[CH3:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:16][CH2:15][O:17][CH2:18][CH3:19])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CCOCCO
Reactant: C=CCNc1cccc(CC(=O)O)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCNc1cccc(CC(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 3-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 3-(allylamino)phenylacetate.
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][NH:14][CH:3]12.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: O=C1c2ncncc2C=C2OCNC12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2ncncc2cc2ocnc12
Reaction time: 18 h
Yield: 22 %

Procedure:
A suspension of 4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98 g, 5.24 mmol) in POCl3 (30 mL) is heated under reflux with vigorous stirring for 18 h, and then concentrated to dryness. The residue is partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion is worked up to give 4-chlorooxazolo[5,4-g]quinazoline (0.24g, 22%) as a yellow solid which is used directly.