Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](O)=O.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:18]([CH2:17][O:16][C:15]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=3[Cl:13])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(COc3ccc(Cl)cc3Cl)nc2c1
Temperature: 160 °C
Yield: 72.6 %

Procedure:
A mixture of 3-amino-4-hydroxy-benzoic acid methyl ester (105.7 mg, 0.63 mmol) and 2,4-dichlorophenoxyacetic acid (100 mg, 0.45 mmol) in PPSE (1.5 mL) was heated at 160° C. for 4 h. At the end of the reaction period, the mixture was taken to 3 mL dichloromethane and neutralized with 4.5 mL 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with 3×3 mL portions of dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:hexanes=1:1) to afford 2-(2,4-dichlorophenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester as a colorless powder (0.115 g, 52% yield).
Reaction SMILES: [ClH:1].Cl[C:3]1([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:8])[C:6]([Cl:9])=[CH:5][S:4]1>C(O)(=O)C>[Cl:9][C:6]1[C:7]([OH:8])=[C:3]([C:10]([O:12][CH3:13])=[O:11])[S:4][C:5]=1[Cl:1]
Reactant: Cl
Reactant: COC(=O)C1(Cl)SC=C(Cl)C1=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(Cl)c(Cl)c1O
Reaction time: 48 h

Procedure:
Dry hydrogen chloride gas was bubbled into a solution of crude 2,4-dichloro-2-methoxycarbonylthiophen-3(2H)-one (6.8 g, 30 mmol) in acetic acid (30 ml) until saturated. The mixture was allowed to stand for 2 days, concentrated under reduced pressure and the precipitate filtered and recrystallised from methanol, m.p. 107°-108° C.
Reaction SMILES: COC(=O)C(N1C(=O)CC[N:11]([C:16](=O)/[CH:17]=[CH:18]/[C:19]2C=CC(Cl)=C(Cl)C=2)CC1)CCO.[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]3[CH2:53][CH2:52][O:51][C:50]3=[O:54])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36].N1CCCC1>CCO>[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]([C:50]([N:11]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:54])[CH2:53][CH2:52][OH:51])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: C1CCNC1
Solvent: CCO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C(CCO)C(=O)N2CCCC2)CC1
Yield: 88 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with pyrrolidine over night at RT gave 88% of the titled compound as white foam. MS: 468.1 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-methoxybenzene. Yield 19%. MS M+H calculated 396.1. found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH:10]([CH3:11])[CH3:12])[C:13](=[O:15])[O:14][CH2:16]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OC(C)(C)C

Procedure:
(4S)-N-tert-Butyloxycarbonyl4-isopropyl-1,3-oxazolidin-5-one (3) was prepared from N-tert-butyloxycarbonyl-(L)-valine (2.17 g, 10.0 mM) and para-toluenesulfonic acid (30 mg) following general procedure A and obtained as a white solid after crystallisation from chloroform (1.67 g, 73%): [a]D20 +104.9 (c 1, CHCl3); mp 43-45° C.; IR (KBr): 1795, 1705 cm-1 ; 1H NMR (200 MHz, CDCl3): 67 5.55 (br, 1H), 5.10 (d, J=4 Hz, 1H), 4.15 (d, J=4 Hz, 1H), 2.21-2.43 (m, 1H), 1.49 (s, 9H), 1.06 (d, J=7 Hz, 3H), 1.02 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): d 171.8, 152.6, 81.6, 78.4, 59.9, 31.1, 27.9, 17.9, 17.5; LRMS (NH3): 230 (MH+). Anal. Calcd for C11H19NO4 : C, 57.63; H, 8.35; N, 6.11; found: C, 57.62; H, 8.54; N, 5.93.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[NH:9][C:8](=[O:16])[NH:7][C:6]2=[O:17].CO.C(O)(=O)C>O1CCCC1.[Pd]>[NH2:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[NH:7][C:8](=[O:16])[NH:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1N
Yield: 96.5 %

Procedure:
120 mg (0.5 mmol) of 6-methoxy-7-nitro-1H-quinazoline-2,4-dione were taken up in a mixture of 5 ml of tetrahydrofuran, 5 ml of methanol and 5 ml of acetic acid and hydrogenated with palladium catalysis at room temperature for 3 hours. The reaction solution was heated to dissolve precipitated product and was filtered hot to remove the catalyst. The filtrate was concentrated and, after addition of toluene, again concentrated. 100 mg (100%) of the desired product were obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[N+:19]([O-])[CH:18]=1.[NH2:26][CH2:27][C:28]1[O:32][C:31]([C:33]2[N:34]=[C:35]([N:38]=[C:39]([NH2:41])[NH2:40])[S:36][CH:37]=2)=[CH:30][CH:29]=1.CN(C)C=[O:45]>>[NH2:40][C:39](=[N:38][C:35]1[S:36][CH:37]=[C:33]([C:31]2[O:32][C:28]([C:27]([NH:26][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)=[O:45])=[CH:29][CH:30]=2)[N:34]=1)[NH2:41]
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: CN(C)C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: NC(N)=Nc1nc(-c2ccc(C(=O)NC(=O)c3cccnc3)o2)cs1
Reaction time: 0.25 h

Procedure:
Dicyclohexylcarbodiimide (2.3 g) was added slowly to a suspension of nicotinic acid N-oxide (1.5 g) in N,N-dimethylformamide (40 ml) with cooling on an ice bath and the mixture was stirred for 15 minutes with cooling on an ice bath. To the mixture 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (2.0 g) was added with cooling on an ice bath. The mixture was stirred for an hour with cooling on an ice bath and then stirred for 41 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in water. 6N-Hydrochloric acid solution was added to the suspension and the resulting precipitate was removed by filtration. The solvent was removed under reduced pressure and the residue was dissolved in methanol. The insoluble material was removed by filtration and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1, V/V). Recrystallization from a mixture of methanol, dioxane and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-[5-(1-oxonicotinoylaminomethyl)furan-2-yl]thiazole (0.30 g).
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:11][C:3]1[C:2]([Br:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([Cl:10])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)c(C#N)cc1Br
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of compound 37 (20.5 g, 88.1 mmol), allyl bromide (11.2 mL, 132 mmol) and K2CO3 (24.4 g, 176 mmol) in acetone (440 mL) was stirred for 3 hours under reflux. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 38 (15.6 g, 65%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.O1CCOC1[CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([F:34])[C:30](F)=[N:31][CH:32]=1.CS(O[CH:40]1[CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1)(=O)=O>>[CH2:41]([N:42]1[CH2:24][CH:25]([O:26][C:27]2[CH:28]=[C:29]([F:34])[C:30]([O:18][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][N:9]=[C:8]4[NH:7][C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[N:31][CH:32]=2)[CH2:43]1)[CH3:40]
Reactant: Fc1cc(OCCC2OCCO2)cnc1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Product: CCN1CC(Oc2cnc(Oc3ccc4ncnc(Nc5ccn(C)n5)c4c3)c(F)c2)C1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol, 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2,3-difluoropyridine and tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate, and in the same manner as in Example 6-5) or according to a method similar to it or according to a combination thereof with an ordinary method, 6-({5-[(1-ethylazetidin-3-yl)oxy]-3-fluoropyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine was obtained.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CCNCC(O)c3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
4 g (20 mmol) of phenacylbromide are dissolved in 20 ml of methylene chloride and added dropwise to a solution of 4.6 g (20 mmol) of 4'-(2-aminoethyl)-4-methoxy-biphenyl and 3.45 ml (20 mmol) of N,N-diisopropyl-ethylamine and 100 ml of methylene chloride at ambient temperature. After 2 hours, 50 ml of methanol are added and, with slight cooling, 1 g (27 mmol) of sodium borohydride is added in batches. After stirring overnight the mixture is evaporated in vacuo, acidified with dilute hydrochloric acid and stirred for 30 minutes. It is then made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform evaporation residue is purified by column chromatography on silica gel (eluant: chloroform/methanol=10:1). Finally, it is recrystallised from acetonitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=CC=CC=1.[O:11]1[CH2:15][CH2:14][CH:13]([C:16](O)=[O:17])[CH2:12]1.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34](C(O)=O)=[CH:33][CH:32]=1)=[O:29]>>[O:11]1[CH2:15][CH2:14][CH:13]([C:16]([N:10]2[CH2:6][CH2:1][CH:7]([C:34]3[CH:38]=[CH:39][C:31]([NH:30][C:28]([N:20]4[CH2:19][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)=[O:29])=[CH:32][CH:33]=3)[CH2:8][CH2:9]2)=[O:17])[CH2:12]1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)C1CCOC1
Product: O=C(Nc1ccc(C2CCN(C(=O)C3CCOC3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting N-(4-(piperidin-4-yl)phenyl)isoindoline-2-carboxamide for 3-phenylpropan-1-amine and tetrahydrofuran-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.46 (m, 2H), 7.31 (m, 4H), 7.12 (m, 2H), 4.74 (bs, 4H), 4.53 (m, 1H), 4.05 (m, 1H), 3.87 (m, 1H), 3.70 (m, 3H), 3.36 (m, 2H), 3.12 (m, 1H), 2.75-2.58 (m, 1H), 2.01 (m, 2H), 1.76 (m, 2H), 1.45 (m, 2H); MS (ESI(+)) m/e 420 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.[Li+].[I:23]I.CCOC(C)=O>C1COCC1>[I:23][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Reactant: II
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 73, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium (trimethylsilyl)amide in THF (1 M in THF, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL of THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes:EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)(C)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(Cl)ncnc1Nc1ccccc1
Yield: 85.1 %

Procedure:
To a mixture of 4,6-dichloro-5-methylpyrimidine (2.27 g, 13.9 mmol) and aniline (1.0 g, 10.7 mmol) in isopropanol (15 mL) was added concentrated aqueous hydrochloric acid (1.5 mL) and heated to reflux for 2.5 h. The mixture was then concentrated and the residue triturated with ethyl acetate:isopropanol 4:1. The solid was collected by filtration and washed with additional ethyl acetate:isopropanol 4:1 then dried to give 6-chloro-5-methyl-N-phenylpyrimidin-4-amine (2.0 g, 67% yield). 1H NMR (400 MHz, d6-DMSO): 8.85 (s, 1H), 8.26 (s, 1H), 7.60 (d, 2H), 7.35 (tr, 2H), 7.11 (tr, 1H), 2.31 (s, 3H). MS (EI) for C11H10ClN3: 220 (MH+).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3=[N:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=[C:5]3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2occ(Br)c2n1
Product: CCOC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2n1
Yield: 32 %

Procedure:
In the same manner as in Reference Example 19 and using ethyl 3-bromofuro[3,2-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 32%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]=O.[CH2:3]([CH2:5][NH2:6])[OH:4].C([O:10][P:11]([O:16]C(C)C)[O:12]C(C)C)(C)C.[OH-].[Na+]>C(O)(C)C>[OH:4][CH2:3][CH2:5][NH:6][CH2:1][P:11](=[O:16])([OH:12])[OH:10]
Reactant: NCCO
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=P(O)(O)CNCCO
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of paraformaldehyde (4 g, 0.13 mol), ethanolamine (48.8 g, 0.8 mmol) and triisopropylphosphite (20.8 g, 0.1 mmol) was stirred at 100° C. for 16 hours. The reaction was allowed to cool to room temperature and 8 ml of 50% w/w sodium hydroxide and 100 ml of isopropanol were added. The mixture was heated to reflux for 48 h. The solution was concentrated under vacuum and 25 ml of distilled water was added to homogenize the mixture. The reaction was analyzed by 31P-NMR in D2O at pH=0.7. N-(2-Hydroxylethyl)aminomethylphosphonic acid was obtained in 80% yield.
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-])=[O:17])=[CH:10][N:9]=1.C[O-].[Li+].O1CCCC1.C(Cl)[Cl:31]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]([Cl:31])=[N:16][OH:17])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])CCc1ccc(Oc2cccc(F)c2)nc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a methanol (20 mL) solution of 2-(3-fluoro-phenoxy)-5-(2-nitro-ethyl)-pyridine (1.96 g, 7.47 mmol) described in Manufacturing Example 71-1-3 was added lithium methoxide (567 mg, 14.9 mmol), which was stirred for 35 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. Titanium (IV) tetrachloride (1.81 mL, 16.4 mmol) was added under nitrogen atmosphere to a tetrahydrofuran (20 mL) and methylene chloride (20 mL) suspension of the residue, and stirred for 1 hour 15 minutes at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.1 g, quant.). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:36][C:35]2[CH:37]=[CH:38][C:32]([C:31]([F:39])([F:40])[F:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Reaction time: 16 h
Yield: 9.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (40 mg, 0.1020 mmol) was dissolved in methylene chloride (5 ml), then 4-trifluoromethylaniline (25 mg, 0.1552 mmol), triethylamine (21 mg, 0.2079 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (52 mg, 0.3076 mmol) were added thereto and the mixture was stirred for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=3:1) to give the title compound (5 mg, 0.0093 mmol, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:43])[CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:43][CH:39]([CH2:38][CH3:37])[CH2:40][CH2:41][CH3:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 28.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hexanol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (20 mg, yield 27%).