Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[CH3:19][O-:20].[Na+].CO>CO>[CH3:19][O:20][C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Agent: [Na+]
Solvent: CO
Product: COc1nnc2n1C=Cc1ccccc1C2

Procedure:
To 0.522 g of 3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine in 5 ml of methanol was added 3 ml of 2 N-sodium methoxide/methanol. The mixture was refluxed for 15 minutes and then the solvent was evaporated off. The residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with isopropyl ether. By the above procedure was obtained 3-methoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate-n-hexane yielded colorless prisms, melting point: 160°-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10]O)=[C:8]([C:12]([F:15])([F:14])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2].P(Br)(Br)[Br:17].O>CCOCC.CO>[Br:17][CH2:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[N:7][C:8]=1[C:12]([F:15])([F:14])[F:13]
Reactant: BrP(Br)Br
Reactant: CCOc1ncnc(C(F)(F)F)c1CO
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCOc1ncnc(C(F)(F)F)c1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.77 g (17.0 mmoles) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol dissolved in 50 ml of ether was cooled to 0° C. Thereto was added 2.0 g (7.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour. The resulting salt was dissolved in methanol and the solution was stirred for 1 hour to give rise to a reaction. The reaction mixture was poured into water and extraction with ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain a crude product of 5-bromomethyl-4-ethoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:39][CH2:40][Cl:41])(=[O:38])[CH3:37]>>[Cl-:41].[C:36]([O:39][CH2:40][N:33]1[CH2:34][NH+:30]([CH2:29][C@@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:35])[C@H:10]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[N:24]4)=[CH:21][CH:22]=3)[C:13]2=[O:28])[CH3:11])[N:31]=[CH:32]1)(=[O:38])[CH3:37]
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)OCCl
Product: CC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (0.30 g) and chloromethyl acetate (1.35 g) was stirred for 24 hours at 100° C. The reaction mixture was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2) to give 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (Compound 3, 45 mg) as a white powder.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[CH3:14][C:12]1[S:13][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][CH3:17])=[CH:15][C:10]=2[N:11]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Yb]
Solvent: ClCCl
Product: CC[C@H](O)COc1ccc2sc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]2[CH2:18][CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:15]([O:57][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][CH2:72][CH2:73][CH2:74][CH3:75])[CH2:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]2[CH2:18][CH:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:15]([O:57][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][CH2:72][CH2:73][CH2:74][CH3:75])[CH2:14]2)[CH:8]=[CH:7][C:4]=1[CH2:5][OH:6]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(CO)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2-Methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (272 mg, 0.26 mmol) was suspended in chloroform-methanol (6 ml+0.5 ml), and sodium borohydride (29 mg, 0.77 mmol) was added. After stirring at 60° C. overnight, the mixture was dissolved in chloroform (12 ml), and washed with 0.5N hydrochloric acid (8 ml) and pure water (8 ml). The solvent was evaporated, and the residue was precipitated with acetonitrile (2.5 ml) to give 2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol (260 mg, 0.25 mmol, 95%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.[C:29](Cl)(=O)[O:30]C1C=CC=CC=1.[OH:39][C:40]([CH3:50])([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42]>O1CCCC1.CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:29]([N:46]4[CH2:45][CH2:44][N:43]([C:41](=[O:42])[C:40]([OH:39])([CH3:50])[CH3:49])[CH2:48][CH2:47]4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CC(C)(O)C(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCN(C(=O)C(C)(C)O)CC4)c3)ccc21
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)([CH3:17])[CH3:16])/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)([CH3:17])[CH3:16])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OC(C)(C)[C@H]1CC[C@H](C)CC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-[1-(trans-4-methylcyclohexyl)-1-methylethoxyimino]acetate (630 mg, 1.78 mmol) in ethanol (14 ml) and water (2 ml) was treated with 1M NaOH (1.78 ml) and the mixture was stirred at room temperature for 5 days. The ethanol was removed by evaporation in vacuo and the residual mixture was treated with ethyl acetate (100 ml) and water (100 ml) and the pH was adjusted to 3.0. The aqueous layer was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were dried (MgSO4) and evaporated to leave the title compound (390 mg, 67%), νmax (KBr) 3290, 3120, 2942, 1724, 1616, 1447, 1380, and 985 cm-1 ; δH (250 MHz, (CD3)2SO), 0.84 (3H, d, J 6.4 Hz), 1.17 (6H, s), 0.7-1.9 (10 H, m), 6.78 (1H, s), 7.25 (2H, s), and 13.5 (1H, broad s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23]([C:34]4[CH2:35][CH2:36][O:37][CH2:38][CH:39]=4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]4[C:23]([CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(C3=CCOCC3)c2n1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(C3CCOCC3)c2n1
Temperature: 35 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
A solution of compound 90h (470 mg, 0.830 mmol) in MeOH (2 mL) and 10% palladium on carbon (300 mg) was placed under a H2 atmosphere using a H2 balloon. The reaction mixture was stirred overnight at 35° C. A solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain compound 90i as a gray solid (465 mg, 99% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H36N6O5: 537.3 (M+H). found: 537.6.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][OH:29])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:31])[CH2:4][CH2:5][C:6](=[O:30])[CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>N1C=CC=CC=1>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:31])[CH2:4][CH2:5][C:6](=[O:30])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOS(C)(=O)=O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 0.80 g of 9-fluoro-16α-(2-hydroxyethoxy)-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 10 ml of pyridine is stirred with 0.5 ml of methanesulfonyl chloride for 90 minutes at 0°C under nitrogen. The solution is poured into cold 5% hydrochloric acid and extracted with chloroform. The chloroform extract is dried and evaporated to give an oil which is chromatographed on a 20 g -- silica gel column. Elution with chloroform gives 521 mg of TLC pure 9-fluoro-16α-(2-mesyloxyethoxy)-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.BrC1C=CC=C([Cl:20])C=1OC.[Li]CCCC.COB(OC)OC>>[Cl:20][C:4]1[C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COc1c(Cl)cccc1Br
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1c(Cl)cccc1B(O)O
Yield: 91 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-6-chloroanisole (0.71 g, 3.2 mmol), n-BuLi (2.5 M in hexanes; 1.28 mL, 3.2 mmol), and trimethylborate (1.09 mL, 9.6 mmol) to afford 0.55 g (91%) of 3-chloro-2-methoxyphenylboronic acid which was used without further purification. Methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate). This compound was prepared in a manner similar to that of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (0.58 g, 2.2 mmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro-2-methoxyphenylboronic acid (0.54 g, 2.9 mmol) to afford 245 mg (35%) of methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) as a clear oil. Data for methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.79 (d, J=2.4, 1H), 8.40 (dd, J=8.4, 2.4, 1H), 7.57 (d, J=8.5, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.75 (s, 3H) 3.47 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:41].C(OCC)C>C(OCC)(=O)C>[ClH:41].[NH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=3[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NCC(=O)OC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h

Procedure:
3-[4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-[(tert-butoxycarbonyl)amino]acetate (39 mg, 0.072 mmol) was dissolved in ethyl acetate (2.5 ml). Hydrogen chloride gas was passed through for 1 minute. The flask was capped and the solution stirred for additional 30 minutes. Diethyl ether was added and precipitate formed. The solid was collected by filtration to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl 2-aminoacetate hydrochloride. The structure was confirmed by 1H NMR and LC/MS (MH+=444).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:11]([OH:12])=[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:9](=[O:20])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.C1(CCN2C(=O)CC(=O)N(C3C=CC=C([N+]([O-])=O)C=3)C2=O)CC1.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>ClCCl>[CH:1]1([CH2:4][CH2:5][N:6]2[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:20])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1
Reactant: O=C(O)CNC(=O)c1c(O)n(CCC2CC2)c(=O)n(-c2cccc([N+](=O)[O-])c2)c1=O
Agent: CCOC(=O)CN=C=O
Agent: O=C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C(=O)N1CCC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=O)c1c(O)n(-c2cccc([N+](=O)[O-])c2)c(=O)n(CCC2CC2)c1=O
Reaction time: 8 h
Yield: 37 %

Procedure:
N-{[1-(2-Cyclopropylethyl)-6-hydroxy-3-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture 1-(2-cyclopropylethyl)-3-(3-nitrophenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.66 g, 5.23 mmole) and diisopropylethylamine (1.80 mL, 10.5 mmoles) in dichloromethane (80 mL) was treated with ethyl isocyanatoacetate (704 uL, 6.27 mmoles) and stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was dissolved in ethanol (6 mL) and treated with 6 molar sodium hydroxide (5.0 mL). The mixture was stirred for 1 hour, acidified and extracted with ethyl acetate (×2), dried and evaporated. A solid was obtained from acetic acid-water, which was purified by trituration in boiling chloroform to give the title compound (800 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s, 1 H), 10.03 (s, 1 H), 8.35 (s, 1 H), 8.32 (ddd, J=8.40, 1.64, 1.33 Hz, 1 H), 7.82-7.88 (m, 1 H), 7.79 (t, J=8.08 Hz, 1 H), 4.14 (d, J=5.81 Hz, 2 H), 3.88-3.97 (m, 2 H), 1.50 (q, J=7.16 Hz, 2 H), 0.66-0.76 (m, 1 H), 0.42 (ddd, J=7.96, 5.68, 4.04 Hz, 2 H), 0.05 (td, J=5.18, 4.29 Hz, 2 H).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=O)[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO>[OH:20][N:19]=[C:5]1[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[C:2](=[CH2:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6]1
Reactant: NO
Reactant: C=C1c2ccccc2CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2ccccc2CC(=NO)c2ccccc21
Yield: 95.3 %

Procedure:
A mixture of 16.5 g of the oxo-compound from Step C, 6.6 g of hydroxylamine hydrochloride, 8.2 of sodium acetate and 300 ml of methanol was heated under reflux for 5 hours. The solvent was evaporated and the residue was treated with 250 ml of water. The mixture was extracted with 3×150 ml of ether, and the extract was dried, filtered, and evaporated to give 16.8 g of 10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, m.p. 156°-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]2[N:11]=1)[CH3:2].[S:26](Cl)([Cl:29])(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Product: CCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.88 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-pentyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 21A). This gives 0.3 g (77.6%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([C:16]4[S:20][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:18][CH:17]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1N=C(NC2C=C(C3CC3)NN=2)C(C)=CN=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([CH3:26])=[CH:14][N:13]=[C:12]([C:16]4[S:20][C:19]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:18][CH:17]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Product: Cc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Yield: 24.8 %

Procedure:
5-(4-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-methylpyrimidin-2-yl)thiophene-2-sulfonamide (Compound 40) (43 mg, 24.8%) was prepared following same procedure as described in Compound 50 by starting with 2-bromo-5-methyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine. LC-MS (m/z)=377.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.75-0.76 (m, 2H), 0.97-0.99 (m, 2H), 1.93-1.95 (m, 1H), 2.18 (s, 3H), 6.51 (s, 1H), 7.57 (d, J=3.6 Hz, 1H), 7.73 (d, J=3.2 Hz, 1H), 7.78 (s, 2H), 8.14 (s, 1H), 9.13 (s, 1H), 12.17 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][O:21][CH3:22])[N:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][CH2:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH2:20][O:21][CH3:22])[N:4]=3)[CH2:25][CH2:24]2)=[N:4]1
Reactant: COCn1nc(CCl)cc1-c1cc(OC)c(OC)c(OC)c1
Reactant: C1CNCCN1
Product: COCn1nc(CN2CCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3-Chloromethyl-1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)pyrazole (101 mg) and piperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:23]OC(OC)OC>>[CH3:23][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCOc1ccccc1-c1nc2cc(N)ccc2c(=O)[nH]1
Reactant: COC(OC)OC
Product: CCCOc1ccccc1-c1nc2cc(NC)ccc2c(=O)[nH]1

Procedure:
7-amino-2-(2-propoxyphenyl)-4(3H)-quinazolinone (0.5 g) was heated under reflux in trimethylorthoformate (5 ml) for 22 hours. The reaction mixture was evaporated to dryness, the residue dissolved in dry tetrahydrofuran and treated with sodium borohydride (0.3 g) and 4A molecular sieves for 24 hours. The reaction mixture was partitioned between water and dichloromethane, the organic layer separated, dried (magnesium sulphate) and evaporated. The residue was recrystallised from dichloromethane-diethyl ether to give 7-methylamino-2-(2-propoxyphenyl)-4(3H)-quinazolinone 0.17 g, m.p. 204°-205° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[CH:12][CH3:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:15]([NH:18][C:19]([NH2:21])=[S:20])(=[O:17])[CH3:16]>CN(C)C=O.O>[C:15]([NH:18][C:19]1[S:20][CH:2]=[C:3](/[C:4](=[CH:12]/[CH3:13])/[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[N:21]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)NC(N)=S
Reactant: CC=C(C(=O)CCl)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C(\C(=O)OC(C)(C)C)c1csc(NC(C)=O)n1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
The crude product of a 2.2 mol batch of tert.-butyl 4-chloro-2-ethylidene-3-oxobutyrate, dissolved in 100 ml of dimethylformamide, is added to a solution, warmed to 85° C., of 236 g (2 mol) of acetylthiourea in a mixture of 360 ml of water and 720 ml of dimethylformamide. The mixture is stirred at 85° C. for two hours and concentrated, the residue is taken up in ethyl acetate and the solution is extracted three times with water. After drying and concentrating, by-products are precipitated with ether.