Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:31])[C:23]1[C:24](=[CH:26][CH:27]=[C:28]([I:30])[CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:24]=1[O:18][CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: COC(=O)c1cc(I)ccc1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)ccc1OCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.0 g) synthesized in Example 4 and 5-iodosalicylic acid methyl ester (7.3 g) were dissolved in tetrahydrofuran (130 mL), triphenylphosphine (9.0 g) and diethyl diazodicarboxylate (14.9 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (14.3 g) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14](F)=[CH:15][CH:16]=[C:11]2[C:10]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[C:22]([O:28][C:29]3[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[C:31]([Cl:37])[CH:30]=3)[CH:21]=2)=[N:9]1)=O)(C)(C)C.COC1C=CC(C[NH2:45])=CC=1>CN1C(=O)CCC1.CCOC(C)=O.C(O)(C(F)(F)F)=O>[NH2:45][C:14]1[N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[C:22]([CH:21]=3)[O:28][C:29]3[CH:34]=[C:33]([CH:32]=[C:31]([Cl:37])[CH:30]=3)[C:35]#[N:36])[C:11]2=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)n1nc(COc2cc(F)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)cc(Oc2cc(OCc3n[nH]c4nc(N)ccc34)cc(F)c2Cl)c1
Temperature: 95 °C
Yield: 4.3 %

Procedure:
Under a nitrogen atmosphere, tert-butyl3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)-5-fluorophenoxy]methyl}-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (50-6) (230 mg, 0.420 mmol) was dissolved in NMP (4 mL, 0.1 M). Next, 4-methoxybenzylamine (288 mg, 2.101 mmol) was added and the reaction was heated to 95° C. for 2 hours. It was then diluted with EtOAc (4 mL). It was partitioned with water (3 mL) and then extracted with EtOAc (3×4 mL). The organic extracts were then washed with water (3×4 mL) and brine (1×4 mL), dried over sodium sulfate and concentrated. The crude reaction material was then diluted with TFA (3 mL) and heated to 65° C. for 2 hours. It was then concentrated and purified on a reverse phase system (5%-95% AcCN/H2O with 0.5% TFA) to give 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile (50-7) (8 mg, 4%). LCMS (ES) m/z 445.9 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (28 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (24.6 mg). LCMS-ESI+: calc'd for C46H54N8O7: 830.97 (M+); Found: 831.33 (M+H+).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([S:21]([O:24][C:25]2[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=2)(=[O:23])=[O:22])[CH:20]=1.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C.ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([S:21]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[C:29]([CH3:31])[CH:30]=2)[O:32][CH2:35][CH2:36][CH2:37][OH:38])(=[O:23])=[O:22])[CH:20]=1
Reactant: OCCCO
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Reaction time: 3 h
Yield: 69 %

Procedure:
Tri-n-butylphosphine (7.6 mL) 30.4 mmol) was added dropwise over 20 min to 3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenol (5.00 g, 15.2 mmol, prepared in step a of Example 2), 1,3-propanediol (3.3 mL, 45.6 mmol) and 1,1′-(azodicarbonyl)dipiperidine (7.68 g, 30.4 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. under a nitrogen atmosphere. Dichloromethane (150 mL) was added mid-way through the tri-n-butylphosphine addition to aid stirring. The slurry was stirred for an additional 5 min at 0° C. then at ambient temperature for 3 h. Diethyl ether (400 mL) was added, and the mixture was stirred for 10 min then filtered. The filtrate was concentrated and the product was purified by flash column chromatography (25% to 60% ethyl acetate in hexane) to give the title compound (4.07 g, 69%) as a gold oil. 1H-NMR (300 MHz, CDCl3) (7.82 (d, 1H, J=2.8 Hz), 7.56 (dd, 1H, J=8.9, 2.6 Hz), 7.03 (d, 1H, J=8.9 Hz), 6.62 (br s, 1H), 6.52 (br s, 1H), 6.47 (t, 1H, J=2.3 Hz), 4.03 (t, 2H, J=6 Hz), 4.01 (s, 3H), 3.85-3.80 (m, 2H), 2.26 (s, 3H), 2.00 (pentet, 2H, J=6 Hz), 1.64 (t, 1H, J=5 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H19ClO6S: 409.0 (M+Na). Found: 409.0.
Reaction SMILES: CC(C1C=C(S[C@@H:16]2CCC[C@H:17]2[OH:21])C=C(C(C)(C)C)C=1)(C)C.[CH3:22][C:23]([C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[S:36][C@H:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[OH:42])([CH3:25])[CH3:24]>>[C:17]([O:42][C@@H:38]1[CH2:39][CH2:40][CH2:41][C@H:37]1[S:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:31][C:26]=1[C:23]([CH3:22])([CH3:24])[CH3:25])(=[O:21])[CH3:16]
Reactant: CC(C)(C)c1ccc(S[C@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1
Product: CC(=O)O[C@@H]1CCC[C@H]1Sc1ccc(C(C)(C)C)cc1C(C)(C)C

Procedure:
The title compounds were prepared by the method described in Example 82, except that the title product of Example 79, Compound B, was substituted for the title product of Example 75, Compound A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:31])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c(=O)n2-c2ccc(Br)cc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cc1ccc(-c2nc3c(-c4ccccc4)nn(C)c3c(=O)n2-c2ccc(Br)cc2)cc1

Procedure:
To a solution of 6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (11.0 mg, 0.024 mmol) in acetonitrile (0.3 mL) are added K2CO3 (6.6 mg, 0.048 mmol) and MeI (5.99 μL, 0.096 mmol). The reaction mixture is stirred at room temperature for overnight before the removal of K2CO3 by filtration. The filtrate is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, 2H), 7.47 (t, 2H), 7.44 (d, 2H), 7.35 (t, 1H), 7.22 (d, 2H), 7.04 (m, 4H), 4.37 (s, 3H), 2.31 (s, 3H); HPLC-MS calculated for C25H19BrN4O (M+H+) 471.1. found: 471.1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCNc1nnc(C)s1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCN(C(=O)Cc1ccccc1)c1nnc(C)s1
Reaction time: 24 h

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexylamine (5.98 g, 0.03 mole) in toluene (60 ml) was stirred together with triethylamine (4.59 ml) and phenylacetyl chloride (4.64 g, 0.03 mole) and refluxed overnight. Further triethylamine (4.6 ml) and phenylacetyl chloride (4 ml) were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The chloroform extract was washed with 2 N sodium hydroxide solution and with water, and was dried (Na2SO4), filtered and evaporated to yield the title product as an oil, b.p. 190° C./0.1 mm (8.03 g). This was recrystallised from ethanol to give the title compound as a solid, m.p. 90° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10](O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>CC#N>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Yield: 89.3 %

Procedure:
At -10° C., to a stirred solution of 4-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol (2.78 g, 9.39 mmol) in CH3CN was added portionwise triethylsilane (two×1.50 mL, 18.78 mmol total, @ 0.5 h interval). To the reaction was added BF3. Et2O (1.19 mL, 9.39 mmol) and the reaction was stirred for 10 min. The reaction was quenched with sat. aq. K2CO3 and extracted with CH2Cl2. The organic extracts were washed with brine (3×), dried (MgSO4) and concentrated. Purification on silica gel gave 2.35 g (89%) the title compound as a white solid, mp 67-70° C. (DMSO-d6) δ 0.87 (t, 3 H), 1.31 (sextet, 2 H), 1.62 (quintet, 2 H), 2.78 (t, 2 H), 3.84 (s, 2 H), 6.64 (d, 2 H), 7.02 (d, 2 H), 7.09 (dt, 1 H), 7.16 (dt, 1 H), 7.31 (d, 1 H), 7.42 (d, 1 H), 9.16 (s, 1 H). IR (KBr) 3300, 2950, 1610, 1510 and 1450 cm-1. mass spectrum (EI) m/z 280 (M+).
Reaction SMILES: [F:1][C:2]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:32]2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.254 g, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.187 g, 0.95 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.795 g, 1.80 mmol). The mixture was stirred at 0° C. and triethylamine (0.194 g, 1.90 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.200 g, 51%) as a tan solid: HR-ES-MS m/z calculated for C26H33FN4O5 [M+H]+ 501.2508, observed 501.2511, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.49 (m, 1H), 1.49-1.64 (m, 1H), 1.68-1.83 (m, 1H), 2.29 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.16 (m, 2H), 4.21 (d, J=18.7 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.59 (d, J=18.7 Hz, 1H), 4.85 (s, 1H), 4.85-4.92 (m, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.13-7.34 (m, 3H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: C(OC([O:6][CH2:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]([C:13]1[S:17][CH2:16][N:15]([CH3:18])[CH:14]=1)[O:11][CH3:12])C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Cl-].[Na+].O>[OH:6][CH2:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]([C:13]1[S:17][CH2:16][N:15]([CH3:18])[CH:14]=1)[O:11][CH3:12]
Reactant: CCOC(C)OCc1ccccc1C(OC)C1=CN(C)CS1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(C1=CN(C)CS1)c1ccccc1CO
Yield: 92.7 %

Procedure:
To 3.05 g (10 mmol) of 5-[2-(1-ethoxyethyl)oxymethyl-α-methoxybenzyl]-3-methylthiazole was added 0.25 g (1 mmol) of pyridinium p-toluenesulfonate and stirred under reflux for an hour. After completion of the reaction, 150 ml of brine was added and extracted twice with 80 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole (2.33 g, 99.9%) as colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[CH3:15][C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]#[CH:9])[C:4](=[O:10])[CH2:3]1)([CH3:17])[CH3:16]
Reactant: C#CCN1C[C@@H](O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1C[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 25 g of (S)-4-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 39.8 g of t-butyldimethylsilyl chloride and 38.5 ml of triethylamine in 200 ml of dichloromethane was stirred under argon overnight. The mixture was washed with 300 ml of water, dried and evaporated. The residual oil was purified by chromatography, (silica gel) giving 42.7 g of (S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=[CH:17][N:18](C)C)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(O)C.O.[NH2:25]N>C(O)(=O)C>[NH2:25][N:18]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: NN
Reactant: CN(C)C=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 0.29 part of 5-chloro-2-dimethylaminomethyleneaminobenzophenone in 4 volume parts of ethanol are added 0.2 volume part of hydrazine hydrate and 0.06 volume part of glacial acetic acid. The mixture is shaken and kept standing at room temperature for about 30 minutes. The resulting crystals are recovered by filtration and washed with ethanol and then dried, whereby 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline is obtained as colorless needles melting at 185° (softening) to 192° C. This compound is identical with the product obtained in Example 1. Yield: 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].O=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C1(C)C=CC=CC=1>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:11]1[NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][O:5]1
Reactant: Nc1ccccc1CO
Reactant: O=CC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)C1Nc2ccccc2CO1
Reaction time: 0.5 h

Procedure:
A solution of o-aminobenzyl alcohol (2.4 g.) in toluene (5 ml.) was stirred at ambient temperature while anhydrous chloral (2.0 ml.) was added dropwise. The mixture was stirred for 30 minutes, and evaporated to dryness to yield an oil, which was crystallised from aqueous ethanol to give 1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, m.p. 90°-92° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].[I-].ClC1C=CC=C[N+]=1C.C(N(CCCC)CCCC)CCC>ClCCl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([O:10][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)c1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
A mixture of 3,6-dichloropyridazine-4-carboxylic acid (5.79 g, 30 mmol), tert-butanol (2.45 g, 33 mmol), 2-chloro-1-methylpyridinium iodide (6.12 g, 24 mmol), and tributylamine (8.9 g, 48 mmol) in dichloromethane (52 mL) was stirred at refluxing under N2 for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using a silica gel cartridge (330 g) which was pretreated with 1% Et3N in hexanes for 10 min at 10 mL/min, eluting with a gradient of EtOAc (0-50%) in hexanes to afford 6.1 g (81%) of the title compound as a white solid. HPLC/MS (Method B): retention time=2.95 min, [M+H]+=249.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: Clc1ncnc2c1CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Reaction time: 8 h
Yield: 51.3 %

Procedure:
77.5 g of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were dissolved in 2 liters of chloroform, and then a solution of 259 g of m-chloroperbenzoic acid in 0.1 liter of chloroform was added dropwise. The mixture was stirred overnight, whilst cooling with water, and then a solution of 375 g of sodium thiosulfate in 1.5 liters of water and a solution of 191 g of sodium carbonate in 0.7 liters of water were added successively dropwise, whilst ice-cooling. The chloroform layer was separated, and the aqueous layer was extracted with chloroform. The separated chloroform layer and extracts were combined and dried over anhydrous sodium sulfate. The chloroform was evaporated off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to give 43.9 g of the title compound as colorless crystals melting at 85°-87° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])=[O:19]
Reactant: CC(C)NNC(=O)c1ccsc1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccsc2)C(C)C)c1C
Yield: 50.5 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (172 mg, 50%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1.C1(C)C=CC=CC=1>[OH:3][CH2:4][CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(CCO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
After a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g) in THF (10 mL) was cooled to −78° C. in an argon atmosphere, a 1.02 M solution of diisobutylaluminium hydride in toluene (17.5 mL) was added dropwise thereto, then, the mixture was stirred at the same temperature for 1 hour, and further stirred at 0° C. for 30 minutes. An aqueous Rochelle salt solution and EtOAc were added the reaction mixture, followed by stirring for 1 hour. After the temperature of the reaction mixture was raised to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=97:3 to 80:20), whereby tert-butyl 3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.83 g) was obtained as a colorless oil.