Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[CH:6][N:5]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][C@@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1>O.CO>[O:3]=[C:4]1[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][N:5]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][C@@H:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:23]2=[O:44])=[O:20])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cn(C2CCN(C(=O)N[C@@H]3N=C(c4ccccc4)c4ccccc4N(CC(F)(F)F)C3=O)CC2)c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(C2CCN(C(=O)N[C@@H]3N=C(c4ccccc4)c4ccccc4N(CC(F)(F)F)C3=O)CC2)c(=O)[nH]1
Reaction time: 2 h
Yield: 17.2 %

Procedure:
Lithium hydroxide (43 mg, 1.03 mmol) in water (2 mL) was added to a solution methyl 2-oxo-1-[1-({[(3R)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]amino}carbonyl)piperidin-4-yl]-2,3-dihydro-1H-imidazole-4-carboxylate (30 mg, 0.051 mmol) in methanol (2 mL) and heated to 40 o C. After 2 h, the reaction was purified by preparative reverse phase chromatography to give the title compound (5 mg). MS 571.2 (M+1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH2:23][N:24](C(C)C)C(C)C.BrCC#N>CC#N>[C:23]([CH2:22][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1)#[N:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl piperidin-4-ylmethylcarbamate (5 g, 23.2 mmol) was dissolved in CH3CN (40 mL). Potassium carbonate (3.5 g, 25 mmol), DIPEA (4.4 mL, 25 mmol) and bromoacetonitrile (2.77 g, 23.2 mmol) were added, and the mixture was stirred at room temperature overnight. The solution was then concentrated and saturated NaHCO3 (40 mL) was added. The mixture was extracted with CH2Cl2 (4×30 mL). The extract was dried over anhydrous Na2SO4. The dried extract was passed through a silica gel plug, and the desired compound was eluted off with EtOAc. The product was further purified by crystallization from EtOAc/petroleum ether as a white solid (5.4 g, 92%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]1.[F-].[K+]>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N#C[C@H]1CC[C@H](N)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (50 mg, 0.168 mmol), Trans-4-aminocyclohexanecarbonitrile (53 mg, 0.22 mmol) and KF (42.2 mg, 0.73 mmol) in DMSO (0.5 mL) was heated at 130° C. overnight. LCMS showed the reaction was almost complete. The mixture was purified by prep. HPLC to give trans-4-((3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanecarbonitrile (20 mg, 30.8%) as an off-white solid.
Reaction SMILES: [C:1]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[OH:14])(=O)[CH2:2][CH2:3][CH3:4].[H][H]>Cl(O)(=O)(=O)=O.[Pt]=O.C(O)(=O)C>[CH2:1]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c(C)cc(C)cc1O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCc1c(C)cc(C)cc1O

Procedure:
10 g. of 2-butyryl-3,5-dimethyl-phenol are dissolved in 100 ml. of glacial acetic acid. After the addition of 3 drops of perchloric acid, the solution is hydrogenated under normal conditions in the presence of 0.5 g. of platinum oxide. After the uptake of 3.0 l. of hydrogen, the hydrogenation is stopped. The catalyst is filtered off. The filtrate is extracted with ether. The ether extract is washed with water to neutral reacton, dried over sodium sulfate and evaporated. There is obtained 2-butyl-3,5-dimethyl-phenol, which melts at 65°-67° C. after absorption on silica gel, using methylene chloride/hexane 1:1 parts by volume as the eluent.
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](OCC)(=[O:17])[CH2:14][CH2:15][CH3:16].Cl>C1(C)C=CC=CC=1.O>[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)OCC
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)CC(=O)CCc1ccccc1
Reaction time: 9 h

Procedure:
Sodium (7.3 g) was added in small portions to a solution of 4-phenyl-2-butanone (46.8 g, 0.31 mol) and ethyl butyrate (110 g, 0.95 mol) in toluene (120 ml) at 20°-60° C. under nitrogen, and stirring was continued for 9 h under reflux. After standing overnight, the reaction mixture was taken up in H2O (300 ml), neutralized with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with H2O, dried over anhydrous MgSO4 and then evaporated. The residual reddish orange oil (84 g) was distilled under reduced pressure to afford the title compound as a pale yellow oil which was an ca 3:7 mixture of Keto/Enol as seen by the methylene singlet at δ3.52 ppm and the methine singlet as δ5.45 ppm in the 1HNMR spectrum; yield: 15.4 g; bp. 166°-168° C./2 mmHg.
Reaction SMILES: Cl.[S:2]1[C:6]([C:7]2[CH:8]=[C:9]([N:16]([CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[CH:10]=[C:11]3[C:15]=2[NH:14][N:13]=[CH:12]3)=[CH:5][C:4]2[CH:35]=[CH:36][CH:37]=[CH:38][C:3]1=2>C(O)C>[NH2:23][C:19]1[N:18]=[C:17]([N:16]([C:9]2[CH:10]=[C:11]3[C:15](=[C:7]([C:6]4[S:2][C:3]5[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=5[CH:5]=4)[CH:8]=2)[NH:14][N:13]=[CH:12]3)[CH2:24][CH2:25][CH2:26][OH:27])[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCN(c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1)c1ccnc(N)n1
Agent: Cl
Solvent: CCO
Product: Nc1nccc(N(CCCO)c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Temperature: 65 °C

Procedure:
6N hydrochloric acid (1 mL) was added to a mixture of N4-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-N4-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-pyrimidine-2,4-diamine (prepared from example #F.8.1, via general procedures O then N, 0.179 g, 0.339 mmol) in ethanol (2 mL). The reaction mixture was heated to about 65° C. for about 1 hour then cooled to about ambient temperature. The solvents were evaporated and the residue was purified by reverse phase chromatography (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% acetonitrile/0.1 M aqueous ammonium acetate −100% acetonitrile over 20 min, 100% acetonitrile hold 5 minutes, 21 mL/min) to afford (3-[(2-amino-pyrimidin-4-yl)-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amino]-propan-1-ol (0.022 g, 0.053 mmol) as an off white solid; RP-HPLC (Table 1, Method e) Rt 1.77 min.; m/z: (M+H)+ 417.1.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2OCCO2)cc1
Yield: 99.2 %

Procedure:
To stirred solution of methyl 4-formylbenzoate (5.0 g, 30.46 mmol) in toluene (196 mL) was added ethylene glycol (8.49 mL, 152.3 mmol) and para-toluenesulfonic acid monohydrate (0.58 g, 3.05 mmol). The reaction mixture was heated at reflux under Dean and Stark conditions for 1.5 hours. The solvent was evaporated at reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was removed and washed with further saturated aqueous sodium hydrogen carbonate, brine and dried (magnesium sulfate). The mixture was filtered and the solvent evaporated at reduced pressure to afford the title compound (6.29 g, 99%).
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1O[CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C:24](C)([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19]([CH3:35])[CH2:18][CH2:17][CH2:16][C:15](C)=[CH:14][CH2:13]2)\[CH3:11])[N:5]=1.CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@@]3(C)O[C@H]3C2)\C)N=1.CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1[S:111]C=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)C[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1.CC1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC=CC2)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC(C)=CC2)\C)N=1>CO>[CH3:3][C:4]1[S:111][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:29][C:27](=[O:28])[CH2:26][C@H:25]([OH:30])[C@@H:24]([CH3:31])[C:22](=[O:23])[C@H:21]([CH3:33])[C@@H:20]([OH:34])[C@@H:19]([CH3:35])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)\[CH3:11])[N:5]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)CC(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: CC1=CC[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C/CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]22D −3 (c 1.5, MeOH); UV (MeOH) λmax nm (ε) 211 (15800), 248 (11900); IR (KBr) νmax 3435, 2963, 2931, 2878, 1731, 1706, 1457, 1273, 979 cm−1; 1H NMR (CDCl3, 600 MHz) δ 6.99 (1H, s, H-19), 6.57 (1H, bs, H17), 5.56*(1H, ddd, J=15.1, 7.4, 7.0 Hz, H-12), 5.41 (1H, ddd, J=15.1, 7.0, 6.9 Hz, H-13), 5.41 (1H, dd, J=7.7, 2.8 Hz, H-15), 4.13 (1H, dddd, J=6.7, 6.2, 5.6, 5.1 Hz, H-3), 3.78 (1H, ddd, J=8.2, 6.5, 1.9 Hz, H-7), 3.18 (1H, d, J=5.6 Hz, 3-OH), 3.06 (1H, dq, J=8.2, 7.1 Hz, H-6),2.98 (1H, dq, J=6.2, 7.0 Hz, H-4), 2.71 (3H, s, H-21),2.64 (1H, dd, J=15.1, 6.7 Hz, H2a), 2.54 (1H, dd, J=15.1, 5.1 Hz, H-2b), 2.44 (2H, m, H-14),2.22 (1H, dddd, J=13.8, 7.0, 6.2, 2.9 Hz, H-11a), 2.10 (3H, d, J=1.1 Hz, H-27), 2.09 (˜H, d, J=6.5 Hz, 7-OH), 1.88 (1H, dddd, J=13.8, 10.9, 7.4, 2.9 Hz, H-11b), 1.65 (1H, m, H-8), 1.63 (1H, m, H-10a), 1.56 (1H, dddd, J=12.7, 12.7, 3.9, 3.9 Hz, H-9a), 1.20 (3H, d, J=7.1 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-23),1.13 (1H, m, H-10b), 1.04 (1H, m, H-9.b), 1.01 (3H, d, J=7.0 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 463 [M]+ (13), 290 (11), 190 (10), 168 (100), 164 (20), 157 (26), 139 (17); HREIMS m/z 463.2383 (calcd. for C25H37NO5S, 463.2392).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:21])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Yield: 91.9 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.28 mL, 2.5 mmol) was added to a stirred solution of chloride 5 (187 mg, 0.8 mmol) in DME (30 mL), and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 6 (201 mg, 88%) as a pale yellow solid: mp (MeOH/EtOAc) 186-190° C.; 1H NMR δ 7.54 (d, J=8.4 Hz, 1H, H-6), 7.37 (d, J=8.4 Hz, 1H, H-5), 5.80 (br s, 1H, NH), 3.63 (br t, J=7.3 Hz, 2H, H-9), 3.52-3.57 (m, 2H, CH2N), 2.96 (br t, J=7 Hz, 2H, H-7), 2.57 (t, J=6.0 Hz, 2H, CH2N), 2.29 [s, 6H, N(CH3)2], 2.12-2.21 (m, 2H, H-8); 13C NMR δ 158.5, 149.0, 142.0, 137.3, 132.2, 129.2, 124.7, 57.6, 45.0 (2), 38.7, 35.3, 32.9, 24.8. Anal. calcd for C14H19N5O.¼H2O: C, 60.5; H, 7.1; N, 25.2. Found: C, 60.6; H, 6.6; N, 25.4%.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1.Cl>C(O)C>[CH3:13][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=[C:2]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=2[CH3:30])[N:11]=1
Reactant: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Reactant: Cc1cc(F)ccc1N
Agent: Cl
Solvent: CCO
Product: COc1ccc2nc(Nc3ccc(F)cc3C)nc(N(C)c3ccccc3)c2c1
Yield: 54.3 %

Procedure:
2-Chloro-4-(N-methylphenylamino)-6-methoxyquinazoline (5.4 g, 0.02M) and 4-fluoro-2-methylaniline (4.96 g, 0.04M) were dissolved in ethanol (50 ml) and heated at 140° for 5 hours in a Berghof pressure reactor. The mixture was cooled and ethereal/HCl added. The precipitated solid was filtered off and recrystallised (isopropanol/ether followed by isopropanol) to yield the title compound (3.8 g) m.p. 248°-250°.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=O)=[CH:16][CH:15]=2)[N:9]=1)CCCCCC.[CH2:23](Cl)[CH2:24]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:16]([C:13]1[CH:12]=[N:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:20])=[CH:21][CH:22]=2)=[N:9][CH:8]=1)[CH2:15][CH2:14][CH2:22][CH2:21][CH2:23][CH3:24]
Reactant: ClCCCl
Reactant: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
1.9 g. of 4-(4-n-heptylpyrimid-2-yl)benzoic acid amide are left for 80 minutes under reflux in a mixture of 40 ml. of ethylene chloride and 0.63 ml. of phosphorus oxychloride, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 1.9 g. of 5-n-heptyl-2-(4-cyanophenyl)-pyrimidine result, which are distilled in a high vacuum, having a m.p. of 44.2°-44.7°; cl.p. 50.1°-50.4°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:9][O:10][CH3:11])[N:6]([CH3:8])[CH:7]=1.OCC1N(C)C(COC)=NC=1.[Cl:23]N1C(=O)CCC1=O.O1CCOCC1>C(OCCO)C>[Cl:23][C:7]1[N:6]([CH3:8])[C:5]([CH2:9][O:10][CH3:11])=[N:4][C:3]=1[CH2:2][OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1nc(CO)cn1C
Agent: COCc1ncc(CO)n1C
Solvent: CCOCCO
Solvent: C1COCCO1
Product: COCc1nc(CO)c(Cl)n1C

Procedure:
A 1:1 mixture of 7.7 g (49 mmol) of 4-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 5-hydroxymethyl-2-methoxymethyl-1-methyl-imidazole and 7.3 g (55 mmol) of N-chloro-succinimide was heated to 50° C. in 48 ml of ethylene glycol monoethylether and 70 ml of dioxan for 10 hours. Then the solvent was distilled off in vacuo and the crude product purified by chromatography (silica gel; methylene chloride/ethanol=99:1 to 90:10) to obtain the isomerically pure title compound. Yield: 3.4 g (36% of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol=19:1)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: N#Cc1cc(F)ccc1Br
Product: N#Cc1cc(F)ccc1-c1cccc([N+](=O)[O-])c1

Procedure:
2-Bromo-5-fluorobenzonitrile was coupled with 3-nitrophenylboronic acid by the method of Example 7, part c) to yield 4-fluoro-3′-nitrobiphenyl-2-carbonitrile, which was reduced to 3′-amino-4-fluorobiphenyl-2-carbonitrile by the method of Example 5, part b). This was converted into 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 7 parts e) and f), using bis(pinacolato)diboron instead of bis(neopentyl glycolato)diboron. The product was isolated as a brown oil which solidified on standing. δH (400 MHz, CDCl3) 1.36 (12H, s), 7.35 (1H, td, J 8.2 and 2.7), 7.44-7.54 (3H, m), 7.65 (1H, dt, J 8.2 and 1.7), 7.88-7.90 (2H, m)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2>C1COCC1.CO.[Pt](=O)=O>[CH3:1][CH:2]1[CH2:11][N:10]2[C:5](=[N:6][S:7](=[O:13])(=[O:12])[CH2:8][CH2:9]2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3ccccc3)cc2)=C1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC(c2ccc(Oc3ccccc3)cc2)C2=NS(=O)(=O)CCN2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a suspension of NaH (60%, 229 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.361 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 5-methyl-3-(4-phenoxyphenyl)pyridin-2-amine (316 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 30 min. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (158.2 mg) as a white solid. Platinum(IV) oxide (30.0 mg) was added to a solution of 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (141 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Platinum(IV) oxide (30.0 mg) was added and the mixture was stirred at 50° C. under hydrogen for 1 day. The insoluble material was removed by filtration, silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and crystallized from THF/IPE to give the title compound (35.4 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(=O)C)(=[O:24])C>>[OH:24][C:6]1[C:5]2[N:4]=[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:2]([CH3:1])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(-c2ccccc2)nc2c[n+]([O-])c3ccccc3c21
Product: Cn1c(-c2ccccc2)nc2c(O)nc3ccccc3c21

Procedure:
20 ml of acetic anhydride was added to 1.0 g of Compound b obtained in Reference Example 2, followed by refluxing for 5 hours. After the reaction solution was concentrated under reduced pressure, methanol was added to the residues. The solution was adjusted to a pH of 9 to 10 with sodium methoxide. The precipitate was collected by filtration and washed with methanol, to afford 0.63 g of Compound c.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]1(=[O:38])[CH2:37][CH2:36][CH2:35]1.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[C:34]5([OH:38])[CH2:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C1CCC1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C4(O)CCC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.9 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (940 mg) in acetic acid (10 mL) were added cyclobutanone (2.1 g) and 20% aqueous titanium trichloride solution (3.1 g), and the mixture was stirred under argon at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and filtered through celite to remove the insoluble material. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. The obtained pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (75 mg, yield 6.9%) as a colorless amorphous solid. MS: 537 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C/C(/O)=C/C(C)=O.C=C.C=C.[Rh].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)Oc1ccc(Br)cc1
Agent: [Rh]
Agent: C=C
Agent: CC(=O)/C=C(/C)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Under nitrogen stream, 4-bromophenylboric acid (15.7 g, 78 mmol), (R)-BINAP 1.17 g (1.9 mmol), and acetylacetonato bis(ethylene)rhodium(I) (486 mg, 1.9 mmol) were dissolved in a solvent mixture of 1,4-dioxane (150 mL) and water (15 mL), followed by degassing with ultrasonic waves. Subsequently, cyclopentenone (2.6 mL, 31 mmol) was added and the mixture was stirred under reflux with heating for 3 hours. The reaction solution was cooled to room temperature, followed by addition of saturated aqueous sodium bicarbonate solution, and then the solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane:20/80-30/70) to give the title compound (6.94 g, 91%).