Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:16][CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C3=NC(c4ccccc4)CO3)cc2C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccccc4)co3)cc2C)cc1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A solution of 2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-4-phenyl-4,5-dihydro-1,3-oxazole (Example 69, 100 mg, 0.3 mmol) in dioxane (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (137 mg, 0.6 mmol), and the resultant mixture was heated at reflux for 16 h. After being cooled to rt, the mixture was diluted with water (10 mL), extracted with ethyl acetate (1×25 mL), washed with NaOH (0.5 N aq., 1×25 mL) and brine (1×25 mL), dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified by HPLC eluting with a gradient from 20% to 80% acetonitrile in water containing 0.1% TFA. The combined fractions were then diluted with ethyl acetate and washed with NaHCO3 (sat. aq., 1×25 mL) dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid (15 mg, 15%): 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), 7.73 (d, 2H), 7.29-7.35 (m, 2H), 7.21-7.25 (m, 1H), 7.04 (d, 2H), 6.95 (d, 2H), 6.62 (s, 1H), 5.28 (s, 2H), 2.20 (s, 3H), 2.18 (s, 3H); ES-MS m/z 330.12, HPLC RT (Method B) 3.89 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8]C2N=C(C(OCC)=O)C=CC=2)[CH:7]=1.Br[C:22]1[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:22]2[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[N:26][CH:27]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2O)n1
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(Cc2cc(Cl)ccc2O)c1

Procedure:
The title compound was prepared in a similar manner to ethyl 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridinecarboxylate using ethyl 5-bromo-3-pyridinecarboxylate instead of ethyl 6-bromo-2-pyridinecarboxylate. Rt=3.18 [MH+] 292, 294.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH2:59][NH2:60])([CH3:58])[CH2:55][CH2:56][CH3:57])([CH3:50])([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH3:58])([CH2:55][CH2:56][CH3:57])[CH2:59][NH:60][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=12)=[O:16])([CH3:48])([CH3:49])[CH3:50]
Reactant: Cc1cc(OCc2c(F)cccc2Cl)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A solution of 26 mg (0.074 mmol) of 7-(2-chloro-6-fluorobenzyloxy)-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 137A) in 3 ml of tetrahydrofuran was admixed with 17 mg (0.09 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 14 mg (0.09 mmol) of 1-hydroxybenzotriazole, 21 mg (0.096 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A and 0.039 ml (0.222 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for a further 18 hours. The reaction mixture was then heated to 60° C. for 3 hours. After concentration under reduced pressure, the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure, which gave 40 mg (99% yield) of the target compound.
Reaction SMILES: [Cl-:1].[NH4+].[N:3]12[CH2:13][CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2>>[ClH:1].[N:3]12[CH2:13][CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Product: Cl

Procedure:
26.8 g (0.5 mol) of ammonium chloride were introduced into a 500 ml stirred reactor fitted with nitrogen inlet and separate feed device and suspended in 200 ml of methanol. Over the course of 30 minutes 76.1 g (0.5 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added, where upon the reaction mixture was solubilized. The mixture was stirred for a further three hours and then the solvent was evaporated and the remaining solid dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[C:27]([N+:34]([O-:36])=[O:35])[C:5]=1[C:6]([NH:8][NH:9][C:10](=[O:26])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]=1[N+:23]([O-:25])=[O:24])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:5]1([C:6]2[O:26][C:10]([C:11]3[C:12]([N+:23]([O-:25])=[O:24])=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[CH:15][C:16]=3[N+:17]([O-:19])=[O:18])=[N:9][N:8]=2)[C:27]([N+:34]([O-:36])=[O:35])=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(NNC(=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])o2)c([N+](=O)[O-])c1

Procedure:
Dacons, Joseph C.; and Sitzmann, Michael E., Journal of Heterocylic Chemistry, 14, 1151-5 (1977) disclose the cyclization of N,N'-bis(2,4,6-trinitrobenzoyl)hydrazine with PCl5 in nitrobenzene to produce 2,5-dipicryl-1,3,4-oxadiazole in yields of 30-35 percent. Separation of the product 2,5-dipicryl-1,3,4-oxadiazole from nitrobenzene (b.p. 210° C.) is very difficult. The nitrobenzene is removed either by steam distillation or by pouring the nitrobenzene reaction mixture into a second solvent (e.g., methanol) in which 2,5-dipicryl-1,3,4-oxadiazole is much less soluble. However, combining the nitrobenzene with a second solvent makes it quite difficult to recycle the nitrobenzene for further use in the process. In summary, this procedure would be difficult and expensive to scale up for commercial production.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C@H:11]([CH2:16][OH:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:17][CH2:16][C@@H:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[C@@H:12]([CH3:13])[CH2:14][CH3:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-thiophenesulfonyl chloride (1 g, 5.48 mmol) in CH2Cl2 (5 mL) and (S)-isoleucinol (642 mg, 5.48 mmol) was added Hunig's base (1.05 mL, 6.02 mmol). The reaction mixture was stirred at 25° C. for 24 h. The solvent was removed and the oil was dissolved in EtOAc (100 mL). The solution was washed with water (2×100 mL), brine (1×100 mL), and dried over Na2SO4. The desired sulfonamide (m/z=264.0 (M+H), rt=0.79 min) was isolated by semi-preparative RP-HPLC using the conditions outlined for example 195.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=2)[C:16]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 5, from [5-(4-isopropylpiperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and 3-(trifluoromethyl)phenylboronic acid to afford the desired product as a light-brown foam (68%). MS (ISP): 606.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[N:9][CH:10]=1.Br[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17](OC)OC.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:22]1([C:16]2[S:13][C:12]([NH:11][C:8]3[N:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=3)=[N:14][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=S)Nc1ccc(CCCO)cn1
Reactant: COC(OC)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCCc1ccc(Nc2ncc(-c3ccccc3)s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[5-(3-Hydroxy-propyl)-pyridin-2-yl]-thiourea (7-4), 2.20 g (10.4 mmol) was stirred in 20 mL EtOH. (1-Bromo-2,2-dimethoxy-ethyl)-benzene (3.83 g, 15.6 mmol)was added, dissolved in 12 mL EtOH. The reaction was heated to reflux. After 30 min, 8 mL of concentrated HCl (aq) was added. After 7 h the reaction was cooled to RT, and diluted with water. Na2CO3 (s) was added to pH 9. The resulting precipitate was filtered, and washed with water. To solid was added ether, the mixture was sonicated and filtered, washing with ether. Afford the titled compound as a white solid. 1H NMR (CDCl3): δ8.74 (bs, 1H), 8.25 (d, 1H, J=2.2 Hz), 7.57 (dd, 2H, J=1.7, 9.0 Hz)7.49 (dd, 1H, J=2.4, 8.4 Hz), 7.38 (t, 2H, J=7.7 Hz), 6.83 (d, 1H, J=8.2 Hz), 3.71 (m, 2H), 2.70 (t, 2H, J=6.7 Hz), 1.89 (m, 2H). Mp 153-154° C. MS [M+H]+=312.2.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[F:26])=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:28]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:29]1[CH:37]=[CH:36][C:35]2[O:34][CH2:33][O:32][C:31]=2[CH:30]=1.O>CN(C=O)C>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH2:28][C:29]3[CH:37]=[CH:36][C:35]4[O:34][CH2:33][O:32][C:31]=4[CH:30]=3)[CH2:39][CH2:40]2)=[O:27])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(2-fluoro-4-nitrophenoxy)phenyl]carbamate phenyl ester (0.700 g, 1.90 mmol) in DMF (15 mL) was added 1-piperonylpiperazine (0.460 g, 2.09 mmol), and the resulting solution was stirred for 2 hours at room temperature. water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.939 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36](=[O:37])[CH2:35][CH2:34][C:33]4=[O:38])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:39])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:39])[C:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:33](=[O:38])[CH2:34][CH2:35][C:36]4=[O:37])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc(CN3C(=O)CCC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {5-[({1-[4-(2,5-Dioxo-pyrrolidin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carbonyl}-amino)-methyl]-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (48 mg, 0.08 mmol), 1 mL TFA and 2 mL DCM was stirred of room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 250×40 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min). The product containing fractions were lyophilised, then dissolved in 1 mL MeOH and the resulting mixture was filtered over a MeOH flushed PL-HCO3 MP-resin column. The column was washed with MeOH, the solvent was removed and the product was dissolved in water/ACN and lyophilised to yield the title compound. 1H-NMR (DMSO-d6, 400 MHz) 88.25 (s, 1H), 7.91 (t, 1H), 7.87 (s, 1H), 7.24 (d, 2H), 7.20 (d, 2H), 6.13 (s, 1H), 5.70 (bs, 2H), 5.28 (s, 2H), 4.52 (d, 2H), 2.67 (s, 4H), 2.29 (s, 3H), 2.15 (s, 3H); LCMS (method A) RtA=0.439 min; [M+H]+=447.1.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([OH:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>[Pt].C(O)(C)C>[CH3:1][C:2]([CH3:19])([OH:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Product: CC(C)(O)CNc1c(N)cnc2cccnc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a suspension of 1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (7 g, 26 mmol) in isopropanol (300 mL). The mixture was hydrogenated on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 3 hours. The reaction mixture was fileted to remove the catalyst. The filtrate was concentrated under vacuum. Toluene was added to the residue and the mixture was concentrated under vacuum to remove all of the alcohol and provide crude 1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]4)[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(CO)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 4-piperidinemethanol (172 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 0.5 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (69 mg, 58%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11](=[O:16])[C:12]#[C:13][CH2:14][CH3:15].[Cl-]>C(N(CC)CC)C.[Cu]I>[CH3:9][O:10][C:11](=[O:16])[CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1
Reactant: CCC#CC(=O)OC
Reactant: Brc1cccc(Br)n1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1cccc(Br)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of 4.73 g of 2,6-dibromopyridine in 150 ml of triethylamine is mixed under ice cooling with 2.69 g of pentynoic acid methyl ester, 350 mg of bis-triphenylphosphinepalladium(II) chloride and 48 mg of copper(I) iodide and the mixture is stirred for 1 hour. Then, the ice bath is removed and it is stirred for 3 hours at room temperature. The precipitate--consisting of 2,6-bis-(4-methoxycarbonyl-1-butinyl)-pyridine and triethylammonium bromide--is suctioned off and the filtrate is evaporated to dryness. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5 to 75/25. 2.32 g of 5-(6-bromo-2-pyridyl)-4-pentynoic acid methyl ester of melting point 59°-61° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=O.CC(C)([O-])C.[K+].[C:26]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:27][CH2:28][C:29]([O-:31])=[O:30].Cl>C(O)(C)(C)C.O>[CH2:34]([O:33][C:26]([C:27](=[C:5]([C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:32])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cccc(F)c2)cc1
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Yield: 75.6 %

Procedure:
35.5 g (0.1275 mol) of 3-fluoro-4'-methanesulfonylbenzophenone, prepared in Example 10, are added in portions to a solution of 15.7 g (0.140 mol) of potassium t-butoxide in 100 ml of t-butanol. The mixture is stirred and 32 ml (0.191 mol) of ethyl succinate are added dropwise at a rapid rate. The mixture is subsequently refluxed for 30 minutes and cooled, water and 1N hydrochloric acid are added to bring the pH to 1 and the mixture is then extracted with t-butyl methyl ether. The organic phase is treated with 2% sodium hydroxide solution and the mixture is decanted. The aqueous phase is acidified with 1N hydrochloric acid and then extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 39.2 g of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid in the form of a thick oil, which is used as such in the next step.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:18][C:19]1[CH:20]=[C:21]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)[CH:24]=[CH:25][N:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCNc1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCNc1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 18.1 %

Procedure:
Methyl thiosalicylate (0.44 g, 2.6 mmol) and 2-(hexylamino)isonicotinonitrile (0.26 g, 1.3 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.40 ml, 2.9 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs, subjected to a silica gel (50 g) chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.08 g, 18%) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(COc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(COc2ccccc2Cl)CCNCC1
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
After dissolving 810 mg of 1-(tert-butoxycarbonyl)-4-(2-chlorophenoxymethyl)-4-methylpiperidine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was all owed to stand at room temperature for 2.5 hours. A sodium carbonate solution was added to the reaction solution, and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (521 mg, 91% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Sc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)[nH]2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(OC)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(4-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is agitated for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 3.92 g of 4,5-bis(4-methoxyphenyl)-2-(4-methoxyphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23]CC)=[O:22].[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 68D (1.70 g, 5.04 mmol) was dissolved in ethanol (40 mL). A solution of lithium hydroxide (1.20 g, 50.10 mmol) in water (10 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI+) m/z 310 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O.CCOC(C)=O>[CH2:1]([O:8][N:9]([CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)[CH:22]=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2SC1CNOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN(CC1Sc2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one (2.96 mmol) in 15 mL of formic acid at 0° C., acetic anhydride is added (15.1 mmol) and the reaction is stirred at room temperature overnight. The mixture is diluted with EtOAc and washed with water followed by brine and NaHCO3. Purification by column chromatography (hexane/EtOAc) gives N-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide. Yield: 81%. MS: (ES+): 329.2 [M+1].