Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17](Br)[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2].[CH3:32]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC(=O)OCC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:32])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(Br)c2n(C)c1=O
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(C)c2n(C)c1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 3-(7-bromo-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (150 mg, 0.297 mmol) in dioxane (2 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (112.0 mg, 0.892 mmol), Cs2CO3 (290.8 mg, 0.892 mmol) and Pd(dppf)Cl2 (20 mg, 0.0274 mmol). The reaction was heated at 150° C. (MW) for 30 min, cooled to RT then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy) phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (120 mg, 91.8% yield) as a solid. LCMS: MH+ 440 and TR=1.571 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[O:27]
Reactant: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C=O)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 0.074 mol, 1.0 equiv.) in dioxane (250 mL) and water (80 mL). To this solution was added sodium periodate (36.77 g, 0.17 mol, 2.3 equiv.) and osmium tetroxide (15 mL, 4% aq. soln.) at 0° C., and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×750 mL). The organic layers were combined, washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (15 g, 77%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.S(=O)(=O)(O)O.[CH3:20]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:20])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1
Reactant: COc1cc2cc(C(=O)O)[nH]c2cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc(OC)ncc2[nH]1
Reaction time: 8 h

Procedure:
To 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1 g, 5.20 mmol) in methanol (100 ml) was added sulfuric acid (0.014 ml, 0.260 mmol). The resulting solution was heated to reflux and stirred at this temperature overnight. Then extra sulfuric acid (0.277 ml, 5.20 mmol) was added and heated at reflux for five days. The heating was stopped and the reaction mixture was concentrated to a smaller volume. The resulting suspension was diluted with ethyl acetate and washed with an aqueous saturated sodium hydrogen carbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give methyl 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (910 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: O=C1CCOCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: Clc1ncc2c(n1)N1CCOC[C@H]1CN2C1CCOCC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol), dihydro-2H-pyran-4-(3H)-one (110 mg, 1.103 mmol), titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) and sodium triacetoxyhydroborate (514 mg, 2.427 mmol) in CH2Cl2 (8 mL) (10 mg, 3%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O2, 311.13; found 311.2.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:21]1[O:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][C:23]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-ethyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.97 min; [M+H]+=405.16.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2c(Cl)c(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)ncnc2c1Cl
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 7,8-dichloro-3H-quinazolin-4-one (0.72 g, 3.35 mmol) in phosphorus oxychloride (6.6 g, 12.8 mmol) was heated at reflux for about 4 hours. The reaction mixture was cooled at ambient temperature then added dropwise to ice-cold water. The precipitate was collected by filtration and dried in vacuo to give 4,7,8-trichloroquinazoline as a brown solid (0.64 g, 2.74 mmol, 82%).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:20]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31](I)[C:25]=2[CH:24]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH3:19])[C:25]=2[CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc2c(I)cccc2s1
Reactant: CCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-propoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene (see Example 14, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:38][CH2:37][C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CCO
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCC(C)(C)C)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.042 g, 0.090 mmol), 3,3-dimethylbutan-1-ol (0.046 g, 0.448 mmol) and Ph3P (0.071 g, 0.269 mmol) in THF (5 mL) was added DEAD (0.043 ml, 0.269 mmol) at 0° C. After 1 h, cold bath was removed and stirred overnight (15 h) at rt. Then, reaction mixture was concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-(3,3-dimethylbutoxyl)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0205 g, 0.037 mmol, 41.4% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.14-7.17 (m, 1H), 7.05-7.09 (m, 1H), 6.95-6.99 (m, 2H), 6.09 (s, 1H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.17 (qd, J=7.1, 10.7 Hz, 1H), 4.08-4.13 (m, 2H), 3.19 (d, J=11.8 Hz, 1H), 2.88 (t, J=12.1 Hz, 1H), 2.61 (s, 3H), 2.28 (d, J=11.8 Hz, 1H), 2.21 (s, 3H), 2.07 (t, J=11.8 Hz, 1H), 1.79 (t, J=7.3 Hz, 2H), 1.56 (td, J=3.7, 12.4 Hz, 1H), 1.34-1.42 (td, J=3.5, 12.5 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.17-1.20 (m, 1H), 1.08 (d, J=12.9 Hz, 1H), 1.04 (s, 9H), 0.90 (s, 3H), 0.66 (s, 3H). LCMS (M+H)=553.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([O:26][CH3:27])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]3[CH2:22][CH2:23][CH2:24][C:17]=3[C:16]=2[CH:25]=1.Br.Br.[OH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C.C(Cl)(Cl)Cl>[OH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][N:40]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([O:26][CH3:27])=[CH:14][C:15]3[O:20][C:19](=[O:21])[C:18]4[CH2:22][CH2:23][CH2:24][C:17]=4[C:16]=3[CH:25]=2)[CH2:39][CH2:38]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: Oc1ccccc1N1CCNCC1
Agent: Br
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2O)CC1)CCC3
Yield: 54 %

Procedure:
Method A (40 h at 50° C.; 4 equivalents of potassium carbonate); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-hydroxyphenyl)piperazine dihydrobromide; yield 54%; fusion point 136°-139° C. (from chloroform and ethanol). Fumarate: method E; yield 84%; fusion point 196°-199° C. (from acetone).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[NH:24])[NH:15][CH:16]([CH3:23])[C:17]1C=CC=CC=1>CC(N)C>[OH:1][C:2]1[C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[NH:24])[NH:15][CH:16]([CH3:17])[CH3:23]
Reactant: CC(NC(=N)c1cccc(Cc2c[nH]cn2)c1O)c1ccccc1
Solvent: CC(C)N
Product: CC(C)NC(=N)c1cccc(Cc2c[nH]cn2)c1O
Temperature: 80 °C
Reaction time: 46 h
Yield: 31 %

Procedure:
5 g (0.0156 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-N-α-methylbenzyl-benzenecarboximidamide prepared in 1.a) above and 50 ml of 2-propanamine are placed in a digester and are heated at 80° C. for 54 hours, then at 100° C. for 46 hours. The solvent is evaporated and the residue is purified by preparative liquid chromatography (silica: 600 g; eluent: 89:10:1 (v/v/v) mixture of dichloromethane-methanol-ammonia). After evaporation of the solvents, 3.6 g of a pale yellow solid product are obtained which are recrystallized twice from acetonitrile. 1.25 g of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-N-(1-methylethyl)-benzenecarboximidamide are obtained. Yield: 31%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:17])#[C-:15].C(=O)([O-])[O-].[K+].[K+].O>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:15]=[N:14][C:16]=2[CH3:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of 3-fluoro-4-(trifluoromethyl)benzaldehyde (0.96 g, 5.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.05 g, 5.00 mmol), and potassium carbonate (0.898 g, 6.50 mmol) was heated to reflux for 2 hours in methanol (25 mL). After this time, the reaction mixture was cooled to room temperature and poured into water, then extracted with ether. Chromatography on silica gel (20 to 40% ethyl acetate-hexane, eluant) afforded the title compound as an off-white solid (1.01 g, 82% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.90 (m, 1H), 7.68 (m, 2H), 2.43 (s, 3H). MS (DCI+) m/z 246 (M+H), 263 (M+NH4).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:33]([CH:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:26])[CH2:28][CH2:29]3)=[O:34])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Product: CCC(NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 300 mg (1.35 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 355 mg (1.35 mmol) 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:13]([O-])([OH:15])=[O:14].NC1C([N+]([O-])=O)=NC=CC=1.NC(C)C#N>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccncc1
Agent: CC(N)C#N
Agent: Nc1cccnc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Nc1ccncc1[N+](=O)[O-]

Procedure:
4-Amino-3-nitropyridine was synthesized by a literature reference [Harris M. G. and Stewart R. Can. J. Chem. 55, 3800 (1977)]; by nitration of 4-aminopyridine with conc. sulfuric acid and fuming nitric acid. This aminonitropyridine was then converted to the aminopropionitrile derivative IV by the method described in Example 1.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[N:35]=[C:34]4[CH2:36][NH:37][CH2:38][CH2:39][C:33]4=[N:32][C:31]=3[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:26][CH2:25]2)=[O:23])[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([CH:21]=1)[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][N:37]([C:5](=[O:7])[CH3:6])[CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:42])[CH3:43])[CH2:26][CH2:25]1)=[O:23].[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(C(=O)c4cc(Cl)ccc4F)CC3)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (3 μL, 0.034 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (9.2 mg, 0.017 mmol) and pyridine (4 μL, 0.051 mmol) in DCM (170 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.0 mg, 40.4%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30-1.34 (m, 6H), 1.88-2.04 (m, 4H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.92 (m, 1.1H), 2.93-3.02 (m, 2H), 3.34-3.43 (m, 1H), 3.50-3.59 (m, 2H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.08-4.17 (m, 1H), 4.54 (br s, 2H), 7.25-7.32 (m, 1H), 7.59-7.63 (m, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([O:18]CC)=[O:17])[C:8]2=[O:21])#[N:2].[C@H:24]12[CH2:32][NH:31][CH2:30][C@@H:29]1[NH:28][CH2:27][CH2:26][O:25]2.O.[OH-].[Li+].[ClH:36]>C(#N)C.O.C(N(CC)CC)C>[ClH:36].[C:1]([C:3]1[C:4]([N:31]2[CH2:32][C@H:24]3[C@@H:29]([NH:28][CH2:27][CH2:26][O:25]3)[CH2:30]2)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:21])#[N:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: N#Cc1c(N2C[C@@H]3NCCO[C@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.63 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are stirred under argon at 40-45° C. for 2 hours with 97 mg (0.75 mmol) of (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.17 ml of triethylamine in 3 ml of acetonitrile. All volatile components are removed in vacuo, the residue is treated with water, insoluble material is filtered off and the filtrate is extracted with dichloromethane. The organic phase is dried over sodium sulphate and then concentrated in vacuo. The resulting residue is dissolved in 6 ml of tetrahydrofuran and 2 ml of water and treated with 30 mg (0.72 mmol) of lithium hydroxide monohydrate. After stirring at room temperature for 16 hours, the mixture is acidified with dil. hydrochloric acid and the resulting precipitate is filtered off with suction and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].Cl.N([O-])=O.[Na+].[PH2](O)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cc(N)cc1Br
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: Cc1c(Br)cccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and the solution of NaNO2 (3.4 g/30 mL H2O) was added. The reaction mixture was stirred for 2 h at 0˜5° C., then the suspension was added to hypophosphorous acid solution (50%, 27.9 g), which was cooled to 0° C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL×2) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. After silica column chromatography, (eluted with petroleum ether), 3.57 g product was obtained, as colorless liquid. 1H NMR (400 MHz, CDCl3): δ 2.57 (s, 3 H), 6.89 (t, J=8.0 Hz, 1 H), 7.50 (d, J=8.0 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC#N>[CH2:19]([O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[CH:18]=[CH2:17]
Reactant: COc1ccc(Br)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(OC)ccc1Br
Temperature: 25 °C
Yield: 111 %

Procedure:
To a solution of 4-bromo-3-hydroxyanisol (14.49, 59.3 mmol), synthesized by known methods, in CH3CN (200 ml), dry potassium carbonate (20 g) and allylbromide (8.0 ml, 92.4 mmol) was added. The reaction mixture was stirred and refluxed for 1 hour and thereafter cooled to room temperature, filtered and evaporated. The residue was dissolved in ether and extracted with water. The organic layer was separated and dried (Na2SO4). Evaporation of the solvent afforded 16.0 g (93%) of 3-allyloxy-4-bromoanisol as an oil. GC/MS (HP-5970A) m/e=244 (40) M+ and M+ -1 at m/e=242 (40), 163 (100), 149 (97), 135 (62).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1(OC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:24]3([O:23][CH3:22])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1(OC)CCCCCCC1
Product: COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCC1
Yield: 13.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-dimethoxycyclooctane (1.62 g, 10 mmol) in the same manner as the example 20 to give the compound 30 (66 mg, 13%). Mp 54-56° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[OH:8].[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][N:13]=1.O>O1CCCC1.[Cl-].[Na+].O>[CH:4]12[CH2:7][CH:1]([CH2:2][CH2:3]1)[CH2:6][CH:25]2[O:24][C:22]([C:15]1[C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]([O:8][C@@H:2]2[CH2:3][C@@H:4]3[CH2:7][C@H:1]2[CH2:6][CH2:5]3)=[N:13][CH:14]=1)=[O:23]
Reactant: OC1CC2CCC1C2
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OC1CC2CCC1C2)c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
To a solution of rac-(1R,2R,4S)-bicyclo[2.2.1]heptan-2-ol (1.12 g) in tetrahydrofuran (10 mL) was added 60% sodium hydride (400 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was further stirred at an external temperature of 60° C. for 30 minutes, and then ice-cooled, and a mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (481 mg) and tetrahydrofuran (2 mL) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture were added water and saturated brine, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=100:0 to 97:3) to obtain a mixture (351 mg) of rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate and rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate as a colorless oily substance.