Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:13]([O:14][CH3:15])=[CH:12][C:10]([NH2:11])=[C:9]([Cl:16])[CH:8]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[NH2:11][C:10]1[C:9]([Cl:16])=[CH:8][C:7]([CH:24]=[O:25])=[C:13]([O:14][CH3:15])[CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1cc(N)c(Cl)cc1Br
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Isopropylmagnesium chloride (2M in tetrahydrofuran, 23 ml, 46 mmol) (commercially available, for example, from Aldrich) was added over 5 minutes to a stirred solution of 4-bromo-2-chloro-5-methoxyaniline (Step A) (10 g, 42 mmol) in tetrahydrofuran (70 ml) at −10° C. The resulting solution was allowed to warm to 0° C. over 50 minutes to give a thick slurry, then cooled to −25° C. and n-butyllithium (1.6M in hexanes, 90 ml, 144 mmol) was added over 20 minutes followed by tetrahydrofuran (20 ml). The solution was warmed to −10° C. over 30 minutes and then N,N-dimethylformamide (16 ml, 207 mmol) was added over 5 minutes and the resulting thick slurry was warmed to 0° C. over 20 minutes. A solution of citric acid (22 g, 105 mmol) in water (50 ml) was added cautiously over 15 minutes keeping reaction at <10° C. The slurry was aged at 20° C. for 30 minutes then filtered under vacuum. The cake was washed with water (100 ml) and then dried under vacuum at 40° C. for 16 hours to give 4-amino-5-chloro-2-methoxybenzaldehyde (6.1 g, 80% th) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[O:9][CH:8]([CH3:10])[CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][N:2]1[O:9][CH:8]([CH3:10])[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2C(C)ON(C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1ON(C)C2CNCC12

Procedure:
13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 39 g of Ba(OH)2.8H2O in 200 ml of water overnight. K2CO3 is added, the BaCO3 is filtered off with suction and the filtrate is extracted several times with CHCl3. The extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4](OS(C)(=O)=O)[CH2:5][O:6][CH3:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(N(C)C)=O.O>[CH3:1][O:2][CH2:3][CH:4]([N:13]=[N+:14]=[N-:15])[CH2:5][O:6][CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: COCC(COC)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCC(COC)N=[N+]=[N-]
Reaction time: 24 h
Yield: 72.5 %

Procedure:
1,3-Dimethoxy-2-methanesulphonyloxypropane (Method 49; 3.74 g, 19 mmol) and sodium azide (2.03 g, 31 mmol) in DMA (55 ml) was heated at 100° C. for 8 hours then left to stand at ambient temperature for 24 hours. The mixture was diluted with water, extracted with ethyl acetate, the extracts combined and washed with water, dried (MgSO4) and the volatiles removed by evaporation to give the title compound (2.0 g, 74%) as a clear oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1>>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:11]=3)[N:29]2[N:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CSc1ncc2ccc(Br)n2n1
Product: CSc1ncc2ccc(-c3ncccn3)n2n1
Yield: 20.6 %

Procedure:
Analogous to Example 1562a, 2-Tributylstannanyl-pyrimidine (0.761 g, 2.06 mmol) and 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.224 g, 0.916 mmol) were reacted to afford 2-Methylsulfanyl-7-pyrimidin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 20%). 1H-NMR (DMSO-d6): 9.14 (s, 1H), 8.95 (d, 2H, J=4.94 Hz), 7.58 (m, 1H), 7.44 (t, 1H, J=4.83 Hz), 7.10 (d, 1H, J=4.83 Hz), 2.59 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3](=[O:12])[C:4]([CH3:11])([S:6][C:7]([F:10])([F:9])[F:8])[CH3:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][C:4]([S:6][C:7]([F:10])([F:9])[F:8])([CH3:11])[C:3](=[O:12])[CH2:2][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(SC(F)(F)F)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(SC(F)(F)F)C(=O)Cn1cncn1
Yield: 61.2 %

Procedure:
26.5 g (0.1 mol) of 1-bromo-3-methyl-3-trifluoromethylthio-butan-2-one were added dropwise to a mixture of 8.3 g (0.12 mol) of 1,2,4-triazole and 28 g (0.2 mol) of potassium carbonate in 150 ml of acetone at room temperature. The mixture was subsequently stirred under reflux for 1 hour, the inorganic salts were filtered off and the filtrate was concentrated. The residue was taken up in methylene chloride, washed with water, dried over sodium sulphate and distilled. 15.5 g (62% of theory) of 3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylmercapto-butan-2-one of boiling point 91° C./0.5 mm Hg and of melting point ~45° C. were obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].Cl>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: OCCCCCCCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCO)ccc(C(C)=O)c1O

Procedure:
A solution of 10 g. of 2,4-dihydroxy-3-propylacetophenone, 8 g. of potassium carbonate, and 7.1 g. of 6-chloro-1-hexanol in 50 ml. of methyl ethyl ketone was heated to reflux overnight. Upon cooling, dilute hydrochloric acid was added and the resulting organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The residue was purified by chromatography giving 2.87 g. of the title product as an oily solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2](/[N:1]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:3][C:4](=[O:9])[NH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(O)ncc1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)/C=N/c1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoropyrimidin-2-ol (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (DMF-DMA; 4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with Et2O (200 mL), and filtered. The solid product was washed with heptane to give (E)-N′-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (5.23 g, 92%) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); ESIMS m/z 185 ([M+H]+), m/z 183 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[C:4]([CH3:19])[CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Cl)ccc1Oc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Oc2cccc3ccccc23)c(CBr)c1
Yield: 38.7 %

Procedure:
1-(4-Chloro-2-methylphenoxy)naphthalene (1.8 g) from Example 1 was dissolved in carbon tetrachloride (10 ml), followed by addition of NBS (1.2 g) and a catalytic amount of benzoyl peroxide under reflux for 2 hours. After leaving the solution to stand at room temperature, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ether=99:1) to give the title compound (900 mg; 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[CH3:22])=[O:16])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.ClCCCl>[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[C:20]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1[nH]ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (4-chlorophenyl)-acetyl chloride (3 mmol) in dichloromethane or 1,2-dichloroethane (4 ml) was added to a solution cooled at −40° C. of 84 (0.229 g, 1.5 mmol) and AlCl3 was added (0.400 g, 3 mmol). The reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with NaOH (2 M) and brine, dried over Na2SO4, and evaporated to dryness under vacuum to give crude product 85. Crude yield: 96%
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1)=O.Cl.[NH2:32][OH:33].C(O)C.[OH-].[K+]>N1C=CC=CC=1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4](=[N:32][OH:33])[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:19](=[O:20])[N:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[N:16][C:15]=2[CH3:25])[CH2:8][CH2:7]1
Reactant: NO
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3F)CC1)CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
To a solution of 7.0 g (0.0143 mole) of 3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 70 ml of pyridine, 5.4 g (0.0777 mole) of hydroxylamine hydrochloride and 100 ml of ethanol 1.6 g (0.0286 mole) of potassium hydroxide are added. The reaction mixture is heated to boiling for 10 hours, cooled to room temperature and the solvent is removed in vacuo. To the residue 100 ml of water are added and the mixture is extracted with 100 ml of dichloromethane. The organic phase is washed twice with 50 ml of water each, dried over anhydrous magnesium sulfate and evaporated. The residual crude product is recrystallized from ethyl acetate. Thus 4.2 g of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one are obtained. Yield 65.1%. According to HPLC analysis the purity of the product is 97.2%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([C:34]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[O:35])[CH:29]=1
Reactant: NCc1ccc(F)cc1C(=O)N1CCOCC1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)N1CCOCC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 44, (2-(aminomethyl)-5-fluorophenyl)(morpholino)methanone. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.59 (6H, s), 3.29 (2H, brs), 3.57 (2H, m), 3.74 (4H, s), 3.98 (4H, m), 5.26 (2H, s), 6.88 (1H, dd, J=8.2, 2.7 Hz), 7.03 (1H, dt, J=8.5, 2.5 Hz), 7.24–7.33 (3H, m), 7.42 (2H, dd, J=8.6, 5.3 Hz), 7.47 (2H, dd, J=7.5, 2.0 Hz), 8.18 (1H, t, J=6.4 Hz); LC/MS m/z 551 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])[C:29](OC)=O>C1COCC1>[Cl:25][C:26]1[CH:27]=[C:28]([C:29]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl

Procedure:
1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 15) (170 mg, 0.557 mmol) was dissolved in THF (30 ml) and stirred with sodium hydride (24.49 mg, 0.612 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (may be prepared as described in WO2005058848) (191 mg, 0.835 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 ml) and water (100 ml). The water layer was washed with DCM (50 ml) and the combined DCM layers dried (hydrophobic frit) and evaporated. The title compound was isolated by silica chromatography (eluting with DCM). 1,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (260 mg, 0.537 mmol, 96% yield) was isolated as an off-white foam. δH (400 MHz, CDCl3) 8.22 (1H, s), 8.05 (1H d), 7.68 (1H, d), 7.30-7.24 (2H, m), 7.06 (1H, d), 4.72 (1H, sept), 3.65-3.55 (4H, m), 3.35-3.25 (2H, m), 2.95-3.05 (2H, m); 1.45 (6H, d), 1.43 (9H, s); MS (ES) C26H3035ClN3O4 requires 483; found 484 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[C@H:3]1[C:15]([O:17]C(C)(C)C)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11]([Cl:13])([Cl:14])[Cl:12])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A mixture of 11.4 g of the product of Step A, 120 ml of toluene and 300 mg of p-toluene sulfonic acid was refluxed for one hour and was cooled to room temperature. The mixture was washed with water, dried and evaporated to dryness under reduced pressure to obtain 9.5 g of (1R,cis)2,2-dimethyl-3-[2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylic acid which used as is for the next step.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH3:24])[N:6]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)nn1C
Yield: 90 %

Procedure:
As described for example 115, 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (76 mg, 90%) which was obtained as a colorless oil. MS: m/e=398.2 [M+H]+.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:5](=O)[CH3:6].[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16]>>[CH3:6][C:5]1[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=[CH:3][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CC(=O)/C(=C/N(C)C)c1ccccc1
Product: Cc1c(-c2ccccc2)cnn1-c1cc(C#N)ccn1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from (3E)-4-(dimethylamino)-3-phenylbut-3-en-2-one and 2-hydrazinylisonicotinonitrile (PREPARATION 2) according to the procedure for the preparation of Example 28, part D. [M+H] Calc'd for C16H12N4, 261; Found, 261.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8](C(C3C=CC=CC=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Clc1ccc2cc[nH]c2n1

Procedure:
A solution of (Intermediate C3) (3.12 mmol) in MeOH (90 mL) was treated with 1 M NaOH (30 mL) at rt for 18 h. The solution was freed of MeOH under reduced pressure and ethyl acetate was added to the aqueous layer. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sat. NaHCO3, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated to give a solid 6-chloro-1H-pyrrolo[2,3-b]pyridine (Intermediate C4).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Br:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 118° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (s, 1 H), 7.24 (s, 1 H), 7.13 (s, 1 H), 4.98–4.90 (m, 1 H), 4.32 (t, J=7.9 Hz, 2 H), 3.66 (dd, J=10.7, 5.9 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.13 (t, J=7.9 Hz, 2 H), 1.85–1.74 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2Br2Cl (M+H)+: 489.0543; Found m/z 489.9534.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:28][CH3:29])[CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].ClC1C=C(C=C(Cl)C=1)C(N(C[C@H](C1C=CC(F)=CC=1)CC=C)C)=[O:35]>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:28][CH3:29])[CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:35])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Product: CCN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2c1CCCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 21b but using 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide rather than 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide (yield, 70%). 1H NMR (500 MHz, CDCl3): 0.9-4.2 (cm, 18H), 5.9 (s, <1H), 6.9-7.5 (cm, 6H), 8.0 (s, <1H), 9.7 (m, 1H). LCMS: m/z 393 (M+1)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][CH2:14][C:15]([CH3:19])([OH:18])[C:16]#[CH:17]>>[Cl:13][CH2:14][C:15]([C:16]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:3]2[C:2]([CH:17]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:18])[CH3:19]
Reactant: C#CC(C)(O)CCl
Reactant: CS(=O)(=O)Nc1ccccc1I
Product: CC(O)(CCl)c1cc2ccccc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Example C, from N-(2-iodo-phenyl)-methanesulfonamide (1.65 g, 5.55 mmol) and 1-chloro-2-methyl-but-3-yn-2-ol (0.79 g, 6.66 mmol) to yield a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([I:17])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:15]([I:17])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(I)nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(nc(I)n2COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of 2-iodo-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 21, 17.25 g, 49.4 mmol) in THF (250 mL) was added NaH (60% in paraffin oil, 2.08 g, 51.9 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C. and SEM-Cl (9.18 mL, 51.9 mmol) was added dropwise. The reaction was stirred at room temperature for 18 hours, cooled to 0° C. and quenched carefully with water (500 mL). The resulting solution was extracted with EtOAc (2×500 mL) and the combined organics layers were dried over MgSO4, filtered through a pad of silica and concentrated in vacuo to give the title compound (23.4 g) in a 99% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: CCOC(=O)c1cccnc1Cl
Solvent: CCO
Product: CCCCNc1ncccc1C(=O)OCC

Procedure:
Ethyl 2-chloropyridine-3-carboxylate (8.00 g) was heated at 100° C. for 5 hours with 16 mL of n-butylamine and 34 mL of ethanol in an autoclave. The product was chromatographed on silica gel to give 7.69 g of ethyl 2-butylaminopyridine-3-carboxylate. This compound was reacted with N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole, prepared as described by P. E. Aldrich, et al., in European Patent Application Number 291969, using the procedure described in Example 87 to give ethyl 2-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyridine-3-carboxylate in 61% yield. m.p. 90°-94° C. Treatment of 1.50 g of this compound with 14 mL of methylene chloride and 21 mL of 88% formic acid for 1 hour at ambient temperature gave 690 mg of the title compound. m.p. 120°-121° C. 1H NMR (CDCl3, 300 MHz) d 0.85 (t, J=7 Hz, 3H), 1.22 (m, 2H), 1.36 (t, J=7 Hz, 3H), 1.55 (m, 2H), 3.29 (t, J=7 Hz, 2H), 4.31 (q, J=7 Hz, 2H), 4.60 (s, 2H), 6.69 (dd, J=4 Hz, 8 Hz, 1H), 7.11 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.45 (dd, J=8 Hz, 2 Hz, 1H), 7.50-7.70 (m, 4H), 7.92 (dd, J=8 Hz, 1 Hz, 1H), 8.05 (dd, J=4 Hz, 2 Hz, 1H), 8.17 (dd, J=8 Hz, 1 Hz, 1H).