Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[C:9]([F:19])[CH:8]=1.[C:20](=[O:22])=[O:21]>C1COCC1.O>[CH:15]1([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17][CH2:16]1
Reactant: Fc1cc(Br)ccc1COC1CCC1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COC2CCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6 M in hexane; 7.0 ml) was added to a solution of 4-bromo-1-cyclobutoxymethyl-2-fluorobenzene (2.6 g) in THF (50 ml) at −78° C. After 15 minutes, dry ice (4.4 g) was added. After warming to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The aqueous phase was acidified and again extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 224.23 (C12H13FO3); MS (ESI): 225 (M+H+) was obtained in this way.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[I-].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Yield: 102.1 %

Procedure:
A solution of 4-methyl-2'-nitro-1,1'-biphenyl (Step J) (6.0 g, 28.2 mmol), N-bromosuccinimide (4.99 g, 28.2 mmol) and AIBN (653 mg) in 75 mL of carbon tetrachloride was heated at reflux until a negative potassium iodide test was obtained (1.5 h). The reaction mixture was cooled and filtered. The filtrate was evaporated under vacuum to yield 8.41 g of crude product. 1H NMR revealed the product composition was approximatly 75% monobromo and 10% dibromo, in addition to 15% of unreacted starting material. 1H NMR (200 MHz, CDCl3): δ 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, 1H). EI-MS: calculated for C14H10BrN 272; found 272,274 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:13][C:14]1[C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Product: CN1CCC(Oc2cccc(Cl)c2C(F)(F)F)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-6-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCCOC1CCCCO1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.32 ml of methanesulfonyl chloride dissolved in 10 ml of benzene was added dropwise, whilst ice-cooling, to a solution of 4.32 g of 7-(tetrahydropyran-2-yloxy)-1-heptanol and 5.56 ml of triethylamine dissolved in 80 ml of benzene. The mixture was stirred at room temperature for 1 hour, after which it was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 5.86 g of 7-(tetrahydropyran-2-yloxy)heptyl methanesulfonate, as an oil.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH2:40][CH2:41][O:42][CH2:43][CH:44]=2)O1>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>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:39]4[CH2:44][CH2:43][O:42][CH2:41][CH:40]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(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: [Cs+]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCOCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, cesium carbonate, 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ ppm 8.85 (t, J=6.00 Hz, 1H), 7.95-8.05 (m, 3H), 7.77 (d, J=9.00 Hz, 1H), 6.98 (s, 1H), 4.33-4.35 (m, 2H), 3.86 (t, J=5.48 Hz, 2H), 3.26-3.28 (m, 2H), 2.66-2.70 (m, 2H), 2.00-2.07 (m, 2H), 1.74-1.87 (m, 5H), 1.23-1.31 (m, 2H). m/z: 421 [M+H]+
Reaction SMILES: [BrH:1].[O:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[Br:1][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: Br
Solvent: ClCCl
Product: BrCc1ccccc1Oc1ccccc1

Procedure:
Add 2-Phenoxy-benzoic acid (1 g, 4.67 mmol), in several portions, to a suspension of Lithium aluminium hydride (372 mg, 9.33 mmol) in dry THF (20 ml) at room temperature and stir. After 1 h, add aqueous 1M HCl dropwise carefully, then pour into H2O and extract three times with Et2O. Combine the organic phases, dry over Na2SO4 and concentrate at vacuum to yield pure (2-Phenoxy-phenyl)-methanol as courless oil. Add aqueous concentrated HBr (16 ml) to a solution of (2-Phenoxy-phenyl)-methanol (900 mg, 4.5 mmol) in CH2Cl2 (5 ml) and stir at room temperature. After 1 h. separate the organic phase and wash the aqueous one with CH2Cl2. Combine organic phases, wash with H2, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane:CH2Cl2, 2:1 to afford 1-Bromomethyl-2-phenoxy-benzene as colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 7.44-7.01 (m, 8H), 6.84 (d, J=1.2 and 8.0 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:6]([CH:8]([CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.C([O-])(=O)C.[NH4+:33].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:33]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccc(OC)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccc(OC)c(OC)c1
Yield: 62 %

Procedure:
A mixture of ethyl 2-(3,4-dimethoxybenzoyl)-5-oxo-5-phenylvalerate (compound no. 314; 7.7 g; 0.02 mole), ammonium acetate (3.1 g; 0.04 mole) and acetic acid (30 ml) is heated to reflux temperature for 4 hours. The reaction medium is poured into water (300 ml): an oil in released. The latter is extracted with ethyl acetate (200 ml). The organic solution is washed with water (3×100 ml), then dried over anhydrous magnesium sulphate and concentrated under reduced pressure. A light brown oil (4.5 g; yield: 62%) is obtained which corresponds to ethyl 2-(3,4-dimethoxyphenyl)-6-phenylnicotinate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:13].[K+]>O.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)([OH:13])=[O:2]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-formylphenylboronic acid (3.35 g, 22.34 mmol) (Lancaster) in a 1:1 mixture of distilled water-acetone (64 mL) was slowly treated with potassium permanganate (6.00 g, 37.98 mmol) in small portions. The dark reaction mixture was stirred at room temperature for 1 h and then filtered through a pad of Celite®. The pad of Celite® was washed with 200 mL of distilled water then washed with 200 mL of acetone. The filtrate was concentrated in vacuo to a volume of approximately 200 mL. The resulting aqueous filtrate was treated with concentrated hydrochloric acid until pH=1 and then cooled using an ice/water bath. The desired product precipitated upon cooling. The solid was filtered and washed well with cold distilled water to provide 3-carboxyphenylboronic acid as a cream-colored solid which was used without further purification. (Yield 1.95 g, 53%; mp 232-234° C.).
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>ClCCl>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]=[CH:17][N:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN(C)C=NC(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.15 g (50 mmol) of (diphenylmethyl)amine and 8.33 g (70 mmol of dimethylformamide dimethylacetal in 25 mL of dichloromethane was refluxed briefly and slowly distilled through a Vigreux column, distilling off all material that boiled at or below 90°. The residue was stripped in vacuo, poured into water, cooled, and the resulting solid filtered off. After drying, it was recrystallized from hexane to provide 8.3 g (70%) of N'-(diphenylmethyl)-N,N-dimethylmethanimidamide, mp 58-60.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[C:27]1([CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:33]([S:34]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:12][CH:13]=2)=[N:5][N:4]=1)(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(=O)(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with α-toluenesulphonyl chloride (33 mg) in pyridine (6 ml) at 0° C. and the reaction stirred at room temperature for 72 hours. Further α-toluenesulphonyl chloride (66 mg) in pyridine (3 ml) was added and stirring continued for 18 hours. The reaction was diluted with DCM and washed with hydrochloric acid (2N, 4×5 ml) and then water (5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents 4′-(5-{[(benzylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)C.[Li+].[OH-].Cl>O1CCOCC1.O>[CH2:32]([O:31][CH:5]([CH2:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
[rac]-2-Ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionic acid ethyl ester (850 mg, 1.83 mmol ) was dissolved in 10 ml of dioxane; 5 ml of water and LiOH (4.58 ml of a 1N solution in water, 4.58 mmol) were then added slowly at room temperature. The resulting mixture was stirred overnight at room temperature and then poured onto ice, neutralized to pH 4 with HCl (1N) and extracted 3 times with AcOEt. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a colorless solid that was triturated in CH3CN for 15 minutes, filtered and dried to yield 470 mg (58.9%) of [rac]-2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]([CH3:9])[CH3:8].Cl.[NH2:13][C:14]([NH2:16])=[NH:15].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH:7]([C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:15]=[C:14]([NH2:16])[N:13]=1)([CH3:9])[CH3:8]
Reactant: COCC(=O)CC(=O)C(C)C
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCc1cc(C(C)C)nc(N)n1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a stirred solution of 1-methoxy-5-methylhexane-2,4-dione (1.08 g, 6.8 mmol) in EtOH (15 mL) was added guanidine hydrochloride (1.3 g, 13.7 mmol). 5 min later, a solution of Na2CO3 (1.45 g, 13.7 mmol) in H2O was added and the resulting mixture was heated to reflux for 20 h. The reaction was cooled to room temperature and the solvent was removed. The residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc in hexanes) to provide 4-isopropyl-6-(methoxymethyl)pyrimidin-2-amine (482 mg, 39%). 1H NMR (CDCl3): d 6.43 (s, 1H), 6.11 (s, 2H), 4.16 (s, 2H), 3.26 (s, 3H), 2.56-2.66 (m, 1H), 1.03 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>>[C:25]([NH:29][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NC(C)(C)C)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), tert-butylamine and DIEA to give 6-[2-tert-Butylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:37].[OH-].[K+]>>[CH2:26]([O:25][CH2:24][CH2:23][N:6]1[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:37])[C:8]=2[N:22]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCc1ccccc1
Temperature: 156 °C
Yield: 40.2 %

Procedure:
2-(Ethoxymethyl)-1-[2-(benzyloxy)ethyl]-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (4.33 g, 10.03 mmol) was placed in a glass reaction flask, and then ammonium acetate (45 g) was added. The flask was sealed with a teflon screw cap and heated to 156° C. for 44 hours. The reaction was determined to be complete by HPLC analysis, and the desired product's molecular weight was confirmed by LC/MS. The resulting solution was basified with 1 N potassium hydroxide to a pH of about 14. The basic solution was extracted with dichloromethane (5×), and the organic layers were combined, washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether. After the resulting solids were filtered off and dried, they were recrystallized from ethyl acetate/diethyl ether and again dried. NMR analysis or the recrystallized solids indicated impurities. The recrystallized solids were dissolved in ethanol. Hydrochloric acid (10 mL, 1 N) was added to the ethanol solution, and the resulting salt was filtered off and dissolved in water. The resulting aqueous solution was basified with 1 N potassium hydroxide to a pH of about 14 and extracted with dichloromethane (4×). The organic layers were combined, washed with water (2×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid. The white solid was dried to provide 1.4285 g of 1-[2-(benzyloxy)ethyl]-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 107.3–108.2° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:15]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH2:16][CH2:17][CH3:18].Cl>>[CH2:15]([NH:19][C:20](=[O:23])[CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][C:14]2=[C:2]([CH3:1])[C:3]3[C:8]([CH:9]2[CH2:10]1)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:16][CH2:17][CH3:18]
Reactant: C=CC(=O)NCCCC
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CCCCNC(=O)CCN1CCC2=C(C)c3ccccc3C2C1

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-n-butyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 14 hours. M.P. of the hydrochloride of the title compound 193°-194° from ethanol (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([F:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:2].[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:15]([F:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[F:19])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)Nc1cc2ccccc2cc1F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Nc1c(F)cc2ccccc2c1F
Temperature: 70 °C

Procedure:
A mixture of 1.63 g (7 mmol) of N-(3-fluoro-2-naphthyl)carbamic acid ethyl ester, and 2.73 g of Selectfluor® (7.7 mmol) in 10 mL of trifluoroacetic acid is heated to 70° C. under an atmosphere of nitrogen for 4 hours. After cooling to room temperature, the mixture is concentrated in vacuo and 30 mL of ice water is added. The mixture is extracted 3 times with 40 mL of CH2Cl2. The combined organic layers are washed with 40 mL each of H2O, saturated aqueous NaHCO3, saturated brine, dried over MgSO4. Evaporation of the solvents gives a residue that is purified by flash chromatography on silica gel (50% CH2Cl2/hexane) to give N-(1,3-difluoro-2-naphthyl)carbamic acid ethyl ester, which is hydrolyzed to 1,3-difluoro-2-aminonaphthalene under conditions described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)COC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Product: CC(C)COC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid isobutyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carbonitrile using isobutyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 524.5 [M]+.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31]I)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:16]2[CH2:17][CH2:18][CH:13]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)=[O:12])[CH2:14][CH2:15]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 46.2 %

Procedure:
4-(4-Methylsulfonylaminobenzoyl)piperidine hydrochloride (1.97 g, 6.19 mmol) and 1-(4-nitrophenoxy)-3-iodopropane (1.90 g, 6.19 mmol) were reacted by the procedure of Example 1 to afford 1.32 g (46%) of the desired product as a white solid: mp 162°-164° C.; 1H NMR (DMSO-d6): δ10.29 (br s, 1H), 8.19 (d, J=9.30 Hz, 2H), 7.93 (d, J=8.86 Hz, 2H), 7.26 (d, J=8.84 Hz, 2H), 7.13 (d, J=9.31 Hz, 2H), 4.15 (t, J=6.34 Hz, 2H), 3.32 (m, 1H), 3.09 (s, 3H), 2.89 (m, 2H), 2.48 (m, 2H), 2.07 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H). IR (KBr): 3620, 3210, 2950, 1660, 1600 cm-1.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 50 mg, 0.23 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (59 mg, 0.27 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 45 min. Na(AcO)3BH (78 mg, 0.37 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc), gave the title compound: RT=2.18 min; m/z (ES+)=414.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:3][CH2:2]1.[CH3:13][C:14]1([O:17][CH2:16]1)[CH3:15]>C(O)C>[CH2:10]([O:9][C:8](=[O:12])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]1)[CH3:11]
Reactant: CCOC(=O)NC1CCNCC1
Reactant: CC1(C)CO1
Solvent: CCO
Product: CCOC(=O)NC1CCN(CC(C)(C)O)CC1
Yield: 96.8 %

Procedure:
A mixture of commercially available ethyl piperidin-4-ylcarbamate (2.067 g, 12 mmol) and isobutylene oxide (868 mg, 12 mmol) in ethanol (15 mL) was irradiated in a microwave apparatus at 110° C. for 90 min. Purification by silica gel column chromatography with ethyl acetate gave the title compound as a colorless oil (2.838 g, 97%); MS: m/e=245.3 (M+H+).