Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:19]1[C:23]2C=CC=CC=2N=N1.Cl.CN[O:31][CH3:32].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15](=[O:17])[NH:19][CH2:23][O:31][CH3:32])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCNC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 20 h
Yield: 60.8 %

Procedure:
An aqueous solution of 1 M sodium hydroxide (15 mL) was added to a solution of 3.02 g (11.8 mmol) of tert-butyl ester of 4-metoxycarbonylmethylenepiperidine-1-carboxylic acid in THF (15 mL) and stirred for 2 hours. Then an aqueous solution of 1 M sodium hydroxide (another 10 mL) was added thereto, and stirred for 18 hours. After the reaction was completed, the reaction mixture was neutralized by addition of 1 M hydrochloric acid and the solvent was removed under a reduced pressure. The residue was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure to obtain 2.78 g of tert-butyl ester of 4-carboxymethylenepiperidine-1-carboxylic acid. To a solution of 2.78 g of this 4-carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester in N,N-dimethylformamide (35 mL) was added 3.8 mL (34.6 mmol) of N-methylmolpholine, 2.34 g (17.3 mmol) of 1-hydroxybenzotriazole, 2.65 g (13.8 mmol) of 1-ethyl-3-(3′-dimethylaminopopyl)carbodiimide hydrochloride and 1.35 g (13.8 mmol) of N,O-dimethylhydroxylamine hydrochloride, and stirred for about 20 hours. After the reaction was completed, water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine twice and dried over anhydrous magnesium sulfate, and the solvent was removed under a reduced pressure. Its purification by silica gel column chromatography (developing solvent, hexane:ethyl acetate=3:2 to 1:1) gave 1.99 g (7.00 mmol) of 4-[(methoxymethylcarbamoyl)methylene]piperidine-1-carboxylic acid tert-butyl ester. Its physical property is shown below.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:19])(=[O:18])[NH:16][CH3:17])[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15](=[O:18])(=[O:19])[NH:16][CH3:17])[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Yield: 11.1 %

Procedure:
A solution of 177 mg (0.326 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with MeOH (300 μL) and TFA (3 mL) at RT for 45 min. MeOH (10 mL) was added, and solvents were evaporated in vacuo. The solid residue was triturated with a minimum amount of acetonitrile with sonication, but further purification was needed. Silica gel chromatography of the solid with 50% EtOAc-hexane also afforded impure material. The solid was purified by RP-HPLC(C18) with 40-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 14.9 mg (11%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 9.38 (s, 1H), 8.27-8.20 (m, 1H), 7.93 (s, 1H), 7.27-7.20 (m, 1H), 7.18-7.14 (m, 1H), 5.89-5.82 (m, 1H), 5.09-5.01 (m, 1H), 3.36-3.26 (m, 2H), 3.08-3.00 (m, 2H), 2.70 (d, 3H, J=5.2 Hz), 2.32-2.25 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H23N5O3S, 414.1 (M+H). found 414.1.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2ccccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccccc2c1Nc1ccccc1C
Yield: 59.1 %

Procedure:
3-Butyryl-4-chloroquinoline (2.33 g, 10 mmol), 2-methylaniline (1.60 ml, 15 mmol) and dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2-methylphenylamino)quinoline (1.80 g), m.p. 107°-109°.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11](O)[CH2:12][OH:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:5]1([C:3]2([CH2:2][OH:1])[O:13][CH2:12][CH2:11][O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CO)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCC1(c2ccccc2)OCCO1
Yield: 97.7 %

Procedure:
2-Hydroxy-1-phenylethanone (49.39 g, 297 mmol), ethylene glycol (84 mL, 1500 mmol), p-toluenesulfonic acid monohydrate (1.0 g) and benzene (500 mL) were added to a one-liter eggplant type flask equipped with a Dean-Stark dehydrating device and heated to reflux for 24 hours. The solvent was evaporated in vacuo, water and ethyl acetate were added to the resulting residue and the organic layer was separated. An aqueous layer was further extracted with ethyl acetate twice and the organic layers were combined and washed with a saturated saline solution. It was dried over anhydrous sodium sulfate, the solvent was evaporated therefrom in vacuo and the resulting crude product was purified by a silica gel column chromatography (toluene:ethyl acetate=4:1) to give (2-phenyl-[1,3]dioxolan-2-yl)methanol (52.30 g, 98%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.51 (d, J=6.4 Hz, 2H), 3.74-3.78 (m, 2H), 4.01-4.05 (m, 2H), 4.09 (t, J=6.4 Hz, 1H), 7.28-7.36 (m, 3H), 7.40-7.43 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[CH3:29][Mg]Br>C(OCC)(=O)C.CCCCCC>[OH:2][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:29]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C=O)cc1)CO2
Reactant: C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Yield: 93 %

Procedure:
Using N-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide and methylmagnesium bromide, the title compound was synthesized in the same manner as Example 22. Yield: 93%. Melting point: 144-145° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:41][CH3:42])([C:37]([O:39]C)=[O:38])[CH2:35][CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[Li+].[OH-].O>CO>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH2:41][CH3:42])([C:37]([OH:39])=[O:38])[CH2:35][CH3:36])[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 40 °C
Yield: 51.1 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.159 mmol), LiOH (19.87 mg, 0.8 mmol), H2O (2 mL) and methanol (3 mL) was heated at 40° C. for 4 h. Then methanol was removed by vacuum. The aqueous solution was acidified to “PH” 1-2 by addition of concentrated hydrochloride acid. The precipitate was collected by filtration and purified by Prep-HPLC to give the title compound as a white solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:17])=[C:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[ClH:1].[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:7]2[C:8](=[N:9][C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: Cc1c2c(nc3cc(Cl)ccc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3cc(Cl)ccc3c(C)c2CC1
Product: Cl
Yield: 70 %

Procedure:
8-Chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 8-chloro-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (96.5 g, 0.216 mol), N-methyl-4-aminopiperidine (29.3 g, 0.259 mol), HOBt (35 g, 0.259 mol), diisopropylethylamine (45 mL, 0.259 mol) in anhydrous DMF (2.6 L) was cooled in ice bath under nitrogen. EDCI (49.8 g, 0.259 mol) was added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into ice water (8 L) and ethyl acetate (3 L) and separated. The aqueous phase was extracted with ethyl acetate (4 L×2) and all organic extracts were combined, washed with water, brine, dried over MgSO4 and concentrated. The resulting solid was triturated with diethyl ether to give 47 g of the title compound. DSC peak at 241.42° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=O)=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl.[NH2:29][OH:30]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=[N:29][OH:30])=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: NO
Reactant: CCn1ncc2c(-c3cncc(Br)c3)c(C=O)c(C)nc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCn1ncc2c(-c3cncc(Br)c3)c(C=NO)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (34 mg) in DMF (1 ml) was added pyridine (0.032 ml) and hydroxylamine hydrochloride (13.7 mg) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo to give 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (35 mg) as a yellow crystal.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([CH3:34])[N:13]=[N:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:32]([O:31][C:29]([CH2:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]3[N:14]=[N:13][N:12]([CH3:34])[C:11]=3[C:9]([OH:10])=[O:8])=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3C(=O)OCc3ccccc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3C(=O)O)cc2)CC1
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a mixture of 5-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-phenyl]-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid benzyl ester (51 mg, 0.11 mmol) and 10% Pd/C (58.8 mg, 0.552 mmol) was added ethyl acetate (5 mL) at room temperature under nitrogen atmosphere. Then, the nitrogen was replaced with a hydrogen gas balloon and the black reaction mixture was stirred for 15 h under hydrogen atmosphere at which time TLC analysis indicated the absence of the starting material. Then, the reaction mixture was filtered and the charcoal was washed with a hot ethyl acetate (50 mL), THF (25 mL), CH3CN (75 mL), and ethanol (25 mL). The filtrate was concentrated under vacuum and the residue was dried under high vacuum to obtain 5-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-phenyl]-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid (40 mg, 97.5% yield) as a white solid. LC/MS calcd. for C20H25N3O4 (m/e) 371, obsd. 372.3 [M+H, ES+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].N1C=CC=CC=1>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:29])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-hydroxy-pyrazolidine-1-carboxylic acid benzyl ester, 38, (366 mg, 1.02 mmol) is dissolved in dichloromethane (10 mL). The solution is cooled to 0° C. and p-nitrophenyl chloroformate (411 mg, 2.04 mmol) is added in one portion. The solution is stirred at 0° C., and pyridine (198 μL, 2.45 mmol) added. Stirring is continued at 0° C. for 1 hour followed by stirring at room temperature for 12 hours. The reaction is diluted with water (40 mL) and extracted with dichloromethane (40 mL). The organic layer is washed with 0.5 N NaOH (2×40 mL). The combined aqueous layers are back-extracted extracted with dichloromethane (30 mL). The combined organic layers are washed with brine (30 mL), dried, filtered, and concentrated in vacuo. The crude material is purified over silica (3:1 to 2:1 to 1:1 hexane/ethyl acetate) to afford 462 mg (86% yield) of the desired product as a white foam.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1
Reactant: [H][H]
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Agent: N
Solvent: O
Solvent: CO
Product: NCC[C@@H]1C[C@H](CC(=O)O)OCO1
Temperature: 45 °C
Yield: 60.6 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(Br)cn1
Solvent: CC#N
Product: Oc1ncc(Br)cc1I
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of 5-bromopyridin-2-ol (5.22 g, 30.0 mmol) and N-iodosuccinimide (7.42 g, 33.0 mmol) in acetonitrile (150 mL) was heated under reflux under a nitrogen atmosphere for 1 hr. After being allowed to cool to room temperature, the resulting solid was collected and washed with acetonitrile to give the title compound (7.07 g, yield 79%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:40][C:39]([NH:38][CH2:37][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][C:22]=1[F:21])=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)ccn2c1=O
Yield: 31.7 %

Procedure:
The general Suzuki coupling method described above was used to couple methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate with tert-butyl N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate. Purification by flash silica column chromatography yielded methyl 8-[4-[(tert-butoxycarbonylamino)methyl]-3-fluoro-phenyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate (24 mg, 31.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH2:21]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[C:15]1([CH2:21][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 50.0 grams (0.29 mole) of 3-bromophenol and 120.0 grams (0.87 mole) of potassium carbonate in 400 mL of N,N-dimethylformamide was stirred, and heated to 80° C. To this was added portionwise, 36.1 mL (0.30 mole) of phenylmethyl bromide during a 20 minute period. Upon completion of addition, the reaction mixture was stirred at 80° C. during a one hour period. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was diluted with 600 mL of water. The mixture was extracted with 600 mL of diethyl ether. The extract was then washed with three 50 mL portions of water, and then it was concentrated under reduced pressure to a residual solid. The solid was recrystallized with 250 mL of methanol, yielding 68.3 grams of 3-(phenylmethoxy)phenyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C@@H:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH3:3].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[F:15][C:14]([F:17])([F:16])[C:6]1[CH:5]=[C:4]([CH:2]([N:18]=[N+:19]=[N-:20])[CH3:3])[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -16.5 °C
Reaction time: 4 h
Yield: 117.2 %

Procedure:
A solution of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) (106 mg, 0.336 mmol, 99% ee) obtained in 1-(a) mentioned above in N,N-dimethylformamide (1 mL) was added with sodium azide (64.4 mg, 0.990 mmol), and the mixture was stirred at −18 to −15° C. for 4 hours. The reaction solution was extracted with ethyl acetate/n-hexane (1:1) and water, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 111.5 mg of 1-[3,5-bis(trifluoromethyl)phenyl]ethyl azide (crude product: 111.5 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(F)c(F)c21
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCc2ccc(F)c(F)c21

Procedure:
6,7-Difluoro-1-indanone (6.000 g, 35.70 mmol), NaBH3CN (15.70 g, 0.25 mol) and NH4OAc (82.60 g, 1.07 mol) in isopropanol were reacted according to the protocols as outlined in general procedure C to give the title amine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.7 (br s, 2H), 1.78-1.90 (m, 1H), 2.44-2.57 (m, 1H), 2.72-2.87 (m, 1H), 2.95-3.09 (m, 1H), 4.7 (t, 1H, J=6.7 Hz), 6.86-7.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(N3CCCC3)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(N3CCCC3)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])=[CH:26][CH:27]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: BrCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
750 mg (1.92 mmol) of [2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-hydroxyphenyl]methanone, 5.23 g (19.2 mmol) of 1,8-dibromooctane, and 2.66 mg (19.2 mmol) of K2CO3 were combined in 150 mL of 2-butanone. The reaction mixture was stirred and heated to reflux under a nitrogen atmosphere. The reaction was allowed to proceed for three hours, cooled to ambient temperature, and filtered. The solvent was removed by evaporation in vacuo to a yellow oil. The crude product was further purified by chromatography on a silica gel column eluted with a linear gradient begining with hexane and ending with hexane-EtOAc (5:1) (v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 1.28 g (114%; some EtOAc was present in the solid) of the title compound as a yellow, amorphous powder.