Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([CH:23]([NH2:25])[CH3:24])[CH2:22][CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>CCOCC>[CH:1]1([CH2:7][CH2:8][NH:25][CH:23]([C:19]2([C:14]3[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=3)[CH2:20][CH2:21][CH2:22]2)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(NCCC1CCCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 3 h

Procedure:
Cyclohexylacetyl chloride (3.21 g) in dry ether (100 ml) was added over 30 minutes to a stirred mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (4.88 g), triethylamine (2.5 g) and dry ether (100 ml) at 0°-6° C. After stirring for a further 3 hours the mixture was filtered and the residue was washed with dry ether. The filtrate and washings were combined, dried and evaporated. The residue was dissolved in tetrahydrofuran (50 ml) and the solution heated under reflux in an atmosphere of nitrogen. Borane-methyl sulphide complex (3 ml) was added from a syringe. The resulting mixture was heated under reflux for 12 hours after which it was cooled and ice-water and then 5N hydrochloric acid were added. The organic solvent was removed by evaporation and the residue was cooled, basified with 5N sodium hydroxide solution and extracted with ether. The extracts were washed with water, dried and the ether removed by evaporation. From the residue N-(2-cyclohexylethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was obtained by distillation (b.p. 170° C./0.5 mm Hg).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:8][CH:7]([CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[CH2:6]1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]([CH:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[CH2:8]1)(=[O:3])=[O:4]
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide (30 mg, 0.049 mmol) in CH2Cl2 (2 mL) was added TFA (0.3 mL, 3.89 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.3 mL, 4.49 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with MeOH/CH2Cl2 (1:9). The organic layer was washed with water and the aqueous was back-extracted with CH2Cl2. The combined organics were concentrated and the residue was triturated with MeOH/EtOAc/Et2O to afford 15 mg (63%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methanesulfonyl-azetidin-3-yl)-ethyl]-amide as a pale yellow solid. MS (M+H)+=488; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.05 (br. s., 1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.41 (d, J=8.7 Hz, 1H), 7.92 (s, 1H), 7.26 (d, J=8.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.22-4.33 (m, 1H), 4.12 (s, 3H), 4.04-4.10 (m, 1H), 3.62-3.74 (m, 1H), 3.45-3.58 (m, 1H), 3.25 (s, 3H), 2.57-2.68 (m, 1H), 1.38 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][N:25](CC3C=CC=CC=3)[N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:19][C:20]([C:22]2[N:23]=[N:24][NH:25][N:26]=2)=[O:21])[CH2:9][C@@H:10]([CH3:18])[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12])=[CH:3][CH:2]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1)C(=O)NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nn[nH]n1)C(=O)NS(C)(=O)=O
Reaction time: 2 h

Procedure:
Next, A solution of 2-benzyl-2H-tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide in MeOH/EtOAc is hydrogenated under H2 baloon by catalyst 10% Pd/C wet for 2 hours. The reaction is filtered off the catalyst and is concentrated. Reverse phase HPLC [35 to 80% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18 column] provides 2H-Tetrazole-5-carboxylic acid ((1S,3R)-1-biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J=7.1 Hz, 2 H), 1.66 (ddd, J=13.8, 10.9, 3.5 Hz, 1 H), 1.91 (ddd, J=13.7, 10.7, 3.4 Hz, 1 H), 2.54-2.63 (m, 1 H), 2.79-2.86 (m, 1 H), 2.86-2.93 (m, 1 H), 3.24 (s, 3 H), 4.15-4.28 (m, 1 H), 7.27 (d, J=8.3 Hz, 2 H), 7.30-7.36 (m, 1 H), 7.43 (t, J=7.6 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H), 7.59-7.65 (m, 2 H), 9.19 (br. s., 1 H), 11.54 (br. s., 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl)#[N:2].[CH3:22][C:23]([NH2:27])([C:25]#[CH:26])[CH3:24]>C(O)C>[C:1]([C:3]1[CH:14]=[C:13]([NH:15][C:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH:27][C:23]([CH3:24])([C:25]#[CH:26])[CH3:22])#[N:2]
Reactant: C#CC(C)(C)N
Reactant: N#Cc1cc(NC(=O)C2CCC2)ccc1OCC(O)CCl
Solvent: CCO
Product: C#CC(C)(C)NCC(O)COc1ccc(NC(=O)C2CCC2)cc1C#N

Procedure:
7.5 gm (0.024 mol) of 1-(2-cyano-4-cyclobutylcarbonylamino-phenoxy)-2-hydroxy-3-chloro-propane were dissolved in 20 ml of ethanol, 8.3 gm (0.1 mol) of 2-methyl-but-3-in-2-yl-amine were added to the solution, and the mixture was refluxed for 3.5 hours. The ethanol was then distilled off, and the residue was digested with H2O. After being acidified with HCl, the mixture was washed with ether, the acidic aqueous phase was made alkaline with NH4OH, and the base precipitated thereby was extracted by shaking twice with ethyl acetate. The organic phase was washed with H2O, dried over MgSO4 and the ethyl acetate was distilled off in vacuo. The crystalline residue (base) was recrystallized twice from acetonitrile, and 3.7 gm of pure substance were obtained. Melting point: 139°-141° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.[CH3:21][C:22]1([CH3:37])[CH2:27][CH:26]([N:28]2[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[C:29]2=[O:36])[CH2:25][CH2:24][O:23]1>C(Cl)Cl>[CH3:21][C:22]1([CH3:37])[CH2:27][CH:26]([N:28]2[CH2:32][CH2:31][N:30]([C:33]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:12]=4)=[CH:19][N:18]=3)=[O:34])[C:29]2=[O:36])[CH2:25][CH2:24][O:23]1
Reactant: CC1(C)CC(N2CCN(C(=O)Cl)C2=O)CCO1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOC(C)(C)C5)C4=O)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A 0° C. solution of Example A2 (0.060 g, 0.224 mmol) and TEA (0.094 mL, 0.673 mmol) in DCM (1 mL) was treated with a solution of crude 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride (0.088 g, 0.337 mmol) in DCM (1 mL). The mixture was warmed to RT, stirred for 0.5 h, then concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide as an off-white solid (74 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.21 (m, 1 H), 8.05 (m, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 4.04 (m, 1 H), 3.84 (s, 3 H), 3.84-3.75 (m, 2 H), 3.70-3.59 (m, 2 H), 3.46-3.39 (m, 2 H), 1.60-1.47 (m, 4 H), 1.18 (d, J=15.1 Hz, 6 H); MS (ESI) m/z: 492.2 (M+H+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>CN(C)C=O.O.ClCCl>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([C:28]([N:10]2[CH2:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]=3[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]2=3)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepine (1.0 g, 5.07 mmol) in N,N-dimethylformamide (10 mL) kept under nitrogen was added solid potassium carbonate (0.74 g, 5.35 mmol). The mixture was treated dropwise with a solution of 4-biphenylcarbonyl chloride (1.4 g, 6.46 mmol) in N,N-dimethylformamide (5 mL) and stirred at room temperature for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with 1N sodium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness to give a pink foam which was purified by flash chromatography. Elution with 25% ethyl acetate in hexane provided a white foam which was redissolved in dichloromethane, concentrated in vacuo to a foam, then crystallized by sonication from ethyl acetate/hexane to give the title compound (1.28 g, 66.9%) as a white solid, m.p. 175-177° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)=[O:8].O1CCCC1.[OH-].[Li+].Cl>O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)=[O:8]
Reactant: CCOC(=O)c1ccc2c(cnn2CCC(=O)Nc2ncc[nH]2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCn1ncc2cc(C(=O)O)ccc21)Nc1ncc[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 37 %

Procedure:
A mixture of the product of Example 1327b Part C (145 mg, 443 μmol), tetrahydrofuran (2 mL) and water (2 mL) was treated with aqueous lithium hydroxide (1.0 M; 0.56 mL, 560 μmol) and stirred at room temperature for 21 h. The reaction was incomplete by thin-layer chromatography, so additional lithium hydroxide solution (a total of 1.35 mL) was added in four portions over the next 8 h. After stirring for 16 h more, the reaction was acidified with aqueous hydrochloric acid (1.0M) and concentrated under vacuum. The residue was partitioned between water and dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to provide the title product (49 mg, 37%): 1H NMR (DMSO-d6) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 6.67 (s, 2H), 4.73 (t, 2H), 3.00 (t, 2H); High resolution mass spectrum (NH3 --CI) calculated (M+H+) 300.1097, found 300.1097.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH2:26]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[CH3:27]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:29]5[C@H:28]([CH2:26][CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cc1
Yield: 67.2 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (292 mg) was obtained.
Reaction SMILES: [N+](C1C=CC(C(O[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:13][CH:12]=2)=O)=CC=1)([O-])=O.FC1C=C(F)C=CC=1C1C=CC=CC=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([C:48]([C:47]2[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=2)=[O:49])=[CH:16][CH:15]=1
Reactant: O=C(Oc1ccc(-c2ccc(F)cc2F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Fc1ccc(-c2ccccc2)c(F)c1
Product: O=C(c1ccc(-c2ccc(F)cc2F)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A process for the preparation of 4-(2,4-difluorophenyl)-phenyl 4-nitro-benzoate comprising the Friedel-Crafts acylation of 2,4-difluorobiphenyl with 4-nitro-benzoyl chloride in order to obtain 4-(2,4-difluorophenyl)-4'-nitro-benzophenone and the Baeyer-Villiger oxidation of this latter.
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:9]([N:19]2[CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17][CH2:18]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitro-N-methyl-aniline (820 mg, 3.7 mmol), 4-trifluoromethyl-piperidine (680 mg, 4.5 mmol) and potassium carbonate (770 mg, 5.6 mmol) in DMSO (10 mL) in analogy to example 3, step (a).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CO>C1(C)C=CC=CC=1.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.CCOCC>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution. of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ 2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.91-8.08 (m, 3 H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[C:24]1([C@@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[B-](F)(F)(F)[O+](C)C>C1(C)C=CC=CC=1>[C:24]1([C@@H:30]([N:32]=[C:2]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Agent: C[O+](C)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](N=C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1

Procedure:
A solution of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (A4) (5.0 g, 15.8 mmol), (S)-1-phenylethanamine (3.0 ml, 23.8 mmol) and boron trifluoride dimethyl etherate (0.5 ml, 5 mmol) in dry toluene (150 ml) was heated at 140° C. under a Dean-Stark trap for 24 hours. The solvent was distilled and the residue was cooled with an ice bath, dissolved in ethyl acetate, washed with saturated NaHCO3, and water. The organic phase was dried over Na2SO4, filtered and concentrated to give (S)-tert -butyl 4-(1-phenylethylimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B1) as a gum. LC-MS analysis of the crude indicated that there is trace of starting material (A4). LC-MS: m/e=419.37 (M+H). Rt=2.24 min.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[CH2:26]([CH2:28][NH2:29])[OH:27].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH2:28][NH:29][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Reactant: NCCO
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1ccc(OCc2c(-c3ccccc3)noc2CO)nc1
Reaction time: 68 h
Yield: 84.6 %

Procedure:
To a stirred solution of 6-(5-hydroxymethyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (0.11 g, 0.32 mmol) in toluene (0.5 mL) was added ethanolamine (0.03 g, 0.39 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.03 g, 0.17 mmol). The reaction mixture was stirred for 68 h, adsorbed on silica gel and purification by chromatography (silica, dichloromethane:methanol=100:0 to 90:10) afforded the title compound as a white solid (0.10 g, 85%). MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH:1]1N=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.CCN(CC)CC.N[C@H]1C2[C:24](=[C:25]([C:30]3[N:34]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([CH:42]=4)[C:40]#[N:41])[O:32][N:31]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.Cl.N1CC([OH:52])C1>C(Cl)Cl>[C:40]([C:39]1[CH:42]=[C:35]([C:33]2[O:32][N:31]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[C:10]4[C:24]=3[CH2:23][CH2:22][C@H:9]4[NH:8][C:6]([N:3]3[CH2:2][CH:1]([OH:52])[CH2:4]3)=[O:7])[N:34]=2)[CH:36]=[CH:37][C:38]=1[O:43][CH:44]([CH3:46])[CH3:45])#[N:41]
Reactant: OC1CNC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)N3CC(O)C3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
Prepared using General Procedure 21: To a stirred solution of CDI ((268.5 mg, 1.66 mmol) and Et3N (279.0 mg, 2.76 mmol) in DCM (10 mL) was added the solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (500.0 mg, 1.38 mmol) and Et3N (279.0 mg, 2.76 mmol) in DCM (10 mL) for 1 h at room temperature and then this solution was added to the preparative solution of azetidin-3-ol hydrochloride (453.54 mg, 4.14 mmol)) and Et3N (418.55 mg, 4.14 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 4 h. The solvent was evaporated and the pure product was isolated after silica gel column chromatography (DCM/MeOH) to afford 474.32 mg (74.8%) of (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamide 234. LCMS-ESI (m/z) calculated for C25H25N5O4: 459.5; found 460.2 [M+H]+, tR=3.20 min. Elemental analysis: C calc.=65.35%; found=65.07%; H calc.=5.48%; found=5.47%; N calc.=15.24%; found=15.14%. 1H NMR (400 MHz, DMSO3) δ 8.50 (d, J=2.3 Hz, 1H), 8.40 (dd, J=9.0, 2.3 Hz, 1H), 8.08-7.89 (m, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.44 (dd, J=7.0, 5.9 Hz, 2H), 6.72 (d, J=8.7 Hz, 1H), 5.57 (d, J=6.5 Hz, 1H), 5.23 (q, J=8.3 Hz, 1H), 4.98 (hept, J=6.1 Hz, 1H), 4.39 (ddd, J=11.3, 6.6, 1.9 Hz, 1H), 4.10-3.91 (m, 2H), 3.60 (dt, J=8.6, 4.3 Hz, 2H), 3.39 (ddd, J=9.4, 7.8, 2.3 Hz, 1H), 3.05 (dt, J=8.4, 5.2 Hz, 1H), 2.47-2.35 (m, 1H), 1.95-1.74 (m, 1H), 1.37 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 173.10, 168.25, 162.48, 159.59, 147.03, 142.45, 134.57, 133.78, 127.32, 127.13, 126.97, 122.25, 115.98, 115.26, 114.86, 102.45, 72.52, 59.93, 59.08, 54.48, 32.86, 31.08, 21.48. Chiral HPLC: (R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-hydroxyazetidine-1-carboxamide 234 was eluted in 15% EtOH in hexane: >99.9% ee, tR=20.30 min (Chiral Method 1). Compound 235 was prepared in an analogous fashion from 50: >99.9% ee, tR for the (S)-enantiomer=23.61 min (Chiral Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]1.[C:25]1([Mg]Br)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[F:21][C:20]([F:23])([F:22])[C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:4]2[CH:5]=[C:6]([S:9]([C:33]3[C:34]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:30]=[CH:31][CH:32]=3)(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:15]1)=[O:24]
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride (0.19 g; 0.5 mmol) in THF (0.5 mL) at 0° C. under argon atmosphere was added dropwise a solution of 1-naphthylmagnesium bromide in THF (0.5M, 2 mL; 1 mmol). After stirring at this temperature for 1 h, a saturated solution of ammonium chloride was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate (7:3, v/v) to give 2,2,2-trifluoro-1-{4-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazin-1-yl}-ethanone (1) as a white solid (0.110 g; 47%), MS, MH+ 479.