Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23](O)=[O:24])[CH:17]=3)=[C:9]([CH3:26])[CH:8]=1)=[O:4].[C:27]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH3:26])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23](=[O:24])[NH:35][C:34]2[CH:36]=[CH:37][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=2)[CH:17]=3)=[C:11]([CH3:13])[CH:12]=1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of 2-[4-(2-methoxycarbonylethyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylic acid (100 mg, 280 μmol), 4-tert-butylaniline (45 μL, 290 μmol), EDCI (82 mg, 430 μmol) and HOBT (42 mg, 310 μmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 3 h. The solvent was removed under reduced pressure and the residue was chromatographed using a 10-60% gradient of heptane/ethyl acetate to give 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-indol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester. MS (m/z) 484.3 (M+1); Retention time=1.50 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:33]([CH2:32][CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:36])=[O:29])=[O:35]
Reactant: CN
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Product: CNC(=O)CCNC(=O)N1CC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 69.9 %

Procedure:
In a manner similar to the method described in Example 59, a mixture of rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid (24 mg, 0.0446 mmole, example 73) was reacted with a solution of methylamine (0.05 mL, 2M in THF, 0.10 mmol, Aldrich) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (2-methylcarbamoyl-ethyl)-amide (17.2 mg, 70%) as a white solid. HRMS (ES+) m/z Calcd for C27H30Cl2F2N4O2+H [(M+H)+]: 551.1787; Found: 551.1789.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.[Br:46][C:47]1[CH:52]=[CH:51][C:50](C2C=CC(OCCCCCCO)=CC=2)=[CH:49][CH:48]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][Br:46])=[CH:41][CH:40]=2)=[CH:37][CH:38]=1
Reactant: OCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of triphenylphosphine (3.46 g, 0.013 mol) and DEAD (2.30 g, 0.012 mol) in dry cold THF (100 ml) was added dropwise over 10 min to a solution of 4-bromo-4′-hydroxybiphenyl (3.00 g, 0.012 mol) and 4-bromo-4′-(6-hydroxyhexyloxy)biphenyl (2.20 g, 0.012 mol) (prepared as described in Example 4 step 2 above) in dry THF (50 ml) stirring at room temperature. The reaction mixture was left stirring overnight The reaction product was extracted into diethyl ether (2×200 ml), and the combined ethereal solutions were washed with water and dried (MgSO4). The crude product was adsorbed onto silica gel and purified by column chromatography [DCM-petroleum fraction (bp 40-60° C.), 1:6] and recrystallised from ethanol to give white crystals.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[ClH:7].Cl.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][NH:18]2)[CH:12]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:7].[CH:1]([NH:4][C:5]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][NH:18]2)[CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (470 μmol) isopropyl isocyanate are dissolved in 5 ml DMF under argon, 80.0 mg (235 μmol) of the compound from Example 35 and 71.4 mg (705 μmol) triethylamine are added and the mixture is stirred overnight at RT. The mixture is then concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:32][C@@H:31]([CH2:39][CH2:40][OH:41])[O:30][C@H:29]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]4[O:48][CH2:49][CH2:50][O:51][C:43]=34)[C:28]=2[CH:52]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]([CH2:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:32][C@@H:31]([CH2:39][CH:40]=[O:41])[O:30][C@H:29]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]4[O:48][CH2:49][CH2:50][O:51][C:43]=34)[C:28]=2[CH:52]=1
Reactant: CC(C)(C)CN1C[C@@H](CCO)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CN1C[C@@H](CC=O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
Dess-Martin periodinane (979 mg, 2.31 mmol) was added to a solution of 2-[trans-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-ethanol (830 mg, 1.92 mmol), pyridine (980 mL) and methylene chloride (18 mL) at 0° C. The mixture was warmed to ambient temperature and stirred 40 minutes before adding more Dess-Martin periodinane (800 mg, 1.89 mmol). After an additional 15 minutes, the reaction was quenched by addition of 5:1 saturated aqueous sodium bicarbonate/saturated aqueous sodium sulfite, stirred 5 minutes, and extracted with ether (2×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (9:1 hexanes/ethyl acetate) to give 562 mg (68%) of the title compound as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].[N:38]#[C:39]Br>O1CCOCC1>[NH2:38][C:39]1[O:23][C:22]([C:21]2[C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]([CH2:31][CH3:32])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[O:16])=[N:24][N:25]=1
Reactant: N#CBr
Reactant: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide (compound 215.6, 600 mg, 1.39 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added 10 mL of an aqueous solution of sodium bicarbonate (350 mg, 4.17 mmol, 1.00 equiv). Cyanogen bromide (220 mg, 2.08 mmol, 1.50 equiv) was added to the reaction mixture dropwise. The reaction mixture was stirred at 25° C. for 2 h, then quenched with 20 mL of FeSO4 (aq., sat.) and diluted with DCM. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 600 mg (95%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile as an off-white solid.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:27](O)=O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.C1(C(=O)C)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:27][N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:15])[CH2:10]3)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: O=C(C[C@@H]1CCCNC1)c1ccccc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)c1ccccc1
Product: O[C@@H](CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
(S)-[1-Phenyl-2-piperidin-3-yl-ethanone] (142 mg, 0.70 mmol) and 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid (148 mg, 0.70 mmol) were dissolved in 5 mL of methylene chloride and treated with the amide coupling agent BrOP (1.05 mmol), and diisopropylethylamine (2.1 mmol). The mixture was kept at room temperature overnight, diluted with 20 mL of water, and 50 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate 2-{1-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-piperidin-3-yl)}-1-phenyl-ethanone (254 mg, 92%). This amide was dissolved in 10 mL of THF at 0° C. and excess lithium aluminum hydride (245 mg) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 205 mg of (S)-[2-{1-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol], 182, was obtained (83%). 1H and 13C NMR data was consistent with the assigned structure. Data for this compound as a mixture of diastereomers: MS 384 (++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (3.34 g, 7.87 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (1.50 g, 6.97 mmol, from Step A) in CH2Cl2 (45 mL) and the mixture was stirred at rt for 40 min. Ether (100 mL) and 1.3 N aq. NaOH (45 mL) were added and stirring was continued for 15 min. After transfer of the mixture to a separatory funnel, the aqueous layer was extracted with ether (50 mL). The organic layers were washed in succession with 1.3 N aq. NaOH (45 mL) and water (50 mL), dried (Mg2SO4), filtered, and evaporated to give 1.21 g of the title compound as a colorless oil.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)[CH3:36]>O>[CH2:35]([O:37][C:38]1[CH:43]=[C:42]([C:13]2[C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=2)[CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CCOc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-ethoxyphenylboronic acid (59 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (43 mg, yield 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+]([O-])=O)=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[NH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C(NCCOC3C=CC=CC=3)=C([N+]([O-])=O)C=[N:39]2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:39])=[C:12]2[NH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccnc2ccc(OCc3ccccc3)c([N+](=O)[O-])c12
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Product: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12

Procedure:
The general method described in Part B of Example 46 was followed using N-(6-benzyloxy-5-nitroquinolin-4-yl)-N-methylamine (11.36 g, 36.7 mmol) in lieu of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-phenoxyethyl)amine. 6-Benzyloxy-N4-methylquinoline-3,4-diamine (7.91 g) was obtained as a dark yellow oil and used without purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:21]([F:24])([F:23])[F:22])([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH2:10][CH2:9][CH2:8]2)[OH:4]>S(=O)(=O)(O)O>[F:26][C:2]([F:25])([F:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:12]3[N:11]([CH2:10][CH2:9][CH2:8]2)[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[C:13]=3[CH:14]=1)([OH:4])[C:21]([F:24])([F:23])[F:22]
Reactant: CC(=O)CC(=O)N1CCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CCC2
Temperature: 60 °C
Yield: 73 %

Procedure:
A stirred mixture of 6.0 g (0.02 mole) of α,α-bis(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, 2.6 g (0.02 mole) of ethyl acetoacetate, and 100 ml of xylene is refluxed for 16 hours. The mixture is allowed to cool and is evaporated. The residue is triturated with a mixture of toluene, ethyl acetate, and hexane (60:10:30). The insoluble portion is filtered off, washed with water, and dried to give 1.6 g (23%) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol. C. A solution of 10.5 g (0.027 mole) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol in 30 ml of concentrated sulfuric acid is heated on a steam bath for 30-45 minutes, cooled to approximately 60° C., and poured into ice. When the ice is melted, the precipitate is filtered off, washed with water, and dried. The solid is recrystallized from 2-ethoxyethanol to give 7.2 g (74% ) of 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7-methyl-1H,5H-benzo[ij]quinolizin-5-one, m.p. 295°-296°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:46]=[C:45]([O:47][CH2:9][CH2:8][Br:7])[CH:44]=[CH:43][C:20]=1[C:21]([NH:23][C:24]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:25]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1OCc1ccccc1
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCBr)cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
Potassium carbonate (1.6 g) and 1,2-dibromoethane (2.6 mL) were added to a N,N-dimethylformamide (5.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-4-hydroxybenzamido)-4-phenylbenzoate (0.29 g), followed by stirring at 120° C. for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-91% hexane/ethyl acetate] to obtain 0.19 g of tert-butyl 2-(2-(benzyloxy)-4-(2-bromoethoxy)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].NC1C=CC=CC=1C(F)(F)F.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3C(F)(F)F)c2cn1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (300 mg, 1.56 mmol), 2-aminobenzotrifluoride hydrochloride (1.00 g, 5.06 mmol) and 2-aminobenzotrifluoride (2.00 g, 12.4 mmol) is stirred at 160° C. for 10 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(2-trifluoromethylanilino)pyrido(4,3-d]pyrimidine (194 mg, 41%) as a cream solid, mp (MeOH/CHCl3/light petroleum) 126-130° C. (dec.). 1H NMR (DMSO) δ 10.60 (1H, brs), 9.17 (1H, brs), 8.13 (1H, brs), 7.76, 7.69 (1H, 1H, m, m), 7.45 (2H, m), 6.66 (2H, brs), 6.36 (1H, s).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[CH:12](=[O:14])[CH3:13]>C1COCC1>[CH3:13][CH:12]([OH:14])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC=O
Reactant: C#CCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#CC(C)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 1-hexyne (116, 2 g, 24.3 mmol) in 30 mL of freshly distilled THF at −78° C. was added n-BuLi (2.5 M solution in hexanes, 11 mL, 27 mmol) under argon (FIG. 2M). The resultant yellow solution was stirred at −78° C. for 30 min and 0° C. for 15 min. Acetaldehyde (˜2 mL) was added to this solution at −78° C. and the reaction mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH4Cl and extracted with Et2O (3×30 mL). The combined organic solution was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (EtOAc:hexanes, 1:99, then 10:90) gave 117 as a colorless oil (2.1 g, 73%). 1H NMR (CDCl3) δ4.48-4.52 (q, 1 H, J=6.0 Hz, CH), 2.17-2.22 (d of t, 2 H, J=6.7 Hz and 1.5 Hz, CH2), 1.37-1.65 (complex m, 7 H, 4 CH2 and 1 CH3), 0.88-0.93 (t, 3 H, J=7.2 Hz, CH3).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O-:29])=O)=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].Cl.[NH2:40][OH:41]>CO.C[O-].[Na+]>[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:40][OH:41])=[O:29])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1
Reactant: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)[O-])c1ccc(C2=CCOc3ccccc32)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
(5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction (34e) (0.10 g, 0.23 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 32%) as a white solid. MS found: (M−H)+=433.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>CC(O)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccccc2)cn1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Cc2ccccc2)cn1
Temperature: 140 °C

Procedure:
5-Benzyl-2-methoxypyridine (2.6 g, 13 mmol) in 15 mL AcOH was added 15 mL 48% HBr. The mixture was heated to 140° C. for 3 h, cooled and poured onto ice. The mixture was basified to pH 6-7 and the resulting solid was collected by filtration, rinsed with water, and dried in vacuo to give 5-benzylpyridin-2-ol as an off-white solid. MS (ESI) m/z: Calculated: 185.1; Observed: 186.0 (M++1).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH2:3]([O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([Br:1])=[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(CCNC(C)=O)cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)c(CCNC(C)=O)cc1OCc1ccccc1
Temperature: 12 °C
Reaction time: 0.17 h

Procedure:
A solution of bromine (16 mL, 0.31 mol) in chloroform (100 mL) was added drop-wise to a solution of N-{2-[3-(benzyloxy)-4-methoxyphenyl]ethyl}acetamide (see M. P. Leese et al., ACS Med. Chem. Lett. 2012, 3, 5-9) (80 g, 0.27 mol) in chloroform (1 L) at 10-15° C. The reaction mixture was stirred at 12° C. for 10 minutes, then washed sequentially with cooled saturated aqueous sodium bicarbonate solution (2×500 mL) and saturated aqueous sodium chloride solution (400 mL), dried, and concentrated in vacuo. Crystallization of the residue from ethyl acetate afforded the product as a yellow solid. Yield: 90 g, 0.24 mol, 88%. 1H NMR (400 MHz, CDCl3) δ 7.41-7.46 (m, 2H), 7.37 (br dd, J=7.5, 7.0 Hz, 2H), 7.28-7.33 (m, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 5.13 (s, 2H), 3.86 (s, 3H), 3.44-3.52 (m, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.02 (s, 3H).