Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=O)[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:2][C:1]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH3:12])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Solvent: CCCC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(C)n(-c2ccccc2)c1C
Yield: 76.2 %

Procedure:
To a solution of ethyl 2-acetamido-3-oxobutanoate (compound 10, 5.0 g, 26.7 mmol), aniline (compound 11a, 7.3 mL, 80.1 mmol) in butyronitrile (10 mL) was added trifluoroacetic acid (6.2 mL, 80.1 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 140° C. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with aqueous K2CO3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane) to provide the title compound (4.97 g, 76%) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[NH2:19][C@@H:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([CH3:24])([OH:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:23][C:21]([CH3:24])([CH3:22])[C@@H:20]([NH:19][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N[C@@H](c2ccccc2)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask charged with boc-4-piperidone (2.412 g, 12.10 mmol, Alfa-Aesar) was added DCM (60.5 mL), acetic acid (0.901 mL, 15.74 mmol), (S)-1-amino-2-methyl-1-phenylpropan-2-ol (2 g, 12.10 mmol, BOC Scientific) and sodium triacetoxyborohydride (3.59 g, 16.95 mmol) respectively. The resulting orange suspension was stirred at room temperature for 3 h. LCMS indicated good conversion to desired product. To the mixture was added saturated NaHCO3 and K2CO3 pellets. The mixture was transferred to a separatory funnel and extracted with DCM (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The material thus obtained was used without further purification.
Reaction SMILES: O[C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[C:16]=1[C:17]([P:19](=[O:40])([C:28](=[O:39])[C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[O:37][CH3:38])[CH2:20][CH:21]([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18]>>[OH:14][C:15]1([C:11]2[CH:22]=[CH:21][CH:20]=[CH:12][C:2]=2[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:15]2([OH:14])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:16]2)=[O:4])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:16]1.[CH3:13][O:14][C:15]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[C:16]=1[C:17]([P:19](=[O:40])([C:28](=[O:39])[C:29]1[C:30]([O:37][CH3:38])=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:20][CH:21]([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18]
Reactant: CC(C)(O)C(=O)c1ccccc1
Agent: COc1cccc(OC)c1C(=O)P(=O)(CC(C)CC(C)(C)C)C(=O)c1c(OC)cccc1OC
Product: O=C(c1ccccc1C1(O)CCCCC1)c1ccccc1C1(O)CCCCC1

Procedure:
Specifically, for example, IRUGACURE-1700 (brand name, which is produced by Chiba specialty chemical Co., Ltd.) in which 2-hydroxy-2-methyl-1-phenyl propane-1-on (Dacrocur 1173, brand name, which is produced by Chiba specialty chemical Co., Ltd.) and bis(2,6-dimethoxy benzoyl)-2,4,4-trimethyl pentyl phosphine oxide (product, which is produced by Chiba specialty chemical Co., Ltd.) are mixed at a rate of 75%:25%; IRUGACURE-1800 (brand name, which is produced by Chiba specialty chemical Co., Ltd.) in which 1-hydroxy-cyclohexyl-phenyl-ketone (IRUGACURE-184, brand name, which is produced by Chiba specialty chemical Co., Ltd.) and bis(2,6-dimethoxy benzoyl)-2,4,4-trimethyl pentyl phosphine oxide (product, which is produced by Chiba specialty chemical Co., Ltd.) are mixed at a rate of 75%:25%; IRUGACURE-1850 (brand name, which is produced by Chiba specialty chemical Co., Ltd.) in which the same components are mixed at a rate of 50%:50%; bis(2,4,6)-trimethyl benzoyl)-phenyl phosphine oxide (IRUGACURE-819, brand name, which is produced by Chiba specialty chemical Co., Ltd.); 2,4,6-trimethyl benzoyl-diphenyl phosphine oxide (Lucirin TPO, brand name, which is produced by BASF Co., Ltd.), and Darocur-4265 (brand name, which is produced by Chiba specialty chemical Co., Ltd.) in which 2-hydroxy-2-methyl-1-phenyl propane-1-on (Dacrocur 1173, brand name, which is produced by Chiba specialty chemical Co., Ltd.) and 2,4,6-trimethyl benzoyl-diphenyl phosphine oxide (Lucirin TPO, brand name, which is produced by BASF Co., Ltd.) are mixed at a rate of 50%:50% are exemplary.
Reaction SMILES: [N:1]([CH:4]([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 813.1 %

Procedure:
A mixture of afford tert-butyl 2-azidopropylcarbamate (7.0 g, 3.6 mmol) and Pd/C (0.7 g) in MeOH (250 mL) was stirred under a H2 (1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with saturated NH3 in MeOH-DCM (0-10%) to afford tert-butyl 2-aminopropylcarbamate (5.1 g, 83.7%) as a light yellow oil. 1HNMR (CDCl3): δ4.9 (bs, 1H, NH), 3.15 (m, 1H, CH), 3.0 (m, 1H, CH2), 2.8 (m, 1H, CH2), 1.7 (bs, 2H, NH2), 1.5 (s, 9H, CH3), 1.0 (d, 3H, CH3).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[C:29]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]=[CH:33][C:32]([CH:35]=[N:36][OH:37])=[CH:31][CH:30]=1>>[C:29]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:30]=[CH:31][C:32](/[CH:35]=[N:36]/[O:37][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:26])[F:24])[CH:6]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Reactant: ON=Cc1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)cc1NC(=O)c1ccccc1C(F)(F)F
Yield: 92 %

Procedure:
The title compound (0.193 g, 92%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and Biphenyl-4-carbaldehyde oxime using a procedure similar to step 1 of example 6. mp=170.5-172.5° C.; mass spectrum API-ES, (M−H) m/z 561. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 12.00 (bs, 1H), 8.32 (s, 1H), 8.27 (d, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.81 (m, 2H), 7.76 (m, 1H), 7.68 (m, 6H), 7.46 (m, 2H), 7.38 (m, 1H), 6.82 (dd, 1H), 4.32 (t, 2H), 4.20 (t, 2H), 2.20 (m, 2H). Elemental analysis: Calcd. for C31H25F3N2O5: C, 66.19; H, 4.48; N, 4.98, Found: C, 65.26; H, 4.49; N, 4.77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Temperature: 35 °C
Yield: 95.7 %

Procedure:
Methyl 5-chloro-2-(3-phenoxyazetidin-1-yl)nicotinate (D75) (305 mg, 0.96 mmol) was dissolved in methanol/tetrahydrofuran (10 ml/10 ml), 5N NaOH (10 ml) was added at 0° C. The resulting reaction mixture was heated to 35° C. for 18 hours then cooled to room temperature and concentrated. Water added (10 ml) and the mixture was acidified with 2.5N HCl (pH1-2). The white solid was collected, washed with water and dried to provide compound (D101) (280 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]([NH2:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:22][C@@H:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH3:21])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccc(Cl)c([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde 1 (1.71 g, 9.2 mmol) and (R)-1-(3-chlorophenyl)ethanamine (1.115 g, 7.2 mmol) in DCE (15 mL) at room temperature was added acetic acid (2.0 mL, 35 mmol) and NaBH(OAc)3 (2.23 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 d, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 10% to 40% EtOAc in hexanes) gave (R)—N-(4-chloro-3-nitrobenzyl)-1-(3-chlorophenyl)ethanamine 30 (2.03 g, 87% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.7 Hz, 3H), 3.66 (s, 2H), 3.77 (q, J=6.7 Hz, 1H), 7.18-7.32 (m, 5H), 7.44-7.48 (m, 2H), 7.83 (s, 1H). Mass spectrum: calculated for C15H14Cl2N2O2 324.0. found 325.1 (M++1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH2:12][CH2:11][CH:10]([F:13])[CH2:9][CH2:8]2)[CH2:4]1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH:34]=O)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21].Cl.Cl.N1CC(N2CCSCC2)C1.FC1C=CC(C(CC=O)CN(C)C(=O)OC(C)(C)C)=CC=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH2:34][N:3]2[CH2:6][CH:5]([N:7]3[CH2:12][CH2:11][CH:10]([F:13])[CH2:9][CH2:8]3)[CH2:4]2)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: FC1CCN(C2CNC2)CC1
Agent: C1CN(C2CNC2)CCS1
Agent: CN(CC(CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: CN(C[C@@H](CCN1CC(N2CCC(F)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C

Procedure:
The compound was synthesized in an analogous way to that of Method 3d but using 1-azetidin-3-yl-4-fluoropiperidine dihydrochloride (see WO 97/27185) and tert-butyl [(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]methylcarbamate (see WO 95/05377) rather than 4-azetidin-3-ylthiomorpholine dihydrochloride and tert-butyl [2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (yield, 13%). 1H NMR (500 MHz, CDCl3): 1.3 (s, 9H), 1.5-3.6 (cm, 23H), 4.6-4.8 (bd, 1H), 6.9-7.1 (dd, 1H), 7.2 (m, 1H), 7.4 (d, 1H), LCMS: m/z 489 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 91 %

Procedure:
A solution of Example 39H (0.050 g, 0.105 mmol), acetic anhydride (0.011 mL, 0.116 mmol), and pyridine (0.068 mL, 0.840 mmol) in methylene chloride (2 mL) was stirred at 25° C. for 4 hours. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.046 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.77 m, 7 H) 1.33 m, 1 H) 1.56 m, 3 H) 2.06 m, 4 H) 2.23 m, 1 H) 7.53 (m, 1 H) 7.66 m, 1 H) 7.77 m, 3 H) 8.16 m, 1 H) 8.29 m, 1 H) 10.38 m, 1 H) 13.84 (m, 1 H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.F[C:23](F)(F)C([O-])=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:23][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=2)[CH2:1]1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(Nc1ccc2c(c1)CCNC2)OCc1ccccc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2cc(NC(=O)OCc3ccccc3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g (3.8 mmol) benzyl (1,2,3,4-tetrahydro-isoquinolin-6-yl)-carbamate (as the trifluoroacetate salt) are suspended in 8 ml of methanol and adjusted to pH 6 with acetic acid. 0.6 ml (8.5 mmol) formalin solution (37% in water) are added and the mixture is stirred for 30 minutes at RT. Then a total of 1.8 g (8.5 mmol) sodium triacetoxyborohydride are added batchwise and the mixture is stirred for two hours. The reaction mixture is poured onto sat. sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate and evaporated to dryness i.vac.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:24].[F:39][C:40]1[CH:48]=[CH:47][C:46](/[C:49](/[NH:52]O)=[N:50]/[H])=[C:45]2[C:41]=1[C:42]([CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:43][NH:44]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:39][C:40]1[CH:48]=[CH:47][C:46]([C:49]2[N:52]=[C:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH:23]([CH3:22])[CH3:24])=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=3)[O:34][N:50]=2)=[C:45]2[C:41]=1[C:42]([CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:43][NH:44]2
Reactant: [H]/N=C(\NO)c1ccc(F)c2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ncc(C(=O)O)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc(F)c12
Reaction time: 2 h
Yield: 60.4 %

Procedure:
HOBT (161 mg) and EDCI (203 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (132 mg) in THF (4 mL). The resulting solution was stirred for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (210 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT overnight. TBAF (770 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (10% EtOAc in hexane) to afford ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D49) (162 mg) as a pale white solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.46 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.15 (2H, q), 5.59 (1H, m), 6.92 (1H, dd), 7.15 (1H, d), 8.05 (1H, dd), 8.64 (1H, d), 9.17 (1H, d), 9.65 (1H, br s). MS (ES): C24H22F4N4O4 requires 506; found 507.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOCC.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>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccoc1
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: CCOCC
Solvent: COCCOC
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccoc3)cc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A round-bottom flash was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (200) (1.0 g, 2.8 mmol), Pd(PPh3)4, (0.323 g, 0.28 mmol), 3-furanylboronic acid (0.627 g, 5.6 mmol), aqueous 2 M Na2CO3, (1.2 g, 4.7 mL, 11.2 mmol), and DME (15 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 5 h. Reaction mixture was cooled at room temperature, diluted with Et2O (30 ml) and filtered. The filtrate was diluted with EtOAc (100 mL), washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using n-hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.887 g (92%) of the title compound 201 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H), 7.48 (t, J=1.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−. Anal. Calcd for C24H24O2, C, 83.69; H, 7.02; Found: C, 82.69; H, 7.06.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[C:2]#[CH:3].[C:7]1([SH:14])[C:8]([SH:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>C1COCC1.C(O[K])(C)(C)C>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:14][CH:3]1[CH2:2][C:1]([OH:5])=[O:4]
Reactant: Sc1ccccc1S
Reactant: C#CC(=O)OC
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(O)CC1Sc2ccccc2S1
Reaction time: 3 h

Procedure:
To a solution of methyl propiolate (0.75 mL) in THF (10 mL) were added a solution of benzene-1,2-dithiol (1.2 g) in THF (10 mL) and tert-butoxy potassium (catalytic amount) under ice-cooling, and the mixture was stirred at the same temperature for 3 hours and then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added methanol (5 mL) at room temperature, and then an aqueous solution (10 mL) of sodium hydroxide (0.45 g). The mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added ion-exchanged water (20 mL), which was washed with ethyl acetate. The aqueous layer was adjusted to pH 2 by addition of 1N hydrochloric acid, and then extracted with ethyl acetate (70 mL) twice. The organic layers were combined, washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2-(benzo[1,3]dithiol-2-yl)acetic acid (1.35 g) as a yellow crystal.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[C:23]2[C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[C:16]4[CH:15]=[CH:14][C:13]3=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:6]2[CH:5]=[C:4]([Br:8])[CH:3]=[C:2]([C:17]3[C:16]4[C:25]5=[C:24]6[C:13](=[CH:14][CH:15]=4)[CH:12]=[CH:11][CH:10]=[C:23]6[CH:22]=[CH:21][C:20]5=[CH:19][CH:18]=3)[CH:7]=2)[C:23]2[C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[C:16]4[CH:15]=[CH:14][C:13]3=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1cccc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cc(-c2ccc3ccc4cccc5ccc2c3c45)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reaction time: 7 h
Yield: 38.6 %

Procedure:
Under the atmosphere of argon gas, 6 g of tribromobenzene available as a commercial reagent, 9.4 g of 1-pyrenyl boronic acid and 0.88 g of tetrakis(triphenylphophine)palladium were dissolved in 150 ml of toluene, and then the 57 ml of 2M sodium carbonate aqueous solution was added therein, followed by 7 hours reflux on heating. After standing to cool, the precipitated solid was separated through filtration, and then followed by washing with water and methanol, and drying. The obtained solid was refined through a silica gel chromatography (developing solvent: toluene/hexane=1/3) and then 4.1 g of 3,5-dipyrenylbromobenzene of pale yellow solid was obtained (Yield: 38%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1.[C:14](#[N:16])[CH3:15]>C1COCC1>[O:9]=[C:8]([C:5]1([C:4]([F:13])([F:12])[F:3])[CH2:7][CH2:6]1)[CH2:15][C:14]#[N:16]
Reactant: COC(=O)C1(C(F)(F)F)CC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a slurry of NaH (432 mg, 18 mmol) in THF (40 mL) heated at reflux was added dropwise over 10 minutes a solution of methyl 1-(trifluoromethyl)cyclopropanecarboxylate (2.0 g, 11.9 mmol) in acetonitrile (940 uL, 12 mmol) and the mixture heated at reflux overnight. After cooling to room temperature, the reaction was partitioned between ether and H2O, the aqueous layer acidified with 1N HCl(aq), extracted with ether, and the combined org layers washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (5-40% EtOAc/hexanes) to give 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (1.04 g, 5.88 mmol, 49%). LC-MS (ESI) m/z 178 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH2:47][CH2:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1CCC=C2

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).