Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42](O)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36].N1CCNCC1=O>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[O:41][C:40]([C:42]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:43])=[CH:39][C:38]=2[C:45]2[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([Cl:52])[CH:46]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CCN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 21A. Instead of 1.5 equivalents of piperazin-2-one, 1.1 equivalents are used. 33.0 mg (53% of theory) of the title compound are obtained.
Reaction SMILES: [O-:1]C#N.[Na+].[NH2:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.O>[Br:16][C:14]1[CH:13]=[CH:12][C:7]2[C:8](=[O:9])[O:10][C:11](=[O:1])[NH:5][C:6]=2[CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
87.0 g (1.33 mol) of sodium cyanate were added to 269.0 g (1.17 mol) of methyl 2-amino-4-bromobenzoate in 1.2 l of acetic acid with stirring at room temperature, and the mixture was subsequently stirred for a further 22 h. The reaction mixture was diluted with 1.5 l of water, and the residue was filtered off with suction. 0.42 l of sodium hydroxide solution (32%) was added to the solid, the mixture was diluted with 3.5 l of water and heated on a steam bath for 4 h. After cooling, the solid residue was filtered off with suction. Conventional work-up gave 205.2 g of 7-bromo-1H-benzo[d]-1,3-oxazine-2,4-dione; HPLC/MS (M+H)+=243 as solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:15]2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38].N1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:27])[CH:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[C:19](=[O:20])[CH2:18][O:17][C:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:15]2)=[CH:11][CH:12]=1)[C:4]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[O:5]
Reactant: COC(=O)/C=C/c1ccccc1N
Reactant: CC(C)C(C(=O)O)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)/C=C/c1ccccc1NC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C(C)C

Procedure:
A solution of 50 mg (0.14 mmol) of 3-methyl 2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoic acid (enantiomer 2; Example 79A), 20 mg (0.11 mmol) of methyl (2E)-3-(2-aminophenyl)prop-2-enoate, 1.5 ml of pyridine and 65 mg (0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) in 5 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 7 mg (0.01 mmol, 9.8% of theory) of a colorless oil.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.S([O-])([O-])(=O)=O.[OH:17][NH3+:18].O[NH3+]>O>[OH:17][N:18]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: [NH3+]O
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 130 °C

Procedure:
0.15 g (1.0 mmol) of phthalic anhydride was mixed with 0.2 to 1 equivalent of hydroxylammonium sulfate (see Table 1) and, optionally after the addition of water (see Table 1), heated to 130° C. in a sealed ampoule. The reaction times were varied for the individual mixtures in accordance with Table 1. The cooled reaction mixture was dissolved in d6-DMSO and analyzed using 1H-NMR spectroscopy. The yields are given in each case in Table 1.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC=CC=2CSCCO)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccccc2CSCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (4.15 g, 13.12 mmol, 1 eq.) in anhydrous THF was treated with phenol (1.61 g, 17.06 mmol, 1.3 eq.), triphenylphosphine (4.47 g, 17.06 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (3.45 g, 17.06 mmol, 1.3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][C:17]([NH2:18])=[O:16])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: N#C[O-]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1CCc2c(sc(NC(N)=O)c2C(N)=O)C1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a stirred mixture of compound F4 (451 mg, 2.00 mmol) in acetic acid (6 mL) at room temperature was added a solution of sodium cyanate (169 mg, 2.60 mmol) in water (2.5 mL) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h and then concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound M1 as a yellow solid (125 mg, 23%): 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.31 (bs, 1H), 6.77 (bs, 3H), 3.41 (s, 2H), 2.73 (d, J=4.8 Hz, 2H), 2.63 (d, J=4.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.06 (t, J=7.0 Hz, 3H). MS (M+H) 269.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63][CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:61]([O:60][CH3:59])[CH2:62][CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH:18](N1CCCCC1)=[O:19]>O1CCCC1>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:18]=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=CN1CCCCC1
Reactant: CCCCCCc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1ccsc1C=O
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of 2-bromo-3-hexylthiophene (13.5 g, 54.6 mmol) in anhydrous tetrahydrofuran (200 mL) in a dry ice/acetone bath at −78° C. was added n-butyl lithium (2.5 M in hexane, 24.0 mL, 60.1 mmol) dropwise under the protection of argon. The reaction solution was warmed to −40° C. and stirred for 60 min. The solution was cooled down to −78° C. again, and 1-formylpiperidine (7.41 g, 65.5 mmol) was added in one shot. Then, the solution was allowed to warm slowly up to room temperature and stirred overnight. The solution was then poured into ice water. The organic layer was separated and the aqueous layer was extracted twice with hexane (100 mL). The organic extracts were combined and washed three times with distilled water (50 mL), dried over anhydrous magnesium sulfate, and rotary evaporated to remove the solvent. The liquid residue was subjected to silica-gel column chromatography (EtOAc/hexane=1/10, Rf=0.4) to yield a clear liquid product (9.8 g, 92% yield). 1H NMR (400 MHz, acetone-d6) δ (ppm): 10.11 (s, 1H); 7.89 (d, 1H, J=5.2 Hz); 7.17 (d, 1H, J=5.2 Hz); 3.04 (t, 2H, J=7.8 Hz); 1.69 (m, 2H); 1.28-1.42 (m, 6 H); 0.87 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:6][CH:7]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1Br
Yield: 24 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a yellow solid (25 mg, 24%). mp: 227-228° C., MS (ESI+): 527, 529 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.35 (s, 1H), 8.73 (br d, 1H), 8.48 (d, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 7.71 (m, 2H), 7.35 (t, 1H), 7.10 (t, 1H), 7.04 (s, 1H), 4.31 (t, 2H), 3.82 (s, 3H), 3.37 (s, 3H), 2.82 (t, 2H), 2.80 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][CH2:20][CH2:21][O:22][CH:23]2[CH:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[CH:31][CH:30]=3)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:24]2)[C:13]=1[CH2:56][C:57](OC)=[O:58].CO.Cl>O1CCCC1>[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][CH2:20][CH2:21][O:22][CH:23]2[CH:28]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[CH:33][CH:34]=3)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:24]2)[C:13]=1[CH2:56][CH2:57][OH:58]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCO)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
4.8 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −70° C. over 10 minutes to the solution of 1.74 g of tert-butyl 3-[2-(6-chloro-5-methoxycarbonylmethyl-2-methylpyrimidin-4-yloxy)ethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 20 ml of tetrahydrofuran. The reaction mixture is warmed slowly to −40° C. over 3 hours, admixed with 0.4 ml of methanol and subsequently warmed to room temperature. The reaction solution is admixed with 20 ml of 0.5N HCl and stirred vigorously over 10 minutes. The reaction mixture is extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with 1M sodium potassium tartrate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (2:1 EtOAc-heptane); Rt=5.75.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)[N:22]=[C:21]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][N:53]=2)=[CH:48][CH:47]=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.O1CCCC1>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:22]=[C:21]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([CH3:42])([CH3:44])[CH3:43])=[CH:39][CH:40]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:46]4[CH:47]=[CH:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([C:58]6[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=6)=[CH:54][N:53]=5)=[CH:50][CH:51]=4)=[CH:18][CH:17]=3)[N:24]=2)=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccc(-c3ccccc3)cn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccc(-c6ccccc6)cn5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under a stream of argon, 0.35 ml of a hexane solution containing 0.55 mmol of butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C. in which 0.25 g of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained by Reference Example 1 had been dissolved. After stirring at −78° C. for 15 minutes, 0.15 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 5 ml portion of tetrahydrofuran prepared by dissolving 0.19 g of 2-(4-bromophenyl)-5-phenylpyridine and 0.03 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=1:1 to 4:5) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(5-phenylpyridin-2-yl)biphenyl-4-yl]-1,3,5-triazin (0.14 g, yield 43%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:47][NH2:48].C[Si](C)(C)NC(=O)C>O1CCCC1>[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[CH2:47][NH:48][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CC(=O)N[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate (356 μl) and 4-methylmorpholine (300 μl) at −15° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783 mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between ethyl acetate and water. The organic layer was separated, washed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (1.36 g) as a foam, which is the same compound obtained in Preparation 7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:26])[CH3:25])[CH:19]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(Cl)nc1

Procedure:
Using an analogous procedure to that described in Example 1, 6-chloropyrid-3-ylcarbonyl chloride was reacted with 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide to give the title compound; Mass Spectrum: M+H+ 409 and 411.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6](/[CH:7]=[N:8]/[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[H][H]>[Pd].CC(=O)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: COc1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNNC(=O)OC(C)(C)C)cc1
Yield: 104.3 %

Procedure:
Add 10% palladium on carbon (water wet, 20 g) slurried in EA (100 mL) to a sealed pressure reactor via vacuum transfer. Rinse transfer line with a minimal amount of EA. Charge (E)-tert-butyl 2-(4-methoxybenzylidene)hydrazinecarboxylate (320 g, 1.28 mol) dissolved in tetrahydrofuran (THF, 1000 mL) via vacuum transfer and rinse line with a minimal amount of THF. Pressurize the reactor to 50 PSI with H2 and mix the contents of the reactor at 20±10° C. Continue the reaction, maintaining the hydrogen pressure at 50 PSI, until no further hydrogen uptake is observed. Filter the reaction solution to remove the catalyst and wash the catalyst filter-cake with THF (500 mL). Add the wash to the reaction filtrate. Concentrate the solution in vacuo to obtain the title compound (337 g, 86%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.1-8.3 (s, 1H), 7.1-7.3 (d, 2H), 6.8-6.9 (d, 2H), 4.4-4.6 (bs, 1H), 3.7-3.8 (s, 2H), 3.6-3.7 (s, 3H), 1.3-1.5 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@@:12]23[CH2:27][CH2:26][C:25](=O)[CH2:24][C@H:13]2[CH2:14][O:15][C:16]2[C:21]3=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:32][O:33][NH2:34].CCN(CC)CC>CCO>[CH3:32][O:33][N:34]=[C:25]1[CH2:24][CH:13]2[CH2:14][O:15][C:16]3[C:21]([C:12]2([S:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:8][CH:7]=2)(=[O:10])=[O:11])[CH2:27][CH2:26]1)=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23]
Reactant: CON
Reactant: O=C1CC[C@@]2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON=C1CCC2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OCC2C1
Reaction time: 8 h

Procedure:
To a solution of trans-10a-(4-trifluoromethyl-benzenesulfonyl)-1,4-difluoro-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one (40 mg, 0.10 mmol) in EtOH (2 mL) was added O-methyl hydroxylamine hydrochloride (20 mg, 0.23 mmol), and NEt3 (20 uL, 0.14 mmol). The reaction mixture was stirred overnight and then PS-dimethylaminoethyl resin was added, the stirring was continued for 2 h and then the resin removed by filtration. The solvent was removed under a stream of N2 and the residue purified by preparative TLC eluting with 25% ethyl acetate in hexanes (22 mg, 47%).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.17 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.16 g, 47% yield), mp=87–89° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=−23.1° (c=1, EtOH).