Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][C:9]([NH:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CC(C)(C)OC(=O)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2-(tert-butoxycarbonyl)acetic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (38 μL, 0.22 mmol) in anhydrous CH2Cl2 (0.5 mL) was stirred at RT for 10 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and anhydrous CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1 h. Activated and added another 0.5 equivalent of the acid as described above and stirred for 1 h. Activated and added another 0.3 equivalents of the acid as described above. Stirred for and additional hour and diluted with CH2Cl2. Extracted with H2O (3×) and the organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (1:1 EtOAc:Hexanes) to give the desired product tert-butyl 5-(2-(3-(2-(tert-butoxycarbonyl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (123 mg, 0.20 mmol, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14]Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:11]([Cl:10])[CH:12]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(Cl)c1O
Solvent: O
Product: Cc1cc(Cc2ccc(Cl)c(Cl)c2)cc(Cl)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
90.4 g (0.63 mol) 2-chloro-6-methylphenol are brought to reaction with 149.4 g (0.765 mol) 3,4-dichlorobenzylchloride and 2.4 g water-free, finely mortared ZnCL2 without solvent. After stirring 5-6 h at 60° C. the reaction mixture is subsequently worked up by washing three times, each with 100 ml water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:19][CH2:18]3)[C:6]=2[CH:31]=1.O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@H:7]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])[CH2:21][CH2:22]3)[C:6]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)C[C@H](N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Reaction time: 72 h

Procedure:
The foregoing precedure is repeated using 100 g. of racemic 3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl }-2-oxazolidinone, 113.2 g. of (+)-camphor-10-sulfonic acid monohydrate and 300 ml. of acetone. The stirring under reflux is carried out for 24 hours in place of 72 hours, and the drying under reduced pressure is prolonged. Whereupon, there is obtained the di-(camphor-10-sulfonic acid) salt of (+)-(S)-3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone; αD =+14.9°, α364 =+104.0° (chloroform; c = 3.0%); melting point 174°-175° C. (after recrystallization from acetone).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]1.CCO>O>[NH:37]1[CH2:38][CH2:39][CH:34]([NH:33][CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:35][CH2:36]1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCO
Solvent: O
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCNC3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), 4-amino-N-Boc-piperidine (0.082 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C., 10 minutes; 150° C., 10 minutes; and 150° C., 30 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.02 g (43%). 1H-NMR (MeOD) δ 7.27–7.30 (t, 1H), 6.96–6.98 (m, 2H), 6.88 (d, 1H), 4.14 (t, 2H), 3.87 (s, 2H), 3.50–3.60 (m, 3H), 3.07–3.10 (m, 2H), 2.36–2.39 (m, 2H), 2.17–2.20 (m, 2H), 1.82–1.90 (m, 2H), 1.30–1.35 (m, 2H). LCMS 459.0 (M+1), HPLC Method B Rt 1.7 minutes.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)[C:16](=[O:35])[CH:15]=1)C1C=CC=CC=1>[H][H].[Pd]>[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:25]=2)[C:16](=[O:35])[CH:15]=1
Reactant: [H][H]
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1cc(O)ccn1-c1ccc(OCCN2CCCCC2)cc1
Yield: 74.6 %

Procedure:
Into a THF (10 mL) solution of 4-benzyloxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one (Example 2, 130 mg, 0.32 mmol), 10% palladium-on-carbon (165 mg) was added and stirred at room temperature for 10 hours in hydrogen atmosphere. The reaction liquid was filtered, washed thoroughly with methanol, and the filtrate was concentrated under reduced pressure. THF was added to the resulting residue and the formed precipitate was recovered by filtration and dried to provide the title compound (75 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22](NC(C3C=CC=CC=3C)CCO)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:16])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:40][CH:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:38][C:37]([F:47])([F:48])[F:36])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CCO)NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: NC(CC(F)(F)F)c1ccccc1
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(CC(F)(F)F)c1ccccc1

Procedure:
In the same way as for the compound from Example 86, 50 mg (0.14 mmol) of the compound from Example 8A and 28 mg (0.15 mmol) of 3,3,3-trifluoro-1-phenylpropan-1-amine were reacted. This gave 44 mg (59% of theory) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:12])[N:10]=[C:4]2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[C:9]([C:11]([NH:13][CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]5)=[O:12])[N:10]=[C:4]4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(O)cc3n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a stirred solution of tert-butyl 4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate (0.18 g, 0.50 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.12 g, 0.6 mmol), 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.12 g, 0.5 mmol), and triphenylphosphine (0.16 g, 0.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.01) to afford tert-butyl 4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate as a off-white solid (0.13 g, 44%). 1H-NMR (CDCl3, 300 MHz): δ 7.97 (m, 2H), 7.47 (m, 2H), 7.18 (m, 1H), 6.95 (m, 2H), 6.81 (s, 1H), 6.58 (m, 1H), 4.56 (m, 1H), 4.11 (m, 3H), 3.61 (m, 2H), 3.26 (m, 2H), 2.92 (m, 2H), 2.15 (m, 2H), 2.03 (m, 4H), 1.66 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 588.4 (M+1).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:42]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:42].[F:28][C:26]([F:27])([F:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1
Reactant: FC(F)(F)Oc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzyhydryloxy]azetidine (140) (4.8 mmol) using the procedure described for compound (9) (1.32 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.CC1(C)C(C)(C)OB([C:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[CH2:31][N:25]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[S:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[C:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH:51]=1)=[N:13][CH:14]=[CH:15]2)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)nccc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.063 g, 0.095 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.044 g, 0.142 mmol), Pd(AmPhos)2Cl2 (6.71 mg, 9.48 μmol), and potassium phosphate (0.070 g, 0.332 mmol). Dioxane (0.474 ml) and water (0.158 ml) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford tert-butyl 4-(2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as an off-white solid. m/z (ESI) 767.3 (M+H)+.
Reaction SMILES: [Na+:1].C(NC([N:12]1[CH2:18][CH2:17][C@@H:16]2[C@H:13]1[C:14](=O)[N:15]2[S:19]([O-:22])(=[O:21])=[O:20])=O)C1C=CC=CC=1.C(N(CC)CC)C.[C:31](Cl)(=[O:40])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Na+:1].[C:34]1(/[CH:33]=[CH:32]/[C:31]([C@:13]23[CH2:14][N:15]([S:19]([O-:22])(=[O:20])=[O:21])[C@@H:16]2[CH2:17][CH2:18][NH:12]3)=[O:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: O=C(NCc1ccccc1)N1CC[C@@H]2[C@H]1C(=O)N2S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)[C@]12CN(S(=O)(=O)[O-])[C@@H]1CCN2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1S,5R)-2,6-Diazabicyclo[3.2.0]heptan-7-one (Example 2) (500 mg, 4.5 mmol) were suspended in 50 ml of dichloromethane. 0.75 ml (5.4 mmol) of triethylamine and subsequently 890 mg (5.4 mmol) of cinnamoyl chloride were added dropwise thereto while cooling with ice and the mixture was left to stir for 30 minutes while cooling and for 3.5 hours at room temperature. Thereafter, it was extracted once each time with saturated aqueous sodium carbonate solution, 2% aqueous citric acid solution, water and saturated aqueous sodium chloride solution. The combined organic phases were dried over magnesium sulphate and concentrated. Purification was effected by flash chromatography over silica gel with ethyl acetate. Yield: 560 mg (52%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=1[Br:24])=[O:28]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 74.9 %

Procedure:
A solution of 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (120 mg, 0.30 mmol), 2-bromo-5-methoxybenzoic acid (82 mg, 0.36 mmol), DIEA (260 μL, 1.5 mmol) and HBTU (157 mg, 0.41 mmol) in DMF (4 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (180 mg) was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (130 mg, 76%). HRMS: Obs. Mass 576.9959. Calcd. Mass 576.9973 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][CH2:11][C:12](O)=[O:13]>C1COCC1>[Cl:10][CH2:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
3,4-Dichloroaniline (8.10 g, 50.0 mmol) was dissolved in THF (50 mL). To the solution was added anhydrous chloroacetic acid (9.40 g, 55.0 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 mL, 20 mL×2), saturated sodium chloride solution (20 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (30 mL), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (10 mL×3), and dried under reduced pressure to give the titled compound (8.08 g) as white crystals. The filtrate was concentrated under reduced pressure. To the concentrate was added diisopropyl ether/hexane (1/1) mixed solvent (30 mL), and the precipitates was collected by filtration. The precipitates were washed with diisopropyl ether/hexane (1/1). mixed solvent (10 mL×3), and dried under reduced pressure to-give the titled compound (3.01 g) as white crystals. Yield (11.09 g, 93%, 46.5 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:21][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 100 °C
Yield: 95.7 %

Procedure:
A mixture of 2-acetylamino-4-chloromethylthiazole (1.9 g), 4-nitrothiophenol (1.6 g) and potassium carbonate (2.0 g) in a N,N-dimethylformamide (50 ml) was heated at 100° C. for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (2.95 g, yield: 95.5%). mp: 165°-166° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:34]3[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:36][CH:28]2[CH2:29]4)[CH2:33]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38][CH3:37])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:28]3[CH2:29][CH:30]4[CH2:31][CH:32]([CH2:33][CH:34]2[CH2:35]4)[CH2:36]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: COc1ccccc1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(Cc2ccccc2OC)CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred solution of diisopropylamine (6.3 g, 62.7 mmol) in dry THF (120 mL) at −20° C. under N2 was added 2.5 M n-BuLi (25.1 mL, 62.7 mmol). The resulting solution was added dropwise to a stirred solution of 1-(2-adamantyl) 3-ethoxycarbonylpiperidine-1-carboxylate (14.0 g, 41.8 mmol) in dry THF (170 mL) at −70° C. The mixture was stirred for 1 h at −70° C. and 2-methoxybenzyl bromide (10.9 g, 54.3 mmol) was added. The mixture was stirred for 4 h at rt, quenched with brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford the title compound (14.3 g, 75%). LC-MS Method 3 tR=2.04 min, m/z=456.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.[Pd]>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=[C:5]1[C:14]1[CH:15]=[CH:16][C:17]2[C:26]([CH:27]=1)=[C:25]1[C:20]([CH:21]=[CH:22][CH:23]=[CH:24]1)=[N:19][CH:18]=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccc2cnc3ccccc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc4cnc5ccccc5c4c3)cc2c1
Yield: 78 %

Procedure:
Benzo[b]thiophene-2-ylboronic acid (884 mg, 5.0 mmol) and 9-chlorophenanthridin (1.0 g, 4.8 mmol) were dissolved in tetrahydrofuran (30 ml), and palladium catalyst (160 mg, 0.14 mmol) and 2M sodium carbonate solution (20 ml) were added, followed by refluxing under a N2 atmosphere for 5 hours. The reaction solution was added to H2O and the mixture was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 1.15 g, yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH3:11])[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc(N)c1)c1ccc(F)c(F)c1
Yield: 99.7 %

Procedure:
Following a similar procedure to that described in Example (1b), 1.30 g of N-[(4-chlorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3,4-difluorophenyl)ethyl]amine [prepared as described in step (a) above], 1.53 g of nickel chloride hexahydrate and 514 mg of sodium borohydride were reacted, to obtain 1.20 g of the title compound as a yellow oil.