Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][C:34](N)=[CH:35][C:28]=4[O:27][C:26]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH2:14][C:15]1([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[O:27][C:26]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.1 %

Procedure:
TFA: To a solution of {1-[4-(7-amino-4-oxo-2-phenyl-4H-1-benzopyran-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (12.2 mg, 0.03 mmol) in dichloromethane (1 mL) was added TFA (1 mL) and the mixture was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to give a white solid (16.0 mg, 100%). 1H-NMR (400 MHz, D2O) δ 8.02 (d, 1H), 7.76 (dd, 2H), 7.55 (d, 2H), 7.42 (dd, 2H), 7.28-7.34 (m, 3H), 7.17-7.22 (m, 3H) 2.60-2.67 (m, 2H), 2.44-2.52 (m, 2H), 2.04-2.08 (m, 1H), 1.80-1.83 (m, 1H). LCMS (Method I): RT=4.50 min, [M+H]+=368
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:29]=[CH:28][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:43][CH2:44][C@@H:45]([C:47]1[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=1)[OH:46].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:46][C@H:45]([C:47]1[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=1)[CH2:44][NH:43][CH2:3][CH2:4][C:5]1[CH:29]=[CH:28][C:8]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(Nc3ccc(CC(OC)OC)cc3)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4ccc(C(=O)O)cc4)CC3)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
Methyl 4-({4-[4-(2,2-dimethoxyethyl)anilino]-1-piperidinyl}carbonyl)benzoate (0.30 g, 0.703 mmol) was added to a pre-prepared mixture of sodium iodide (0.264 g, 1.76 mmol) and trichloro(methyl)silane (0.166 mL, 1.4 mmol) in anhydrous acetonitrile. The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent partially removed under vacuo. The aidehyde solution was used directly and treated with methanol (17 mL), acetic acid (0.043 mL, 0.75 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.127 g, 0.516 mmol) followed by sodium cyanoborohydride (0.048g, 0.764 mmol). The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.127 g, 0.208 mmol).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][NH:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1>>[CH3:22][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([N:33]2[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]2[NH:31][CH3:30])[N:10]=3)[CH2:18][CH2:17]1)([CH3:23])[CH2:20][OH:21]
Reactant: CNc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and N-methyl-1H-benzo[d]imidazol-2-amine were reacted to give 453. LCMS m/z: 535.3 (MH+)
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12]C=O)[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3.C(O)C.CCOCC.[ClH:26]>>[ClH:26].[O:1]=[C:2]1[CH:11]([NH2:12])[CH2:10][C:9]2=[CH:15][CH:16]=[CH:17][C:7]3=[C:8]2[N:3]1[CH2:4][CH2:5][CH2:6]3
Reactant: O=CNC1Cc2cccc3c2N(CCC3)C1=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NC1Cc2cccc3c2N(CCC3)C1=O

Procedure:
A solution of N-(2,3,6,7-tetrahydro-3-oxo- 1H,5H-benzo(ij)quinolizin-2-yl)-formamide (0.8 g, 3.4 retool) in ethanolic hydrogen chloride (10 mL of 4.2 M) was heated at 50° C. for 2 hours. The ethanol was cooled, an equal volume of ether was added, and the precipitate was filtered off and washed with ether to give 0.78 g of 2,3,6,7-tetrahydro-3-oxo-1H,5H-benzo(ij) quinolizin-2-amine hydrochloride, mp 216°-221° C. The product was recrystallized for analysis; mp 219°-222° C. Anal. Calc'd for C12H14N2O·HCl: C, 60.37; H, 6.33; Cl, 14.85; N, 11.74. Found: C, 59.89; H, 6.42; Cl, 15.41; N, 11.68.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([Cl:27])[C:23]([CH2:25]Cl)=[CH:24][C:18]=2[O:17]1.CCN(CC)CC>O1CCCC1>[Cl:27][C:22]1[C:23]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[CH:24][C:18]2[O:17][CH2:16][O:20][C:19]=2[CH:21]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: c1ccc(OCCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1cc2c(cc1CN1CCN(CCOc3ccccc3)CC1)OCO2
Temperature: 60 °C

Procedure:
1-[2-(phenoxy)-ethyl]piperazine (200 mg, 0.974 mmol), 6-chloropiperonyl chloride (200 mg, 0.974 mmol), and Et3N (415 μL, 3 mmol) were combined in tetrahydrofuran (THF 20 mL). The reaction mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated. The crude residue was chromatographed on silica (20% EtOAc/Hexanes) and the product fractions were collected and evaporated to an amber solid (186 mg, 51%). 1H NMR (CDCl3) δ: 2.5-2.7 (m, 8H), 2.8 (t, 2H), 3.5 (s, 2H), 4.1 (t, 2H), 5.9 (s, 2H), 6.81 (s, 1H), 6.9-6.94 (m, 3H), 6.96-6.98 (m, 1H), 7.26-7.3 (m, 1H). MS ELS+ 376. CHN: calc., 64.08, 6.18, 7.47; found, 63.87, 6.12, 7.44. mp: 72-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[N:10]=1)[C:5]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:7]
Reactant: NC1CC1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (1 eq.) in DMF (0.05 M) was added sequentially cyclopropylamine (1.05 eq.), Hunig's base (3 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting solution was stirred at RT for 4 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) CH2Cl2:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH2:22].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:13]([CH:11]1[O:12][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=2[NH:9][CH2:10]1)=[O:15]
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Reactant: Cc1ccc(N)c(Br)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (600 mg, 2.28 mmol) and 2-bromo-4-methyl-aniline (424 mg, 286 μL, 2.28 mmol) were dissolved in 2-methyltetrahydrofuran (7 mL) and pyridine (461 μL, 5.70 mmol). T3P (2902 mg, 2.7 mL of 50% w/w solution, 4.56 mmol) was added and the reaction was stirred for 30 min at room temperature. Purification by silica gel chromatography (10-100% ethyl acetate/hexanes) provided N-(2-bromo-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (743 mg, 76% yield). LC/MS m/z 432.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[N+]([C:20]([CH2:47][CH2:48][CH2:49][CH3:50])=[CH:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])([O-])=O>>[C:29]([O:28][C:26]([C:25]1[CH:33]=[CH:34][C:22]([C:21]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:20]=2[CH2:47][CH2:48][CH2:49][CH3:50])=[C:23]([C:35]([N:37]2[CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38]2)=[O:36])[CH:24]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)/C=N/Nc1ccc(OC)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(OC)cc1
Yield: 45 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-methoxyphenyl)hydrazono)acetate (24 mg, 0.108 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (50 mg, 0.108 mmol) were converted to the title compound (31 mg, 45%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.03-8.02 (m, 1H), 7.42-6.81 (m, 9H), 5.02-4.98 (m, 1H), 4.46-4.38 (m, 1H), 4.32-4.26 (m, 2H), 4.15-3.98 (m, 1H), 3.86 (s, 1.5H), 3.85 (s, 1.5H), 3.54-3.33 (m, 1H), 2.81-2.45 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.22 (t, J=8 Hz, 1.5H), 1.30-0.95 (m, 4H), 0.61-0.57 (m, 3H); MS(ESI+) m/z 638.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([OH:22])=[C:4]([Cl:21])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].C([Li])(C)(C)C>>[Cl:21][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[CH:7][C:6]=2[Cl:20])[CH:11]=[CH:2][C:3]=1[OH:22]
Reactant: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1
Agent: [Li]C(C)(C)C
Product: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-1,8-dichloro-6-(4-methoxyphenyl)-2-naphthol (0.30 g, 0.754 mmol) with t-butyl lithium (1.75 mL of 1.7N solution, 3.0 mmol) and quenching with water according to the method use to prepare intermediate 84 to yield 0.19 g (79%) of a yellow solid. An analytical sample was further prepared by reverse phase preparative HPLC to yield the title compound as a light yellow solid: mp 132-134° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.06 (2H, d, J=8.77 Hz), 7.37 (1H, d, J=8.90 Hz), 7.77 (2H, d, J=8.75 Hz), 7.89-7.93 (2H, m), 8.15 (1H, d, J=1.85 Hz), 10.68 (1H, s); MS (ESI) m/z 317/319/321 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[CH2:10]([NH2:12])[CH3:11]>>[CH2:10]([NH:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[CH3:11]
Reactant: Cc1ccsc1C(=O)O
Reactant: CCN
Product: CCNC(=O)c1sccc1C
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 18, making variations only as required to use 3-methylthiophene-2-carboxylic acid in place of 3-methylfuran-2-carboxylic acid to react with ethylamine in place of benzylamine, N-ethyl-3-methylthiophene-2-carboxamide was obtained as a colorless liquid in 92% yield: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=5.0 Hz, 1H), 6.88 (d, J=5.0 Hz, 1H), 5.77 (br s, 1H), 3.51-3.40 (m, 2H), 2.51 (s, 3H), 1.24 (t, J=7.3 Hz, 3H); MS (ES+) m/z 170.2 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([NH:33][C:34]2[CH:46]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:44]=[CH:43][C:35]=2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C1(C)C=CC=CC=1>[C:47]1([C:45]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])=[C:34]([NH:33][C:31]([C:28]3[CH:29]=[N:30][C:25]([C:9]4[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=4)=[CH:26][CH:27]=3)=[O:32])[CH:46]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccncc2)nc1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (48 mg), tripotassium phosphate (91 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.6 mg), and palladium(II) acetate (1.8 mg) were added to a toluene (1.6 mL) suspension of tert-butyl 2-(6-chloropyridine-3-carboxamido)-4-phenylbenzoate (80 mg), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48 mg), tripotassium phosphate (91 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.6 mg), and palladium(II) acetate (1.8 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and then 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.6 mg) and palladium(II) acetate (1.8 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and chloroform and water were added to the residue. The insoluble substance was removed by filtration. 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 [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-15% hexane/ethyl acetate] to obtain 25 mg of tert-butyl 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[C:27]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:28]C([O-])=O.[K+].Cl>O1CCCC1.O>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4](=[O:6])[CH2:28][C:27]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-difluorobenzoic acid (15 g, 0.095 mol) and carbonyldiimidazole (18 g, 0.14 mol, 1.5 equiv) in anhydrous tetrahydrofuran (150 mL) was stirred at ambient temperature for 6 hours. In a separate flask, a suspension of anhydrous magnesium(II) chloride (9.0 g, 0.095 mol, 1.0 equiv) and potassium ethyl malonate (22 g, 0.13 mol, 1.4 equiv) in tetrahydrofuran (225 mL) was stirred at 50-60° C. for 6 hours, cooled to ambient temperature, which was then added via syringe to the solution of activated acid, and the mixture was stirred for an additional 18 hours at ambient temperature. The mixture was refluxed for 3 hours, cooled to ambient temperature, poured into water and acidified with hydrochloric acid (12 N aqueous) to pH<2. The aqueous layer was extracted with ethyl acetate and the organic extract was washed with water, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:11][NH:12]C(O)C>C1(C)C=CC=CC=1>[CH3:11][N:12]1[CH2:6][CH2:5][O:4][C:2](=[O:3])[C:1]1=[O:8]
Reactant: CNC(C)O
Reactant: CCOC(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CN1CCOC(=O)C1=O

Procedure:
Following the procedure of G. Drefahl, M. Hartmann and A. Skurk, Chem. Ber. 1966, 99, diethyl oxalate (1.81 mL, 0.0133 mol) and N-methylamino-ethanol (1 g, 0.0133 mol) were dissolved in toluene(50 mL) and heated at reflux for 5 h. The reaction mixture was concentrated to dryness, triturated with ether, and the residue chromatographed (SiO2, 0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]([C:20]1[CH:19]=[C:18]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[CH:23]=[CH:22][N:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(Br)ccn1
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)c2)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A mixture of 2-acetamido-4-methylthiazole (1.2 g, 7.7 mmol, 1.1 eq), cesium carbonate (4.55 g, 14 mmol, 2 eq), tri-tert-butylphosphinium tetrafluoroborate (0.406 g, 1.4 mmol, 0.2 eq), palladium (II) acetate (0.15 g, 0.7 mmol, 0.1 eq) and 4-bromo-2-tert-butyl-pyridine (Step 1.4) (1.5 g, 7 mmol) in DMF (50 mL) is stirred for 1.5 h at 90° C. under an argon atmosphere, allowed to cool, quenched by addition of a saturated solution of NaHCO3 and filtered through a pad of celite. The filtrate is extracted with EtOAc. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→97:3) to afford 2.02 g of the title compound as a yellow solid: ESI-MS: 290.1 [M+H]+; TLC: Rf=0.35 (DCM/MeOH, 9:1).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]O.C(N(C(C)C)CC)(C)C.O>ClCCl>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1CO
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 1, 2-methoxybenzyl alcohol (0.075 g) and diisopropylethylamine (0.24 g) in dichloromethane (2 ml), EPPA (0.20 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless oil (0.15 g, 62%).
Reaction SMILES: [F:1][C:2]1[C:7]([I:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]1OCC[O:12]1.Cl>CC(C)=O>[F:1][C:2]1[C:7]([I:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: COc1ccc(C2OCCO2)c(F)c1I
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(F)c1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.6 %

Procedure:
To a solution of 2-(2-fluoro-3-iodo-4-methoxy-phenyl)-[1,3] dioxolane (5.284 g, 16.30 mmol) in acetone (170 mL) was added HCl (1N, 170 mL) and the solution stirred at room temperature for 48 hrs. The solution was extracted with ethyl acetate and washed successively with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel (eluent: 10% ethyl acetate in hexane) to give 2.22 g of 2-Fluoro-3-iodo-4-methoxy benzaldehyde (38% for 2 steps). 1H NMR (300 MHz; CDCl3): 4.00 (s, 3 H), 6.74 (d, J=8.4 Hz, 1 H), 7.88 (t, J=8.1 Hz, 1 H), 10.21 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[F:12][C:13]([F:23])([F:22])[C:14]1[N:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:17][CH2:16][C:15]1[C:14]([C:13]([F:23])([F:12])[F:22])=[N:21][CH:20]=[CH:19][CH:18]=1)=[S:11]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: N#Cc1cccnc1C(F)(F)F
Product: FC(F)(F)c1ncccc1CNC(=S)Nc1cccc(Cl)c1Cl
Yield: 95 %

Procedure:
Prepared in 95% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 203A according to the procedure described for Example 153B. MS (ESI+) m/z 379.9 (M+H)+; 1H NMR (CDCl3) δ 5.11 (d, J=5.4 Hz, 2H), 6.38 (br s, 1H), 7.15-7.28 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.34-7.38 (m, 1H), 7.44 (d, J=7.8, 1.7 Hz, 1H), 7.51 (dd, J=5.1, 4.7 Hz, 1H), 7.65 (br s, 1H), 8.18 (d, J=7.5 Hz, 1H), 8.63 (d, J=4.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].[I:19]Cl>C(O)(=O)C>[I:19][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccsc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A vial was charged with 199 mg (1.0 mmol) 3-(tert-butoxycarbonylamino)thiophene, 164 mg (2.0 mmol) NaOAc, 4.0 mL HOAc, and a stir bar. The mixture was stirred at room temperature, giving a homogeneous solution “A”. A second vial was charged with 162 mg (1.0 mmol) iodine monochloride and 2.0 mL glacial acetic acid. The second mixture was swirled at room temperature. This second homogeneous solution “B” was added to solution “A” dropwise over three minutes. A white solid began to precipitate immediately. After the addition, the mixture was allowed to stand overnight, at which time the white solid had separated from the brown supernatant. With stirring, 200 uL sat. Na2S2O3/H2O was added, decolorizing the mixture from brown to yellow. 10 mL water was added, and then the mixture was evaporated, affording a semi-solid light brown residue. The residue was partitioned between EtOAc and H2O, and the separated EtOAc phase was washed (sat. NaHCO3, then sat. NaCl). The EtOAc phase was filtered, and concentrated to give 262 mg (81%) of the title compound as light brown crystals. 1H NMR (CDCl3, 300 MHz) δ 7.49 (bs, 1H), 7.45 (d, J=5.4 Hz, 1H), 6.50 (bs, 1H), 1.54 (s, 9H). Method [5]: rt=1.40 min; m/z=269.9 (MH+ minus isobutylene).