Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:14][O:15][CH3:16])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].C(N(CC)CC)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]1>ClCCl>[F:1][CH2:2][CH:3]([N:14]([O:15][CH3:16])[C:30]([C:28]1[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26][N:25]([CH3:24])[CH:29]=1)=[O:31])[CH2:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[Cl:11]
Reactant: CONC(CF)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(CF)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a stirred solution of N-[1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-O-methyl-hydroxylamine (0.20 g; 0.70 mmol), prepared as described in example P6f2 and triethylamine (0.12 ml; 0.84 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.15 g; 0.70 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. Triethylamine (0.19 ml; 1.4 mmol) was added again to the mixture followed by 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (74 mg; 0.35 mmol). The mixture was stirred at 24° C. for 18 h. The mixture was washed with 1M sodium hydroxide (20 ml), 1M hydrochloric acid (20 ml) and brine (20 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.17 g (51% of theory) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [1-fluoromethyl-2-(2,4,6-trichlorophenyl)-ethyl]-methoxy-amide as a yellow solid (melting point: 131-133° C.).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1cccs1
Product: O=C1C=C(c2cccs2)CCC1
Yield: 83 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 2-thiophene boronic acid according to the general procedure described for the Suzuki coupling. The product was purified by passing the product through a small silica gel plug eluting with methylene chloride and recrystallization from hexanes and ethyl acetate to yield a pale yellow crystalline solid (125 mg, 83%). 1H NMR (CDCl3, 300 MHz): δ 7.42 (d, J=5.4 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 7.08 (t, J=3.9 Hz, 1H), 6.41 (s, 1H), 2.79 (t, J=6.3 Hz, 2H), 2.46 (t, J=6.3 Hz, 2H), 2.14 (quintet, J=6.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 199.2, 152.3, 142.6, 128.7, 128.2, 127.2, 122.7, 37.3, 28.1, 22.5. LCMS (ESI): mass calcd for (C10H10OS) m/z 178.05; measured [M+H]+: m/z 179.04.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CCOC(C)=O>[CH3:14][N:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[CH:28][CH:27]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][C:10]1=[O:15]
Reactant: CN1CCC(c2cccnc2F)CC1=O
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1=O
Temperature: 100 °C
Yield: 42.9 %

Procedure:
4-(2-Fluoropyridin-3-yl)-1-methylpiperidin-2-one (0.07 g, 0.33 mmol), 4-(pyridin-2-ylamino)phenol (0.144 g, 0.77 mmol), cesium carbonate (0.274 g, 0.84 mmol), and 1-methyl-2-pyrrolidinone (1 mL) were combined in a sealed tube and heated at 100° C. for 18 h. The cooled mixture was diluted with EtOAc and washed with water; the aqueous layer was back-washed with EtOAc (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 20% to 80% EtOAc (10% MeOH)/Hexanes afforded 1-methyl-4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)piperidin-2-one (0.053 g, 42.1% yield) as a tan amorphous solid. MS (ESI, pos. ion) m/z: 375.0 (M+1). IC50 (uM) 0.005.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]2)[CH2:2]1.[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31](O)=[O:32])(=[O:19])[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH:21]1[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10]2)[CH2:4]1)=[O:32])(=[O:19])[CH3:18]
Reactant: O=C(N1CCN(C2CNC2)CC1)C(F)(F)F
Reactant: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of compound 1g (228 mg, 0.74 mmol), compound 25c (22 mg, 0.74 mmol), and Et3N (0.3 mL, 2.22 mmol) in CH2Cl2 (7 mL) was added HATU (338 mg, 0.89 mmol). The reaction mixture was stirred at room temperature for 18 h. The resultant mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc+0.5% Et3N) gave compound 25d (265 mg). LC/MS m/z (M+H+), 517.0 (M+2H+), 519.0.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH3:6])[C:3]#[N:4].C(O)C.[CH3:11][NH:12][NH2:13].[ClH:14]>O>[ClH:14].[NH2:4][C:3]1[N:12]([CH3:11])[N:13]=[C:5]([CH3:6])[C:2]=1[CH3:1]
Reactant: CC(=O)C(C)C#N
Reactant: CNN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c(N)c1C

Procedure:
2-Methyl-3-keto-butyronitrile (J. Am. Chem. Soc. 79, 723, 1957) (25.25 g.) in 120 ml. ethanol was treated with 15 g. methylhydrazine while cooling. The solution was refluxed 3 hours then concentrated in vacuum, benzene added and the solution concentrated again. Ether was added to give 29.12 g. mp 70-106 of base (contained H2O). This was converted to the hydrochloride with HCl in isopropyl alcohol. HCl had mp 286-288.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:22])[C@H:18]2[CH2:19][C@@H:14]1[CH2:15][CH2:16][C@H:17]2CN.CC[N:25](CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:25][CH:17]2[CH2:16][CH2:15][CH:14]3[CH2:19][CH:18]2[C:13]3([CH3:22])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC1(C)[C@H]2CC[C@@H](CN)[C@@H]1C2
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 4-bromo-benzenesulphonyl chloride (0.6 g, 2.34 mmol) in anhydrous CH2Cl2 (5 ml) and Et3N (0.65 ml, excess) at 0° C. was added (−) cis-myrtanylamine (0.36 g, 2.34 mmol) and the stirring was continued overnight at room temperature. The reaction mixture was diluted with CH2Cl2 (15 ml) and washed with H2O (2×100 ml). The organic layer was separated and dried over MgSO4 and the solvent was distilled to afford the title compound (0.87 g, 100%), as pale paste, which was solidified on standing. 1H-NMR (CDCl3) 7.70 (d, 2H, J=6.78 Hz); 6.64 (d, 2H, J=6.90 Hz); 2.91 (t, 2H, J=7.59 Hz); 2.32-2.29 (m, 1H); 2.11-2.06 (m, 1H); 1.91-1.81 (m, 6H); 1.39-1.31 (m, 1H); 1.11 (s, 3H); 0.86 (s, 3H).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.O.[CH3:23]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:23])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoic acid (1.40 g) in methanol (50 mL) was added dropwise thionyl chloride (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.30 g) as a colorless oil. Ethyl acetate (250 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][N:9]=1
Reactant: Fc1ccc(Br)cc1-c1ccncn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1ccc(F)c(-c2ccncn2)c1

Procedure:
4-(5-Bromo-2-fluorophenyl)pyrimidine (503 mg, 2.0 mmol) was reacted with bis(neopentyl glycolato)diboron (494 mg, 2.2 mmol) using the method in Example 14 part c) to give 4-fluoro-3-pyrimidin-4-yl-phenylboronic acid as a tan solid: m/z (ES+) 219 (M++H).
Reaction SMILES: Cl.O1CCOCC1.[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[CH:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:25]5=[N:26][CH:27]=4)[C:18]3=[O:39])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[S:8]1[C:12]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[C:24]5[CH:30]=[CH:29][NH:28][C:25]5=[N:26][CH:27]=4)[C:18]3=[O:39])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(N3CCN(c4ccc5ncsc5c4)C3=O)cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1N(c2cnc3[nH]ccc3c2)CCN1c1ccc2ncsc2c1
Temperature: 110 °C
Yield: 2.7 %

Procedure:
1,4-Dioxane HCl (10 ml) was added to 1-(benzothiazol-6-yl)-3-(1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)imidazolidin-2-one (I-187b: 0.07 g, 0.19 mmol) and the resulting mixture was heated to 110° C. for 2 days. The reaction was monitored by TLC (20% MeOH in CHCl3). The reaction mixture was basified with Na2CO3 solution (pH˜8), cooled to room temperature, concentrated and the concentrate was washed with diethyl ether. Purification by preparative HPLC afforded 1.7 mg of the product (25.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])[CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][N:45]=[C:44]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]6)=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CN1CCN(C(=O)c2cc(Cl)ccn2)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)N4CCN(C)CC4)c3)cn2)cc1
Yield: 96.4 %

Procedure:
Using 4-chloropicolinic acid chloride and N-methylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg, 0.398 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone (105 mg, 0.438 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-methyl-piperazin-1-yl)-methanone as a yellow solid (285 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-200) as a yellow powder (69 mg, 38%).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C1(C)C=CC=CC=1.CCOCC>[C:2]([O:6][C:7](=[O:11])[C@@H:8]([N:9]1[C:24](=[O:25])[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:26])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A suspension of (2S) alanine tert-butyl ester hydrochloride (2.05 g, 11.2 mmol), diisopropylethylamine (1.83 mL, 10.6 mmol) and phthalic anhydride (1.48 g, 10 mmol) in toluene (10 mL) was refluxed for 3 hours under Dean-Stark conditions. The reaction was cooled to room temperature, diluted with Et2O, washed with 1N HCl and then with aq.sat. NaHCO3. The organic layer was dried (MgSO4), filtered and evaporated to afford the sub-title compound as a white powder (2.465 g, 90%): 1H NMR (400 MHz CDCl3) δ 1.45 (9H, s), 1.68 (3H, d), 4.90 (1H, q), 7.75 (2H, d), 7.88 (2H, d)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:41])([F:40])[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[CH:38]=O.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([O:28][C:27]([F:40])([F:26])[F:41])[CH:30]=4)[NH:34][N:33]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1n[nH]c2ccc(OC(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccc(OC(F)(F)F)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
A solution of tert-butyl 4-[1-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.103 g, 0.295 mmol) in methanol (1.2 mL) was added with 5-(trifluoromethoxy)-1H-indazole-3-carbaldehyde (0.0680 g, 0.295 mmol), and piperidine (0.00251 g, 0.0295 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-[(6-hydroxy-3-oxo-2-{[5-(trifluoromethoxy)-1H-indazol-3-yl]methylene}-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0660 g, 40%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.CC[N:15](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](N[Si](C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-indancarboxylic acid (1.4 g, 8.63 mmol) was dissolved in anhydrous DMF (20 mL), and the following was added sequentially: DIPEA (3.02 mL, 17.26 mmol), HATU (3.94 g, 10.36 mmol), and HMDS (2.17 mL, 10.36 mmol) after 30 min of stirring at rt. After stirring for 20 h at rt, the solution was taken up in EtOAc and washed with 0.5M HCl (3×), water (3×), and 10% aq. sodium carbonate (3×). The organic phase was collected and dried over magnesium sulfate, and concentrated in vacuo. The solid residue was recrystallized from EtOH to afford the title compound as sharp, colorless crystals. (Yield: 861 mg, 5.06 mmol, 59%) 1H NMR (400 MHz, CDCl3) 7.34-7.12, 5.52, 3.41-3.08
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([O-:15])=[O:14])=[O:9].[NH2+]1CCCCC1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:6]=[CH:7][C:8]([NH:10][C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)[O-])cc1OC
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 98 %

Procedure:
A 20 g of quantity of piperidinium N-(3,4-dimethoxycinnamoyl)anthranilate is dissolved in 60 ml of water with heating, and the resultant aqueous solution is added dropwise to 45 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 40 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield 15.5 g of N-(3,4-dimethoxycinnamoyl)anthranilic acid (98.0% yield), m.p. 208°-208.5° C. The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:13]([OH:16])(=O)[CH3:14].[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[N+:17]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([O:1][C:13](=[O:16])[CH3:14])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)([O-:19])=[O:18]
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
8-Hydroxy-3,4-dihydrocarbostyril (20 g) was suspended in acetic anhydride (100 ml). Sulfuric acid (5 drops) was added to the resulting suspension and the mixture was stirred at 80° C. for 1.5 hours. To the reaction mixture was added acetic acid (100 ml) and the mixture was ice-cooled, and a solution of 10.1 ml of concentrated nitric acid (d=1.38) in 30 ml of acetic anhydride was added thereto with stirring. The stirring was continued for one night at room temperature. The reaction mixture was poured into ice water to precipitate crystals, which were collected by filtration to give 21.74 g of 6-nitro-8-acetoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[C:23]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:22]=[CH:21][CH:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (14.7 g, 0.10 mol), 3-bromo-phenyl-carbamic acid tert-butyl ester (27.2 g, 0.10 mol), Pd(Ph3P)4 (11.6 g, 0.01 mol) and K2CO3 (21 g, 0.15 mol) in DMF/H2O (1:1, 350 mL) was stirred under argon at 80° C. overnight. The DMF was evaporated under reduced pressure, and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (petroleum ether/EtOAc 50:1) on silica gel to give (4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester (17 g, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.32-7.48 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14](OC)=[O:15])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8].[OH-].[NH4+:20]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14]([NH2:20])=[O:15])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: [NH4+]
Reactant: COC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [OH-]
Solvent: CC#N
Product: NC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (−)-methyl (5R)-3-[3-fluoro-4-iodophenyl]-2-oxo-5-oxazolidinecarboxylate (Step 2, 6.23 g, 17.1 mmol) in acetonitrile (85 mL) was treated with concentrated ammonium hydroxide (85 mL), and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was then diluted with saline (100 mL) and extracted with methylene chloride (3×100 mL), and the combined organic phase was washed with saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was diluted with hot ethyl acetate (200 mL) and filtered to remove inorganic residue, and the filtrate was diluted with hexanes (300 mL). The resulting precipitate was isolated by filtration to give the title compound, mp 176-178° C.; MS (ESI+) for C10H8FIN2O3 m/z 351 (M+H)+; [α]25D=−19 (c 0.97, DMSO).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:31](O)=[O:32])=[CH:24][CH:23]=1.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][C:31]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]3[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16]2)=[O:32])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
(R)-1-(3-Methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.29 mmol, 79 mg) in DMF (15 mL) was added to (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.32 mmol, 115 mg) and N-methylmorphine (1.16 mmol, 0.13 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (0.32 mmol, 122 mg) and kept stifling at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (35-60% CH3CN in H2O) to afford tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (0.26 mmol, 160 mg, yield: 89.7%). ESI-MS: m/z 614.4 (M+H)+.