Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:11]([O:13][C@H:14]([CH3:21])[C@H:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C.[C:43]([O:46][CH2:47][CH3:48])(=[O:45])C>ClCCl.CCCCCC>[CH2:34]([O:33][C:31]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11]([O:13][C@H:14]([CH3:21])[C@H:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][C:43]([O:46][CH2:47][CH3:48])=[O:45])=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)[C@@H](C)OC(C)=O)cc1OC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of (1R,2R)-2-acetyloxy-1-methylpropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (34) (0.5 g, 1.2 mmol) and ethyl chloroformate (0.3 mL, 3.0 mmol) in anhydrous dichloromethane, triethylamine (0.4 mL, 3.0 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The solution was partitioned between dichloromethane and 10% citric acid and washed with water. The organic layer was dried over MgSO4, and concentrated to dryness. Chromatography (25% ethyl acetate in hexane) provided the title compound (35) (0.6 g, 90% yield) as a white, foamy solid. 1H NMR (400 MHz, CDCl3): δ 1.11 (d, J=6.4 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 1.40 (s, 9H), 2.02 (s, 3H), 3.02 (dd, J=14.0, 6.8 Hz, 1H), 3.07 (dd, J=14.0, 6.8 Hz, 1H), 4.27 (q, H=7.2 Hz, 2H), 4.28 (q, J=7.2 Hz, 2H), 4.51 (dd, J=14.0, 6.8 Hz, 1H), 4.93 (m, 2H), 5.03 (d, J=8.4 Hz, 1H, NH), 7.03 (dd, J=8.0, 2.0 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H). MS (ESI) m/z 578.1 (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.ClCCl>[N:14]1([CH2:9][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH2:3][CH2:2][OH:1])[CH:13]=[CH:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(C#CCCO)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a mechanical stirrer, a rubber septum with a nitrogen inlet and a stopper. The flask was charged with the product of Example 5 (14.6 g) and dichloromethane (250 mL). Morpholine (8.85 mL) was added, and then to this well-stirred reaction mixture was added sodium triacetoxyborohydride (32 g) in 4 equal portions. After the addition, the reaction mixture was stirred at room temperature overnight. Aqueous NaOH (10% w/v, 75 mL) was added, and the reaction mixture was transferred to a 1-L separatory funnel, to which water(100 mL) was then added. After separation of the layers, the aqueous phase was extracted once with dichloromethane (100 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to yield the product as yellow oil. The crude product was purified by filtration through a pad of silica gel (ethyl acetate/hexanes; 7:3) to obtain the title compound as a pale yellow oil (13.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
42 mg (50%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170 mmol), 1-(2,3-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:15][CH:16]=O>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[CH:16][N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: O=CCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2ccnc12
Reaction time: 21 h
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (EXAMPLE 1, METHOD B, Step 1, 2.0 g, 9.92 mmol) and chloroacetaldehyde (1.2 mL, 10.91 mmol) in methanol (100 mL) was refluxed for 135 min. A further chloroacetaldehyde (1.2 mL, 10.91 mmol) was added and refluxing continued over 21 hours. The solvent was evaporated and the resulting solid co-evaporated with methanol (75 mL×2) prior to drying under vacuum, giving 2.62 g of crude material. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (96.5:3.5:0.5 to 93:7:1) to give 1.52 g (68%) of the title compound as an off white powder.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:26][OH:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:26]=[O:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH:18]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
Pyridiniumchlorochromate (1.67 g, 7.77 mmol) was added to N-(5-chloro-2-(hydroxymethyl)phenyl)pivalamide (1.34 g, 5.55 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 3 hrs. Then it was passed through a thin silica gel pad with CH2Cl2 (100 mL), concentrated on rotary vacuum and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (800 mL) to afford the expected product as a white solid (937 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.28-1.34 (s, 9 H), 7.15 (dd, J=8.31, 2.01 Hz, 1 H), 7.53-7.59 (m, 1 H), 8.87 (d, J=2.01 Hz, 1 H), 9.84-9.88 (m, 1 H), 11.42 (s, 1 H); Mass spec. 240.07 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([N:16]=O)[CH2:12][C@H:11]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.O.Cl.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[ClH:1].[NH2:16][N:13]1[CH2:14][CH2:15][C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:12]1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(N=O)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(N)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.9 %

Procedure:
To a solution of the compound obtained in Example 548 (300 mg) in acetic acid (3 mL) was added Zn powder (229 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was treated with 1 equivalent of 4N hydrogen chloride/ethyl acetate to give the title compound (243 mg, 76%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FN1C=C[CH:22]=[CH:21][CH:20]1[Br:25].[CH3:26][N:27]([CH3:30])C=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:11])=[N:8][N:9]([C:26]2[C:20]([Br:25])=[CH:21][CH:22]=[CH:30][N:27]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: FN1C=CC=CC1Br
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(-c2ncccc2Br)nc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To the solution of 3-methyl-pyrazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol) in dry dimethylformamide (30 mL) is added potassium carbonate (7.2 g, 52 mmol) at room temperature. The reaction mixture is stirred at 40° C. for 30 min and then 1-fluoro-2-bromopyridine (3.0 g, 17 mmol) is added. The reaction mixture is stirred at 70° C. for 4 h. The reaction mixture is cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture was purified by chromatography on silica gel eluting with hexane/ethyl acetate (85:15, 80:20) to yield 3.2 g (79%) of 1-(3-bromo-pyridin-2-yl)-3-methyl-pyrazole-4-carboxylic acid ethyl ester. MS (m/z): 312 (M+3), 310 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.N.O>CO>[N:12]1([C:15]2[CH:21]=[CH:20][C:18]([NH:19][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:14][CH2:13]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: N
Solvent: O
Solvent: CO
Product: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 25 °C

Procedure:
The title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 4-morpholinoaniline. The semi-solid reaction mixture received after cooling to room temperature is dissolved in warm methanol, basified with conc. aqueous ammonia solution and the mixture concentrated to half of its volume. The precipitate obtained after addition of H2O is filtered off, washed with H2O and dried in vacuo to afford the title compound. Faintly violet solid, ESI-MS: 272.3 [MH]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O.O1CCOCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:11][C@@H:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:8]([OH:10])=[O:9])(=[O:30])=[O:29])=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a solution of L-phenylglycine (0.227 g, 1.5 mmol) in water (5 ml) and dioxane (5 ml) was added triethylamine (0.42 ml, 3.0 mmol) followed by slow addition of 4-nitrobenzene sulphonyl chloride (0.5 g, 2.3 mmol) in dioxane (5 ml) at 0° C. After stirring for 45 minutes the reaction mixture was evaporated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution (2×20 ml) and water (10 ml). The EtOAc layer was dried over Na2SO4, filtered and evaporated to dryness. LCMS purity 75%, (molecular ion not observed) yield 0.58 g, (76%). This material was used without any purification.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9].O.O.[I:36](O)(=O)(=O)=O.II>C(O)(=O)C.O>[CH2:6]([O:10][C:11]1[C:20]([I:36])=[C:19]2[C:14]([CH:15]=[C:16]([CH2:23][CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]3)[C:17]([F:22])=[C:18]2[F:21])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc2cc(CC[C@H]3CC[C@H](CCC)CC3)c(F)c(F)c2c1I
Yield: 378.2 %

Procedure:
(The following is performed in a draft chamber.) A mixture of concentrated sulfuric acid (1.5 ml), water (10 ml), and glacial acetic acid (50 ml) was dropped for about 10 minutes into a suspension of 7-butoxy-3-[2-(trans-4-propylcyclohexyl)ethyl]-1,2-difluoronaphthalene(21.4 g, 0.053 mol), periodic acid dihydrate (2.6 g, 0.011 mol), and iodine (5.4 g, 0.021 mol) in glacial acetic acid (100 ml) with vigorously stirring. After stirring at 60° C. for 4 hours, the reaction liquid was cooled, poured into water, and the reaction was terminated. The precipitated solid was dissolved with toluene, the organic layer was separated, and was extracted with toluene from the aqueous layer. After collecting organic layers, it was rinsed, in order, with 10% sodium thiosulfate aqueous solution, with saturated sodium hydrogen carbonate aqueous solution, and with saturated brine, and was dried with anhydrous sodium sulfate. A light yellow solid (21.4 g) was obtained by removing the solvent under reduced pressure and by recrystallizing the obtained orange solid (from acetone). (Yield 73.9%)
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-9H-purine (0.077 g, 0.39 mmol), 1-[4-chloro-1- (3-fluorophenyl)-2-naphthyl]ethanamine (0.058 g, 0.19 mmol), and N,N-diisopropylethylamine (0.067 mL, 0.39 mmol) in ethanol (0.6 mL) was heated at 100° C., in a sealed tube overnight. The volatiles were removed under reduced pressure. The residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H18ClFN5(M+H)+: m/z=418.1; Found: 418.1.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].O>C(Cl)Cl>[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)=[O:35]
Reactant: CCOC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.096 mol) was added at room temperature to a mixture of 4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol), 2-iodo benzoic acid (0.096 mol) and,1-hydroxybenzotriazole (HOBT) (0.096 mol) in DCM (500 ml). The mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was taken up in DIPE. The precipitate was filtered off and dried, yielding 39 g of 4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethyl ester (intermediate 27).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Br:11].CC(C)([O-])C.[K+].[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].Cl>CN(C=O)C.C1COCC1>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 96 h
Yield: 21.8 %

Procedure:
To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium tert-butoxide (2.02 g, 18.0 mmol) and 2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture was stirred at 140° C. for 4 days, cooled and poured into ice-water (100 mL). 2 M Hydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (548 mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 [M−H−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Reactant: Nc1ccccc1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 62 %

Procedure:
The compound was prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]acrylic acid (300 mg, 0.89 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired product in a yield of 62%, 227 mg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:61]3[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CCl)cc2)n1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCCC6)n5c4)c4ccccc43)cc2)CC1
Temperature: 50 °C
Yield: 7.3 %

Procedure:
To a solution of Intermediate 106b (0.25 mmol) in THF (2.5 mL) was added DIPEA (130 μL, 0.75 mmol) followed by N-methylpiperazine (83 μL, 0.75 mmol). The reaction mixture was heated at 50° C. for 18 h in a sealed tube, then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (C18 X-select column, 10-98% gradient MeCN in H2O, 0.1% HCO2H), to give the title compound (13 mg, 7%). LCMS (Method 5): Rt 3.44 min, m/z 717 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.57-1.66 (2H, m), 1.68-1.77 (4H, m), 1.79-1.95 (2H, m), 1.98-2.19 (5H, m), 2.22-2.46 (8H, m), 3.14 (4H, t, J=5.3 Hz), 3.49 (2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J=4.4 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=9.8, 2.2 Hz), 7.25-7.47 (8H, m), 7.59-7.65 (2H, m), 8.11 (1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Nc1cc(F)ccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylacetyl chloride (4.2 mL, 34.1 mL) was fast dropwise added to a solution of 2-bromo-5-fluorobenzenamine (4.31 g, 22.7 mmol) in CH2Cl2 (50 mL) at room temperature, followed by the addition of DIEA (7.9 mL, 45.4 mmol). The resulting mixture was stirred at room temperature for 2 hrs, and then partitioned between HCl (1N, 200 mL) and EtOAc (250 mL). After separation, the organic phase was washed with brine (50 mL), dried on MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (1200 mL) to afford the expected product, as a colorless oil (6.07 g, 98% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9H), 6.69 (ddd, J=8.81, 7.55, 3.02 Hz, 1H), 7.45 (dd, J=8.81, 5.79 Hz, 1H), 8.04 (s, 1H), 8.28 (dd, J=11.08, 3.02 Hz, 1H); Mass spec. 274.04 (MH+), Calc. for C11H13BrFNO 273.02.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)[C:20]([CH3:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:28].[ClH:1].[C:20]([NH:19][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:18][CH2:17]2)=[CH:25][CH:24]=1)(=[O:21])[CH3:22]
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: O=C(CCN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(CN2CCN(CCC(=O)c3ccccc3)CC2)cc1
Yield: 65 %

Procedure:
A mixture of N-benzoylethyl piperazine dihydrochloride (1.5 g, 5 mmol), 4-acetamino-benzylchloride (1.1 g, 6 mmol) and K2CO3 (3.2 g, 24 mmol) in 60 ml of acetone was treated according to general preparation 2 to give compound (IV-21) yield 65%, mp 238-240° C. M+ 351.