Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:37])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=2)[CH:21]=[CH:22][CH:23]=1.[CH2:38]=O.[C:40]([BH3-])#[N:41].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:35]([C:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:3]2[CH:4]=[CH:5][C:6]3[N:7]=[C:8]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[S:9][C:10]=3[C:2]=2[N:41]([CH3:40])[CH3:38])[CH:19]=1)=[O:37])([CH3:34])[CH3:33])#[N:36]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3N)c2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.4 %

Procedure:
To a solution of N-[3-({7-amino-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}oxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.195 mmol) produced in Example 43 in acetic acid (2 mL) were added para-formaldehyde (36 mg, 1.19 mmol) and sodium cyanoborohydride (45 mg, 0.644 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (72 mg, 68%) as a white powder.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].[CH:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1)=O>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccc(C(=O)O)cc4)n[nH]c3c1)C(=O)N2
Yield: 22.9 %

Procedure:
The title compound (20 mg, 23%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5-methoxylindolin-2-one (32.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 12.90 (s, br, 1H), 10.45 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.79 (s, 1H), 7.74 (d, J=16.8 Hz, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.86 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.60 (s, 3H); MS ESI 438.2 [M+H]+, calcd for [C26H19N3O4+H]+ 438.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under argon, Compound V (433 g, 1.37 mol) was dissolved in dry DMF (1.6 L) and to this sodium hydride (60% in oil, 60.4 g, 1.51 mol) was added. To the resulting orange solution, p-fluorobenzaldehyde (185 mL, 1.71 mol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3 L) and extracted with water (3 ×1 L), then brine (1×1 L). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. The residue was suspended in methanol (3 L) and stirred overnight. The suspension was chilled and then filtered. Solid obtained was dried under vacuum at 40° C. Yield 445 g (77%). 1HNMR(CDCl3): δ 9.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 7.28J=8.6 Hz, 2H), 7.11(d, J=2.9 Hz, 2H), 7.08(d, J=2.9 Hz, 2H), 6.36(t, J=2.2 Hz, 1H), 6.25 (d, J=2.2 Hz, 2H), 3.83(s, 3H), 3.63 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=2[CH:7]=1)=O.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].N1CCCCC1.[CH2:28]([O:30][C:31](=[O:46])[CH:32]=[C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1)[CH3:34])[CH3:29]>C(O)C>[NH2:15][C:14]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=2)[C:33]([CH3:34])=[C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:46])[CH:1]([C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=3[CH:7]=2)[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc2oc(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(N)=C(C(=O)OCC)C1c1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Formyl-1-benzofuran-5-carbonitrile (157 mg, 0.915 mmol) and ethyl cyanoacetate (103 mg, 0.915 mmol) are dissolved in ethanol (8 ml). Piperidine (2.3 mg, 0.027 mmol) is added, and the reaction mixture is stirred for two hours at room temperature. A solution of Example 1A (253 mg, 0.915 mmol) and piperidine (7.8 mg, 0.091 ml) in ethanol (2 ml) is added, and the reaction mixture is stirred at reflux (95° C.) overnight (18 h). The crude reaction mixture is concentrated in vacuo, dissolved in DMSO (7 ml) and purified by preparative HPLC.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.N>C(Cl)Cl.CO>[N:25]1([C:23]2[N:24]=[C:19]([N:18]3[C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=5)[N:15]=[CH:14][C:13]=4[CH:16]=[N:17]3)[CH:20]=[CH:21][CH:22]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cnn(C(C)(C)C)c5)cc43)n2)CC1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)n1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 56.9 %

Procedure:
A solution of tert-butyl 4-(6-(6-(1-tert-butyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (100 mg, 0.19 mmol) and TFA (2 mL) in DCM (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, concentrated, and purified by preparative HPLC to afford 145 as a white solid (45 mg, 56%). 1H-NMR (500 MHz, CD3OD) δ (ppm) 9.03 (s, 1H), 8.71 (d, J=6.5 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.65-7.68 (m, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 3.90-3.94 (m, 4H), 3.14-3.16 (m, 2H), 2.91-2.94 (m, 2H), 2.05-2.10 (m, 2H), 1.68 (s, 9H); MS (ESI) m/z: 417 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C@@H:16]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]1.C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[Si:6]([O:14][CH2:15][C@@H:16]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC[C@H](CO)N1
Agent: c1c[nH]cn1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Imidazole (773 mg, 11.4 mmol) and tert-butyldimethylsilyl chloride (787 mg, 5.22 mmol) were added sequentially to a solution of (R)-6-hydroxymethyl-piperidin-2-one (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485–3496, 613 mg, 4.75 mmol) in DMF (8 mL) at 0° C. The reaction mixture was allowed to warm to rt and was stirred at rt for 20 h. Benzene and EtOAc (3:7, 200 mL) was added and the solution was washed with brine (3×50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 1.13 g (98%) of (R)-6-(tert-butyldimethylsilanyloxymethyl)-piperidin-2-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1[Br:21].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[C:28](=[O:31])([O-])[O-].[K+].[K+]>C1COCC1>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[O:8][C:7]1[C:2]([Br:1])=[C:3]([Br:21])[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:4]3[CH2:3][CH2:2][CH2:7][CH2:28][O:31]3)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[C:5]([Br:10])[C:6]=1[Br:9]
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Reactant: C1=COCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(OC2CCCCO2)cc1)c1c(Br)c(Br)c(OC2CCCCO2)c(Br)c1Br

Procedure:
56.6 g of tetrabromobisphenol A are dissolved in 50 ml of THF. After addition of 17.5 g of dihydropyran and 0.25 g of Amberlyst, the mixture is refluxed for 3 hours, cooled, neutralized by addition of 5 g of potassium carbonate, stirred for a further hour, filtered and evaporated to dryness: oil. NMR: 7.27 ppm (arom.), 6.0 ppm (t, acetal), 1.57 ppm (methyl).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and TEA (242 μl; 1.74 mmol; 3.0 eq.) in DMF (3.8 mL) was added acetyl chloride (46 μl; 0.70 mmol; 1.2 eq.) and the reaction mixture was stirred overnight at RT. Reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a white solid. 1H NMR (300 Mz, DMSO) δ: 13.36 (brs, 1H), 8.29 (s, 1H), 8.47 (t, J=5.9 Hz, 1H), 8.36 (dt, J=8.0 Hz, J=1.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.4 Hz, J=1.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 1.90 (s, 3H). HPLC (Condition A): Rt 2.81 min (purity 97.7%). MS (ESI+): 333.2, MS (ESI−): 331.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]Br>C(O)(=O)C>[BrH:26].[Br:26][CH:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:14]=1)[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:17]
Reactant: BrBr
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Solvent: CC(=O)O
Product: Br
Product: COc1ccc(C(=O)C(Br)c2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 159.3 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.36 g, 1.1 mmol) in acetic acid (5 mL) was added bromine (0.058 mL, 1.1 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated, and the residue was washed with isopropyl ether to obtain a title compound (0.44 g, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:26])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNCc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
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: CN(Cc1ccccc1)C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid (50 mg, 0.14 mmol), N-methylbenzylamine (0.022 mL, 0.17 mmol), iPr2NEt (0.07 mL, 0.50 mmol) in DMF (3 mL) was added HATU (68 mg, 0.18 mmol) and stirred at rt overnight. The reaction mixture was poured into ice-water, and the solid was collected by filtration. The solid was re-dissolved in CH2Cl2 and purified by preparative TLC (CH2Cl2-MeOH-Hexane, 8:2:2) affording the product as a light yellow powder. LC-MS: 467 (M++1). 1H NMR (CDCl3): δ 2.92 and 3.00 (each s, 3H), 3.05˜3.12 (m, 4H), 3.62˜3.72 (m, 4H), 4.12˜4.20 (m, 2H), 4.52 and 4.62 (each s, 2H), 5.08 (br.s, 2H), 5.94 (m, 1H), 6.15 (m, 1H), 7.14˜7.24 (m, 3H), 7.26˜7.40 (m, 3H), 7.58˜7.62 (m, 1H), 7.68˜7.72 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.CCOC(C)=O.CCCCCC>C(O)(C(F)(F)F)=O>[Br:14][C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:11])[F:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCOc1ncccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
2-Ethoxy-3-trifluoromethyl-pyridine (900 mg, 4.71 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (1.35 g, 4.71 mmol) were placed in a round-bottom flask. To this mixture was slowly added 10 mL trifluoroacetic acid. The mixture was stirred at ambient temperature for overnight. More 1,3-dibromo-5,5-dimethylhydantoin (540 mg, 1.9 mmol) was added and the reaction mixture was stirred at ambient temperature for another day. After the completion of the reaction, TFA solvent was evaporated in vacuo and the resulting residue was neutralized to pH 7 by the addition of saturated NaHCO3. The aqueous layer was extracted with dichloromethane three times and the combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a mixture of oil and white solid. The residue was redissolved into 20% EtOAc/Hexane, and the unsoluable white solid was filtered out. The filtrate was concentrated and then purified by column chromatography on silica gel (10% EtOAC/Hexane) to give 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine as a colorless liquid (1.0 g, 79% yield). 1H-NMR (400 MHz, CDCl3): δ 1.41 (t, 3H, J=7.07), 4.46 (q, 2H, J=7.07), 7.94 (dd, 1H, J=0.51, J=2.53), 8.34 (dd, 1H, J=0.51, J=2.53).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([S:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.[Cl-].[NH4+]>O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:25])[C:16]3[C:21]([S:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=c1c2ccccc2sc2cc(F)ccc12
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Sc3cc(F)ccc32)CC1

Procedure:
The Grignard reagent prepared from 0.62 g. of magnesium turnings and 3.5 g. of 4-chloro-N-methylpiperidine in tetrahydrofuran is treated with a solution of 3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydrofuran. The mixture is refluxed for four hours, cooled, treated with saturated ammonium chloride solution and extracted with ether. The ether extract is washed with water, dried and concentrated to give 3-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 120°-130° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=2)[CH3:21])=[O:16])=[CH:11][CH:12]=1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: Cc1ncoc1-c1ccc(CC(=O)O)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a solution of 3.00 g (14.0 mmol) 4-bromophenyl acetic acid in 25.0 ml DMF was added 3.60 g (27.9 mmol) 4-methyl-1,3-oxazole-5-carboxylic acid, 6.80 g (20.9 mmol) cesium carbonate, 4.1 g (14.0 mmol) tetrabutyl ammonium chloride monohydrate, and 0.400 g (0.700 mmol) bis(tri-t-butylphosphine)palladium(0). After 3.00 h at 140° C., the reaction mixture was, diluted with CH2Cl2, washed with 10% citric acid, washed twice with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by preparative HPLC (5→95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 50×150 mm) afforded 0.730 g (24%) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid. 1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H); 7.61 (d, 2H, J=8.32 Hz); 7.41 (d, 2H, J=8.33 Hz); 3.65 (s, 2H); 2.41 (s, 3H). ESMS+1 for C12H11NO3: 218.1. To a solution of 0.725 g (3.34 mmol) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid in 7.00 ml CH2Cl2 was added 0.978 g (3.34 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.591 g (4.34 mmol) HOAT, 0.832 g (4.34 mmol) EDC, and 1.75 mL (10.0 mmol) DIEA. After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 20-100% EtOAc:hexane) afforded 0.720 g (51.4%) 2-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H, J=2.38 Hz); 7.83 (s, 1H); 7.59 (dd, 2H, J=1.83 Hz, 6.59 Hz); 7.36 (d, 2H, J=8.42 Hz); 7.22 (m, 2H); 6.72 (br d, 1H, J=7.51 Hz); 5.12 (m, 1H); 4.38 (q, 2H, J=8.06 Hz); 3.62 (s, 2H); 2.45 (s, 3H); 1.41 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H20F3N3O3: 420.1540, Found: 420.1530.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:15])=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Solvent: CC(=O)O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Temperature: 100 °C
Yield: 49.7 %

Procedure:
A microwave vial was charged with 6-bromo-4-nitro-1H-indazole (available from Sinova) (363 mg) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (691 mg) followed by acetonitrile (5 ml) and acetic acid (1 ml). The reaction vessel was sealed and heated under microwave irradiation at 100° C. for two periods of 30 min then at 150° C. for two periods of 30 min. The solution was evaporated to dryness, dissolved in chloroform (˜10 ml) and loaded onto a 20 g silica cartridge which was eluted on the Flashmaster 2 with a gradient of 0 to 100% ethyl acetate in cyclohexane over 60 min. The appropriate fractions were combined and blown to dryness to give the title compound (187 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[CH:14](OC)(OC)OC.C(O)(=O)C>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:14]=[N:12][N:11]=[N:10]2)=[C:4]([I:9])[CH:3]=1
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1I
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-n2cnnn2)c(I)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Alternatively, 62B can be prepared as follows. To a cold suspension (0-5° C.) of 4-chloro-2-iodoaniline (10.0 g, 39.5 mmol) and sodium azide (7.95 g, 122 mmol) in trimethyl orthoformate (13.08 mL, 118 mmol) was added acetic acid (150 mL). The resulting clear, slightly brown solution was stirred vigorously at 0-5° C. for 30 min and then warmed to rt. A beige precipitate formed overtime and then redissolved to give a clear brown solution. After 22 h, water (400 mL) was added and the suspension was stirred vigorously for 1 h. The solid was collected by filtration, rinsed with water, air-dried, and dried under vacuum to give 11.16 g (92%) of 1-(4-chloro-2-iodo-phenyl)-1H-tetrazole as a beige solid. LCMS m/z 307.0. (M+H)+. A flame-dried sealed tube vessel containing this intermediate (0.250 g, 0.816 mmol) and palladium acetate (0.018 g, 0.082 mmol) was purged with argon for several minutes. Next degassed acetonitrile (3.26 mL) was added followed by the addition of ethyl acrylate (0.133 mL, 1.224 mmol) and triethylamine (0.171 mL, 1.224 mmol). The vessel was sealed and the orange brown solution was warmed to 85° C. to give a brown suspension. After 21 h, the reaction was stopped and cooled to rt. The reaction was filtered through a 0.45 micron Glass microfibre (GMF), rinsing with acetonitrile, and the filtrate was concentrated to give a brown residue. Flash chromatography gave 0.098 g (43%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid ethyl ester as a pale yellow solid. LCMS m/z 279.1 (M+H)+ and 281 (M+2+H)+. Saponification as described above gave 62B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: CC(C)CCCC(C)Br
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 19, by reacting p-hydroxybenzoic acid methyl ester with 2-bromo-6-methyl heptane, there is obtained p-[(1,5,-dimethylhexyl)oxy]benzoic acid methyl ester; B.P. 132°-134° C/.1 mmHg.