Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:21])=[CH:5][CH:4]=1.CC(C)=O.C(=O)=O.CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.[Li].I[CH2:45][CH2:46][CH2:47][Cl:48]>C1COCC1.C(Cl)Cl>[Cl:48][CH2:47][CH2:46][CH2:45][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[C:9]1=[O:21]
Reactant: ClCCCI
Reactant: COc1ccc(CN2C(=O)CCc3cc([N+](=O)[O-])ccc32)cc1
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C(CCCCl)Cc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (350 mg, 1.12 mmol) in 10 mL THF was cooled to −78° C. (acetone/dry ice bath) then treated with lithium hexamethyldisilazine (1.23 mL of a 1M solution in THF). The resulting dark solution was stirred for 30 minutes then treated with 1-iodo-3-chloropropane dropwise. The mixture was allowed to warm to room temperature and kept at this temperature overnight. The reaction was quenched with brine and extracted with 3×50 mL CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and concentrated to give a dark residue which was subjected to flash chromatography on silica gel using CH2Cl2. A yellow viscous oil was obtained (130 mg, 29.8%). 1H-NMR (CDCl3) δ: 8.08-8.00 (m, 2H), 7.12-7.09 (m, 2H), 7.00 (d, J=8.7 Hz, 1H), 6.86-6.84 (m, 2H), 5.15 (dd, J=4.2, 20.4 Hz, 2H), 3.76 (s, 3H), 3.60 (t, J=6.3 Hz, 2H), 3.17 (dd, J=5.4, 15.6 Hz, 1H), 2.93-2.71 (m, 2H), 2.05-1.67 (m, 4H).
Reaction SMILES: [C:1]1([Pb:7](Cl)(Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[Na]>CC(C)=O>[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[C:8]1([Pb:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cl[Pb](Cl)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: O=Cc1ccccc1O
Solvent: CC(C)=O
Product: c1ccc([Pb]c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
Diphenyl lead dichloride (0.01 mol) is mixed with 0.02 mol of sodium salicylaldehyde in acetone. The solution is allowed to stand 10 minutes and then filtered. Water is added to the filtrate to precipitate the lead chelate complex, which is then separated by filtration.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2].CN(C)C=O.[H-].[Na+].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=1>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[N:17]([CH2:52][C:51]3[CH:54]=[CH:55][C:48]([F:47])=[CH:49][CH:50]=3)[CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2]
Reactant: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4ncc[nH]4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4nccn4Cc4ccc(F)cc4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To the solution of N-{4-[3-cyano-4-(2,4-dichlorophenyl)-5-(1H-imidazol-2-yl)-2-thienyl]pyridin-2-yl}-N-(4-methoxybenzyl)acetamide (60.0 mg, 0.104 mmol) in dry N,N-Dimethylformamide (5.0 mL, 64 mmol) was added Sodium hydride (3.96 mg, 0.157 mmol). The resulted red-brown solution was stirred at r.t. for 10 min. 4-Fluorobenzylbromide (32.6 mg, 0.172 mmol) was added and the mixture was stirred at r.t. for 2 hours. The mixture was quenched with aqueous saturated NaHCO3 (10 mL), diluted with water, extracted with DCM (4×25 mL), washed with water, brine, dried over Na2SO4, filtered, rotovaped to give a crude residue. Chromatograph in silica column using DCM/EtOAc (30/70 to 0/100) afforded a solid product (0.055 g, yield 77.1%). LCMS: (AA) ES+, 682, 684. 1H NMR (400 MHz, d1-chloroform) δ: 8.60-8.62 (d, J=5.02 Hz, 1H), 7.63 (s, br, 1H), 7.51-7.53 (m, 1H), 7.34 (m, 1H), 7.14-7.26 (m, 5H), 6.92-6.97 (m, 2H), 6.80-6.86 (m, 3H), 6.70-6.73 (m, 2H), 5.14 (m, 2H), 4.71-4.84 (m, 2H), 3.76 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C:1]([N:17]1[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OC1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCC(O)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-hydroxypiperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][C:53]=1[C:62]([F:65])([F:64])[F:63])([O-:51])=[O:50].O>ClCCl>[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:60])=[O:59])=[CH:54][C:53]=1[C:62]([F:65])([F:63])[F:64])([O-:51])=[O:50]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (439 mg, 0.78 mmol) and triethylamine (330 μL, 2.35 mmol) in dichloromethane (7.0 mL) was added 4-nitro-3-(trifluoromethyl)benzenesulfonyl chloride (340.7 mg, 1.18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then water was added. Organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/n-hexane=15/85) to give the desired product (4 h, 470 mg, 74%) as a light yellow solid.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:43])[CH2:7][C:8]1[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:13]=1>C1COCC1.O.CO>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=4[CH2:7][C:6]([OH:43])=[O:5])[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH.H2O (24 mg, 0.56 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A8) (44 mg, 0.081 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the resulting residue was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound A9 as brown oily residue (36 mg, 84%); LCMS-A: rt 5.737 min; m/z 532.2 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:50]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:51])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was added triethylamine (30.8 μL, 0.221 mmol), followed by morpholine-4-carbonyl chloride (17.2 μL, 0.147 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 50% to 75% ACN gradient to give the title compound, as a TFA salt, as a yellow solid (11.9 mg, 25.6%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.6 Hz, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.81 (t, J=5.8 Hz, 2H), 3.10 (m, 2H), 3.33 (m, 4H), 3.45 (m, 2H), 3.59 (t, J=5.9 Hz, 2H), 3.70 (m, 4H), 4.13 (m, 1H), 4.37 (s, 2H), 4.50 (tt, J=7.2, 3.5 Hz, 1H), 6.88 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+517.5.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:15])=[N-]>ClCCl.CO>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a mixture of 2-bromo-4,5-difluorobenzoic acid (1 g, 4.22 mmol) in dichloromethane (10 mL) and MeOH (1 mL) was added trimethylsilyl)diazomethane (2.110 mL, 4.22 mmol) and the reaction was stirred at rt for 1 h. It was then concentrated to obtain methyl 2-bromo-4,5-difluorobenzoate (1 g, 3.98 mmol, 94% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=10.5, 8.3 Hz, 1H), 7.57-7.49 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:52]1([CH2:57]O)[CH2:56][CH2:55][CH2:54][CH2:53]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC(C)C)=O)=NC(OCC(C)C)=O>C(Cl)Cl.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:57][CH:52]5[CH2:56][CH2:55][CH2:54][CH2:53]5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(O)c1)CO3
Agent: CC(C)COC(=O)N=NC(=O)OCC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCC2CCCC2)c1)CO3
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (25 mg), cyclopentyl methanol (11 mg), triphenyl phosphine (38 mg) were taken in 1 mL of anhydrous DCM and cooled to 0° C. Diisobutyl azodicarboxylate (22 mg) was added and reaction was warned to room temperature and stirred for 4 hours. After the completion of the reaction, the reaction mixture was loaded onto a silica gel column (1:1 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to give (3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (24 mg). This was taken up in 2 mL anhydrous DCM and cooled 0° C., HCl (0.5 mL, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles are evaporated and residue was precipitated from DCM/hexanes to get (S)-2-{[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (22 mg).
Reaction SMILES: C1C(C(O)=[O:8])=CC2C(OC3(C4C=CC(O)=CC=4OC4C=C(O)C=CC3=4)C=2C=1)=O.ON1C(=O)CCC1=O.[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[C:44]([NH:43][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.08 h

Procedure:
A synthetic aldehyde, Pro4-de novo CHO, was prepared as follows. To a stirred solution of 5-carboxyfluorescein (5-FAM) (190 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (DMF (5 mL) were added N-hydroxysuccinimide (NHS) (77 mg, 0.67 mmol) and 1,3-dicyclohexylcarbodiimide (DCC) (126 mg, 0.61 mmol). After approximately 5 minutes, a white solid (dicyclohexylurea) started forming. The reaction mixture was stirred overnight under nitrogen. Thin layer chromatography (TLC) (40:9:1 CH2Cl2—CH3OH-water) indicated complete disappearance of the starting material. The mixture was then filtered, and the filtrate was added dropwise to a stirred solution of ethylene diamine (46 mg, 0.77 mmol) in DMF (3 mL). A solid was obtained. As evident from TLC, the reaction was complete instantaneously. This reaction mixture was subsequently treated with glyoxylic acid NHS ester prepared below.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].CC(C)=O.O.[C:15]([OH:23])(=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>CC(C)=O.O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:15]([O-:23])(=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 10 °C
Yield: 143.9 %

Procedure:
9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40° C., and a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetone-water was added dropwise thereto and stirred at 10° C. The produced crystal was filtered and dried in hot air, thus obtaining 11.24 g (yield: 95.3%) of metformin glutarate.
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[C:22](=[S:24])=[S:23].Br[CH2:26]Br>C1COCC1>[S:23]1[CH2:26][S:24][C:22]1=[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: BrCBr
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(C(=C1SCS1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 1,2-diphenylethanone (10.0 g, 51.0 mmol) in anhydrous THF (100 mL) was added KOtBu (1M in THF, 51.0 mL, 51.0 mmol). The mixture was stirred for 30 min at room temperature, and carbon disulfide (7.76 g, 102 mmol) was added. After 10 min, dibromomethane (17.72 g, 102 mmol) was added and the reaction was stirred for 4 h at room temperature. The reaction was quenched with water (10 mL) and diluted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated to give the title compound as a yellow solid (13.0 g). LCMS m/z=285.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])(C)(C)C.CN(C)[CH:17]=[O:18].C(=O)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][CH3:9])[C:5]([CH:17]=[O:18])=[CH:6][CH:7]=1
Reactant: COc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 2-Chloro-6-methoxypyridine (25, 0.511 g, 3.56 mmol) in tetrahydrofuran (10 mL) cooled in a −78° C. acetone/dry ice bath was added tert-butyllithium (1.7 M in pentane, 5.0 mL, 7.66 mmol). The reaction was allowed to stir for 1 hour. Dimethylformamide (0.673 mL, 17.4 mmol) was added and the reaction was allowed to continue for an additional 30 minutes at −78° C., then stirred for 30 minutes outside of the dry-ice bath. The reaction was placed back in the dry-ice bath and quenched with 6 N HCl (1.5 mL) followed by water and allowed to warm to room temperature. The reaction was extracted with diethyl ether and aqueous (1M) sodium bicarbonate. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and volatiles removed by rotary evaporation, and the resulting yellow solid was dried under vacuum to provide 561 mg of compound 26 (3.27 mmol, 92% yield). MS (ESI) [M+H+]+=172.0.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-628A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrorninated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([F:10])[CH:3]=1.S(Cl)([Cl:13])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Fc1cc(Cl)ccc1CCl

Procedure:
Then, 16.5 g of 4-chloro-2-fluorobenzylalcohol was dissolved in 150 ml of tetrahydrofuran and 1 ml of pyridine, to which 10 ml of thionyl chloride was added dropwise at 5° C., and the mixture was stirred for 2.5/6 hours. After cormpletion of the reaction, the reaction mixture was concentrated, and the precipitated crystals were collected by filtration. The filtrate was subjected to silica gel column chromatography, which afforded 18.5 g of 4-chloro-2-fluorobenzyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][C:30]([CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[O:31])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cccc(NC(=O)C3CCOCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added tetrahydro-2H-pyran-4-carbonyl chloride (prepared from tetrahydro-2H-pyran-4-carboxylic acid (156 mg) and oxalyl chloride (0.15 mL) in dichloromethane (2.5 mL)) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution (3 times) then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (267 mg, 81%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[F:28][C:29]([F:37])([F:36])[C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:26][C:2]([CH3:1])([CH3:27])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:35][C:32]1[S:33][CH:34]=[C:30]([C:29]([F:37])([F:36])[F:28])[N:31]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (200 mg, 0.517 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (105 mg, 0.621 mmol) in the presence of EDCI hydrochloride (198 mg, 1.035 mmol) and DMAP (95 mg, 0.776 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 114 mg of the product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.56 (s, 2H), 3.80 (s, 3H), 6.98-6.99 (m, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.43-7.48 (m, 2H), 7.85 (d, J=16.2 Hz, 1H), 8.05-8.09 (m, 2H), 12.97 (br s, 1H); ESI-MS (m/z) 535.20 (M−H)−.