Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:28]#[N:29])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>CO.Cl[Ni]Cl>[F:27][C:25]1[CH:26]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@H:11]3[O:10][C:9]([CH3:31])([CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]3[CH2:13][F:14])=[CH:20][CH:19]=2)[CH:22]=[N:23][C:24]=1[CH2:28][NH:29][S:44]([CH3:43])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(C#N)c(F)c3)cc2)OC1(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(CNS(C)(=O)=O)c(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl-5-(4-(6-cyano-5-fluoropyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1440 mg, 3.4 mmol) in methanol (25 mL) at 5° C. is treated with NiCl2 (80 mg, 0.34 mmol) and then sodium borohydride (380 mg, 10 mmol) is added in portions. The mixture is stirred for 1 hour at room temperature, concentrated to remove the methanol, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil is dissolved in dichloromethane (5 mL), cooled to 5° C. and treated with diisopropylethylamine (0.88 mL, 5.0 mmol) and methanesulfonyl chloride (0.30 mL, 3.7 mmol) and stirred for 2 hours at room temperature. The mixture is concentrated and chromatographed on silica eluting with ethyl acetate in heptane to give the title compound. 1H NMR (400 MHz, CDCl3) 1.53 (s, 9H), 1.63 (s, 3H), 1.75 (s, 3H), 3.80-4.00 (m, 1H), 4.40-4.50 (m, 0.5H), 4.55-4.65 (m, 2.5H), 5.22 (d, 1H, J=7.33 Hz), 5.72 (bs, 1H), 7.60-7.70 (m, 5H), 8.63 (s, 1H). m/z (CI) M+H 512.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:22][CH:21]([C:23]4[N:27]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[NH:25][N:24]=4)[CH2:20]3)=[CH:14][CH:13]=2)[C:4]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:9]1[N:8]2[C:3]([NH:2][CH3:1])=[C:4]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:5]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:20][CH:21]([C:23]5[N:27]=[C:26]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[NH:25][N:24]=5)[CH2:22]4)=[CH:16][CH:17]=3)=[N:6][C:7]2=[N:11][CH:10]=1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2ncc(Br)n12
Yield: 26.1 %

Procedure:
50 mg (0.097 mmol) Methyl-(6-phenyl-7-{4-{3-[5-(pyridine-2-yl)-1H-[1,2,4]triazole-3-yl)-azetidine-1-ylmethyl]-phenyl}-imidazo[1,2-a]pyrimidin-5-yl)-amine are dissolved in 3.9 mL chloroform. 19.1 mg (0.11 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane/methanol). 15 mg (24.7%) of the desired compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:25]([OH:29])=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[N:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1cnc2c(O)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2n1

Procedure:
The title compound was prepared analogous to the procedure in Example 29 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol), 2-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, J. Med. Chem, 1988, 41, 4062.) DMF (3 mL), and a 60% dispersion of sodium hydride in mineral oil (0.040 g, 1.0 mmol, Aldrich). Purification by flash chromatography (0→75% EtOAc/hexanes) gave the title compound as an ivory powder. Mp: 135-141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:16])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]1[C:6]1[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:16][C@@:4]1([CH2:3][CH2:2][O:1][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][C@H:12]2[CH2:14][CH2:15][C@@H:5]1[C:6]1[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CC2CCC1c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 2.0 g of rac-(1R*,8R*,9R*)-9-(2-hydroxy-ethyl)-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-ol, 1.9 g of TsCl, 1.5 mL of NEt3 and 0.22 g of DMAP in 120 mL of toluene was stirred overnight at rt. The reaction mixture was quenched with water, the organic phase was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by CC with Hept/EtOAc (1:1) to yield 2.7 g of the desired compound as yellow oil.
Reaction SMILES: [CH2:1]([O:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:11])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[S:25](Cl)([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[S:25]([O:27][CH2:28][CH3:29])([O:10][CH2:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])=[O:26]
Reactant: CCOS(=O)Cl
Reactant: CCCCCCOC(C)(CO)OCCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
To a solution of alcohol 4 (20.6 g, 79.1 mmol) in CH2Cl2 (200 mL) is added pyridine (8.12 g, 102.8 mmol) and ethyl chlorosulfite (12.2 g, 94.9 mmol). The reaction mixture is stirred at 23° C. for 10 hours. The reaction is quenched with water (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers are washed with HCl (1N, 100 mL), saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfite 6 (24.5 g, 88%) as a colorless oil: Rf(15% EtOAc/hexane)=0.44; IR (thin film, cm−1) 2932, 2872, 1467, 1379, 1213, 1194, 1176, 1001, 888; 1H NMR (600 MHz, CDCl3) δ 4.11-4.00 (m, 2H), 3.93 (d, J=10.8 Hz, 1H), 3.77 (d, J=10.8 Hz, 1H), 3.42-3.37 (m, 4H), 1.51-1.48 (m, 4H), 1.33 (s, 3H), 1.31-1.24 (m, 15H), 0.85 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 99.0, 62.9, 60.8, 58.5, 58.3, 31.6, 29.8, 25.9, 22.6, 20.9, 15.3, 14.0.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1O)[C:11]([O:13][CH3:14])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:6][CH:3]([CH2:4][F:5])[CH2:2][F:1])[C:11]([O:13][CH3:14])=[O:12]
Reactant: OC(CF)CF
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CF)CF)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
To a solution of 1,3-difluoropropan-2-ol (2.57 g, 26.8 mmol) in THF (35 mL) was added methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.72 mmol), followed by triphenylphosphine (7.03 g, 26.8 mmol) and DIAD (5.21 mL, 26.8 mmol). The reaction was stirred overnight at room temperature, diluted with EtOAc and washed with brine. The organics were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound (3.743 g) as a clear oil. LCMS m/z=265.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH:10](N(C)C)N(C)C)[CH3:9]>>[CH3:7][N:8]([CH:10]=[C:2]1[CH2:3][CH2:4][O:5][C:1]1=[O:6])[CH3:9]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: O=C1CCCO1
Product: CN(C)C=C1CCOC1=O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A mixture of γ-butyrolactone (1 mol) and tris(dimethylamino)methane (1.5 mol) is stirred under dry nitrogen at 75° C. for 2 days to give 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone. A solution containing 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone (1 mol), n-butanethiol (1.1 mol) and para-toluenesulfonic acid (1 mol) in benzene is heated at reflux overnight to give upon aqueous work-up 3-[(butylthio)methylene]dihydro-2(3H)-furanone. After a solution of 3-[(butylthio)methylene]dihydro-2(3H)-furanone (1 mol) in anhydrous diethyl ether is added to a solution of lithium di-n-butylcuprate (1.1 mol) in diethyl ether at -78° C., the resulting mixture is stirred at -78° C. for an additional 0.5 hours and then quenched with methanol. Work-up affords 3-ethylidenedihydro-2(3H)-furanone. Freshly prepared W-2 Raney nickel (about 3 parts) is deactivated by refluxing in benzene for 1 hour, whereupon 3-ethylidenedihydro-2(3H)-furanone is added and the mixture is heated at reflux under nitrogen for 24-48 hours; the reaction is monitored by thin layer chromatography. After complete washing of the Raney nickel with hot benzene, the title compound is obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][N:30]([CH3:34])[CH3:29])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) and 1-dimethylamino-2-propyne (830 mg, 10.0 mmol) in toluene (6 ml) was treated with N,N-diisopropylethylamine (1.5 ml), copper(I) iodide (19.2 mg, 0.10 mmol), and dichlorobis(triphenylphosphine)palladium(II) (36.0 mg, 0.05 mmol). The resulting reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was concentrated in vacuo. The residue was extracted into methylene chloride from water. The combined organic layers were dried and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 ethyl acetate/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (360 mg, 74%) as a pale brown solid: (ES)+-HRMS m/e calcd for C24H29ClN4O3S (M+H)+ 489.1722, found 489.1725.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH2:13][C:12]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])[NH2:11]
Reactant: C1CCNCC1
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)C(CCC(=O)O)(CCC(=O)N1CCCCC1)c1ccc(Cl)c(Cl)c1

Procedure:
0.3 g of racemic 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 1 ml of methanol and 0.5 ml of piperidine are placed at 60° C. for 15 hours in a round-bottomed flask. The reaction medium is diluted with 10 ml of water and acidified with 1 N HCl to pH 2-3. The white crystals formed are filtered, drained and then dried to give 0.3 g of the expected compound.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([NH2:16])[CH3:15])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[ClH:1].[C:19]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([N:16]=[C:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]3)[CH3:15])=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example 7 above and substituting p-(2,2-diphenylvinyl)-α-methylbenzylamine hydrochloride for the α-methyl-p-phenethylbenzylamine hydrochloride above, results in the formation of 2-[p-(2,2-diphenylvinyl)-α-methylbenzylimino]hexahydroazepine hydrochloride having a M.P. of 219°-21° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][C@@H:37]([F:40])[CH2:36]3)[N:30]=[C:31](I)[C:18]=12>>[Cl:16][C:17]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][C@@H:37]([F:40])[CH2:36]3)[N:30]=[C:31]([C:4]3[CH2:3][CH2:2][O:1][CH2:6][CH:5]=3)[C:18]=12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Product: F[C@@H]1CCN(CCn2nc(C3=CCOCC3)c3c(Cl)c(-c4ccccc4)nnc32)C1

Procedure:
Compound Iq was synthesized according to Example 1, but using 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10% palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20](C)C.Cl.CNC1CC1>CS(C)=O>[CH:23]1([N:19]([CH3:20])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: CNC1CC1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.20 mmol) in DMSO (6 mL) was added DIEA (1.35 g, 10.47 mmol), and N-methylcyclopropanamine hydrochloride (490 mg, 4.58 mmol). The solution was stirred 10 mins at room temperature and 2 h at 75° C. Then the reaction was quenched by the addition of water (100 mL) and the solids were collected by filtration to afford methyl 3-(cyclopropyl(methyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (405 mg, 35%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[SH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)(C)C>[CH2:1]([S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(O)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCSCCC(=O)O
Temperature: 80 °C

Procedure:
To a solution of 86.8 gm (0.25 mole) octadecyl bromide, 29.2 gm (0.275 mole) 3-mercaptopropionic acid and 90.0 gm isopropanol at 80° C. was added 95.0 gm (0.275 mole) 40% aqueous potassium carbonate solution dropwise. The mixture was heated at 80° C. for 8 hours and then cooled to 60° C. After adding 125.0 gm water and 36.8 gm of 30% hydrochloric acid solution, the mixture was slowly heated to 94° C. while distilling aqueous isopropyl alcohol from the reaction. The product separated as an oil from the aqueous phase. It was isolated using a separatory funnel and washed with hot water. Upon cooling, the product solidified as a light tan waxy solid. It was dried in a vacuum oven at 50° C. to yield 91.35 gm (98%)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:8]=[CH:9][C:10]([I:13])=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Ic1cnc(N2CCNCC2)nc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Ic1cnc(N2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)nc1

Procedure:
In 100 ml of methylene chloride was dissolved 13 g of 2-piperazin-1-yl-5-iodopyrimidine which was then reacted with 15 g of triphenylmethyl chloride at room temperature for 1 hour in the presence of 16 ml of triethylamine with stirring. The reaction mixture was added with methylene chloride, after which the organic layer was washed with water and brine, dehydrated, filtered and concentrated under vacuum. The residue was purified by use of ethyl acetate and a small quantity of methanol to obtain the title compound. 10 g.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].O1CCCC1.[C:13](Cl)([Cl:15])=[O:14]>C1(C)C=CC=CC=1>[Cl:15][C:13]([NH:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:14]
Reactant: NN1CCNC1=O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)NN1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.01 g. (0.01 mol.) of 1-amino-2-imidazolidinone are dissolved in 20 ml. of anhydrous tetrahydrofuran and 20 ml. of a 1M solution of phosgene in toluene are added at 0°. The solution is stirred overnight at room temperature. The almost clear solution is filtered and evaporated to dryness. The 1-(chlorocarbonylamino)-2-oxoimidazolidine is obtained as an oily residue which is used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:9][C@@H:10]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][OH:29])=[CH:21][C:20]=2[CH3:30])=[C:16]([CH:31]([CH3:33])[CH3:32])[NH:15][N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:29][CH2:28][CH2:27]/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:11]3[O:34][C@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:10]3[O:9][C:6](=[O:8])[CH3:7])=[N:14][NH:15][C:16]=2[CH:31]([CH3:33])[CH3:32])=[C:20]([CH3:30])[CH:21]=1)(=[O:4])=[O:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Add methanesulfonyl chloride (0.54 mL, 7 mmol) to a solution of 4-{4-[(1E)-4-hydroxybut-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (3.7, 5.87 mmol) in dichloromethane (15 mL) and triethylamine (4 mL, 29 mmol) at 0° C. After refluxing at room temperature for 30 min, concentrate to remove the solvent under the reduced pressure. Purify residue by flash chromatography to yield the title compound (2.9 g, 4.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[C:4]=2[CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=3[S:6][CH:7]=2)[C:11]1=[O:19])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.16 mmol) in DMF (2 mL) were added ethyl acrylate (0.02 mL) and benzyltrimethyl ammonium hydroxide (20 mg, 0.01 mmol). The resulting mixture was stirred at room temperature overnight. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 50 mg of the desired product as a colorless oil. LCMS (ESMS): m/z 415.78 (M+H+).