Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3].Cl.[C:13](=O)(O)[O-].[Na+]>CO>[CH3:13][O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: O=C([O-])O
Reactant: C=CCOC(=O)NCC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)NCC(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)glycine, prepared as described by F. Guibe, O. Dangles, and G. Balavione in Tetrahedron Letters, 1986, 27, 2365-2368, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)glycine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:12][C:13]=2[CH2:14][CH2:15][CH2:16][O:17][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)c(Cl)c2)c(CCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a mixture of 4-(3,4-dichlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (352 mg), 2-methylphenol (216 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (450 mg) at room temperature, and the mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. The title compound was obtained as crystals from an eluate from ethyl acetate-hexane (2:3, v/v). Recrystallization from acetone-isopropyl ether gave colorless prism crystals (271 mg, 61%). melting point: 116-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19]>C(Cl)Cl.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: [Ni+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
57.2 g (0.2 mole) of crystalline all-trans vitamin A alcohol are dissolved in 1 liter of methylene chloride. The solution is then stirred at -20° C. to -35° C. in 10 minute intervals with a total of 90 g of nickel peroxide prepared in Example 4 in 5 portions. After the last portion has been introduced, the mixture is stirred for a further 15 minutes at -20° C. to -35° C., filtered off under suction and washed with a total of 1 liter of methylene chloride at -30° C. The residue collected on the filter has the spent nickel peroxide. The methylene chloride solution is subsequently concentrated to a volume of about 500 ml on a rotary evaporator. The residual solution is then treated with 500 ml of n-hexane, again evaporated to 500 ml, again treated with 500 ml of n-hexane and finally concentrated to a volume of 100 ml. The concentrate is cooled to 10° C., seeded with vitamin A aldehyde crystals and then left overnight at -20° C. to completely crystallise out. The crystals are then filtered off under suction, washed with 250 ml of pentane at -20° C. and dried in vacuo at 30° C. in a constant weight. There are obtained 49 g (86%) of vitamin A aldehyde with the expected melting point of 63.5°-65° C. and the UV value E11 = 1750 at 366 nm (hexane).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[C:4]1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].N1C=CC=CC=1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>ClCCl>[CH:30]1([S:33]([N:21]2[CH2:20][CH2:19][N:18]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([C:5]=3[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=4)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(N2CCN(S(=O)(=O)C3CC3)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) is added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture is stirred at room temperature overnight. This is then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][CH:26]1[CH2:27][NH:28]2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][N:28]2[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1cc(-c2cc3nccn3c(Cl)n2)ccn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(Cl)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 100 mL RBF was added 5-chloro-7-(2-chloro-pyridin-4-yl)-imidazo[1,2-c]pyrimidine (2.0 g, 7.6 mmol), 20 mL NMP, (S)—N-Boc-2,5-Diaza-bicyclo[2.2.1]heptane (1.6 g, 8.3 mmol), K2CO3 (1.05 g, 7.6 mmol) and DIEA (1.3 mL, 7.6 mmol). The mixture was stirred at rt under nitrogen for 15 h, and all starting material was converted. The reaction mixture was added to a 100 mL ice water slowly, and a white solid was precipitated out. The precipitate was filtrated and washed with 50 mL water, and further purified by flash chromatograph. The title compound was obtained. MS (ES+):427 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[C:36](Cl)=[O:37]>>[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]=1[C:36]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:37]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Product: Cc1onc(-c2ccccc2)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 504.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@H:9]2[CH2:13][NH:12][C@H:11]([C:14]([NH:16][C:17]3([C:20]#[N:21])[CH2:19][CH2:18]3)=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([O-])=[O:38])[CH2:29][CH2:28]1)=[O:26])[CH3:23].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@H:9]2[CH2:13][N:12]([C:37]([CH:34]3[CH2:35][CH2:36][N:33]3[CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:32][CH2:31]3)=[O:38])[C@H:11]([C:14](=[O:15])[NH:16][C:17]3([C:20]#[N:21])[CH2:19][CH2:18]3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccc(Cl)cc3)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccc(Cl)cc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(4-chlorophenylthio)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 12G and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(4-chlorophenylthio)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 560.3/562.1 (100/62) [(M+H)]+.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:14]2[CH:13]=[C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:31]5[CH:32]=[C:27]([CH2:26][OH:25])[CH:28]=[CH:29][CH:30]=5)[N:10]4[N:9]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(Br)n4n3)c2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(CO)c5)n4n3)c2)CC1
Yield: 19.1 %

Procedure:
Analogous to Example 1504, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0731 g, 0.189 mmol) and (3-Hydroxymethylphenyl)boronic acid (0.0513 g, 0.338 mmol) were reacted to afford (3-{2-[3-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol as a yellow powder (15 mg, 20%). LCMS: 415 (M+H); 1H-NMR (CDCl3): 8.70 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.62 (d, 1H, J=6.96 Hz), 7.49 (m, 2H), 7.20 (t, 1H, J=8.19 Hz), 6.93 (d, 1H, J=4.50 Hz), 6.88 (s, 1H), 6.84 (d, 1H, J=4.50 Hz), 6.87 (d, 1H, J=8.19 Hz), 4.77 (s, 2H), 2.98 (t, 4H, J=4.96 Hz), 2.44 (t, 4H, J=4.96 Hz), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][CH:7]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O>[OH-].[K+].O>[CH2:9]([O:4][C:3](=[O:5])[CH2:2][Cl:1])[CH2:8][CH:7]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:6]
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)=CCCC(C)CCOC(=O)CCl
Yield: 85.1 %

Procedure:
A mixture of 94.5 g (1.0 mol) of monochloroacetic acid and 203.2 g (1.4 mol) of 3,7-dimethyl-6-octen-1-ol (citronellol) was heated for 6 h at 50 mbar to 130° C., wherein the water formed by esterification was distilled off via a column. The reaction mixture obtained had an acid value of 5 mg KOH/g. Unreacted citronellol was then distilled off at 6 mbar and a bottoms temperature of up to 130° C. Distillation of the residue at 6 mbar yielded 198 g of chloroacetic acid citronellyl ester as a colourless liquid.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH:14]=[CH2:15])[C:7]=2[O:6][CH:5]=1>C(OC)(C)(C)C.[Pd]>[CH3:17][C:2]([CH3:1])([CH3:18])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[O:6][CH:5]=1
Reactant: C=CCc1c(O)ccc2c(CC(C)(C)C)coc12
Agent: [Pd]
Solvent: COC(C)(C)C
Product: CCCc1c(O)ccc2c(CC(C)(C)C)coc12

Procedure:
A solution of the product from Step G (1.912 grams) in methyl tert-butyl ether (20 mL) was combined with 5% Pd/C catalyst (200 mg) in a hydrogenation bottle. The mixture was hydrogenated using a Parr apparatus at 14psi for 1 hour. The catalyst was removed by filtration through Celite and the filtrate evaporated. The resultant solid was employed without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[C@H:3]1[OH:9].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>C(#N)C.C(O)(C)C>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[C@H:3]2[OH:9])[C:14]([F:18])=[CH:13][N:12]=1
Reactant: N[C@H]1CCC[C@@H](O)[C@H]1O
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CC#N
Product: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Temperature: 100 °C

Procedure:
The starting racemic diol, 31a, (1R,2S,3S)-3-aminocyclohexane-1,2-diol, was prepared following the procedure described in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al. To a solution of racemic diol 31a (0.66 g, 5.00 mmol) in acetonitrile (5 mL) and isopropanol (5 mL) was added 2,4-dichloro-5-fluoro-pyrimidine (0.84 g, 5.03 mmol) and iPr2NEt (3.25 g, 4.38 mL, 25.20 mmol). The reaction mixture was sealed and heated to 100° C. for 90 minutes and then concentrated to dryness. The crude was purified via silica gel chromatography (40%-100% EtOAc/Hex) to afford a racemate, which was further purified via chiral HPLC separation to give compound 31b (0.26 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[OH:18][C:19]1[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][C:22]([SH:29])=[CH:21][C:20]=1[C:30]([CH3:33])([CH3:32])[CH3:31]>>[OH:18][C:19]1[C:20]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:21][C:22]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)=[CH:23][C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 198°-199° C.) and 4-hydroxy-3,5-di-tert. butyl-thiophenol (m.p. 84.5°-86.0° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC#N.CCOC(C)=O.O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:28](=[O:31])[CH2:29][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2′-{[(2-Chloro-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.55 mmol), pyrrolidine (0.05 mL, 0.61 mmol), potassium carbonate (0.152 g, 1.1 mmol), and sodium iodide (0.082 g, 0.55 mmol) were combined in MeCN (3 mL), and the reaction was stirred for 3 hours at room temperature. Analytical LCMS indicated that some starting material was still present, so additional potassium carbonate (0.053 g, 0.39 mmol) was added, and the reaction was stirred for 45 minutes. The mixture was diluted with EtOAc and H2O, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH3:32])=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[O:9][C:8]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=1)([CH3:15])[CH2:7][CH2:6]2.CC(C)=[O:35]>O>[OH:35][C:8]([CH3:15])([CH2:7][CH2:6][C:5]1[C:10](=[O:9])[C:11]([CH3:14])=[C:12]([CH3:13])[C:3](=[O:2])[C:4]=1[CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)=C(C)C1=O
Reaction time: 8 h

Procedure:
15 ml of an aqueous solution of ferric chloride acidified with hydrochloric acid [a mixture of about 65% by weight of ferric chloride (FeCl3.6H2O) and about 35% by weight of concentrated hydrochloric acid] were added dropwise, whilst ice-cooling and stirring, to a solution of 6.3 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine dissolved in 50 ml of acetone, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was diluted with 500 ml of water and then extracted with ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of benzene and ethyl acetate as the eluent, to afford 4.2 g of the title compound as a yellow powder softening at 55°-65° C.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.S(Cl)([Cl:15])=O>>[S:1]1[C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2c(s1)CCCC2

Procedure:
1.0 g of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid was reacted with 4 ml of thionyl chloride for 3.5 hours under reflux. Then, excess thionyl chloride was distilled off under reduced pressure to obtain 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.P(Br)(Br)[Br:12].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(F)c(Br)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(CBr)cc1Br
Yield: 242.5 %

Procedure:
20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 10 g of phosphorus tribromide were added dropwise at 0° to 10° C., while stirring. The mixture was then stirred at room temperature for 2 hours. The reaction batch was subsequently poured into 500 ml of water, the organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The residue was distilled in vacuo. 24 g (89.6% of theory) of 3-bromo-4-fluoro-benzyl bromide with a boiling point of 99°-100° C./3 mbars were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:14][O:15][CH:16]=[O:17]>C(Cl)Cl.CO>[CH3:14][O:15][C:16](=[O:17])[NH:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=COCCl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of [2-(4-nitrophenyl)ethyl]amine (6.06 g, 30 mmol) in CH2Cl2 (75 ml), MeOH (5 ml), and TEA (9.5 ml) at 0° C. was added chloromethylformate (3.39 g, 36 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour concentrated in vacuo, and partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow solid (6.6 g, 98%). Mp: 38° C., MS (ES−): 223 (M−H).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[NH2:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[N:4]=1
Reactant: Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cccc(-c2cn3ccc(N)nc3n2)c1
Temperature: 120 °C

Procedure:
To a microwave vial were added 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (500 mg, 1.63 mmol), acetic anhydride (199 mg, 185 μA, 1.95 mmol) and pyridine (5.00 ml). The vial was capped and heated in the microwave at 120° C. for 15 min. H2O was added to the reaction mixture and the pH was installed around 7-8 by addition of 10% NaHCO3 aq. solution. The product was extracted with CH2Cl2, then the solvent was partially evaporated and the formed solid was collected and purified by flash chromatography (SiO2 cartridge; eluent: CH2Cl2/MeOH/NH3aq. 140:10:1). White solid (207 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH2:7]Br.[C-:12]#[N:13].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH2:7][C:12]#[N:13])[CH:9]=1
Reactant: COc1cc(Br)cc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Br)cc(CC#N)c1
Reaction time: 16 h

Procedure:
A mixture of the crude benzyl bromide and sodium cyanide (4.9 g, 0.1 m) in ethanol (500 ml) is stirred at 65° for 16 hours. The mixture is cooled, filtered and concentrated in vacuo. The residue is partitioned between water and chloroform and the chloroform phase is washed, dried with sodium sulfate and concentrated in vacuo to afford 5-bromo-3-methoxyphenylacetonitrile.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:14]2[O:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([C:29]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:30]=1[O:31][C:32](=[O:39])[CH:33](Cl)[CH2:34][CH2:35][CH2:36][CH3:37])([CH2:27][CH3:28])([CH3:26])[CH3:25]>>[C:24]([C:29]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][C:30]=1[O:31][C:32](=[O:39])[CH:33]([N:16]1[C:15]2[CH:20]=[C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:14]=2[O:18][C:17]1=[O:19])[CH2:34][CH2:35][CH2:36][CH3:37])([CH2:27][CH3:28])([CH3:25])[CH3:26]
Reactant: O=c1[nH]c2cc(OCc3ccccc3)c([N+](=O)[O-])cc2o1
Reactant: CCCCC(Cl)C(=O)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Agent: [H-]
Agent: [Na+]
Product: CCCCC(C(=O)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)n1c(=O)oc2cc([N+](=O)[O-])c(OCc3ccccc3)cc21
Yield: 72.8 %

Procedure:
60% sodium hydride in oil dispersion (3 g, 0.075 mole) was added to the benzoxazolone ((d), 18.12 g, 0.063 mole) and α-(2,4-ditert.-pentylphenoxy)-hexanoylchloride (23.23 g, 0.063 mole) in dry refluxing toluene (400 ml) and the resulting solution was refluxed for further 2 hours. Water (100 ml) was added and azeotropically distilled. The organic solution was filtered and evaporated to dryness under vacuum. The oily residue was purified by column chromatography on silica gel using toluene as eluant. The obtained yellow oil was crystallized from methanol (150 ml) to give the acylated benzoxazolone ((e), 28.3 g, 72.5%) as white prisms. The product structure was confirmed by NMR and IR spectra.