Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:46]([N:48]3[CH2:56][C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)C3)=O)[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.[C:58](=[O:61])(O)[O-].[Na+]>O1CCOCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([CH:46]3[C:50]4[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:56][N:48]3[C:58]([N:48]3[CH2:56][C:55]4[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]3[C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[C:12]([C:16]6[NH:17][N:18]=[CH:19][N:20]=6)[CH:11]=5)[NH:7][N:8]=4)[CH:41]=3)=[O:61])[CH:43]=[CH:44][CH:45]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)N1Cc2ccccc2C1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N1Cc2ccccc2C1c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)N1Cc2ccccc2C1c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
To a stirred solution of isoindolin-2-yl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl ketone (0.240 g, 0.327 mmol) was added 4.0 M hydrochloric acid in dioxane (10.0 mL) and the mixture stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0458 g, 34% yield). 1H NMR (CD3OD) δ 8.74 (s, 1H), 8.50 (br s, 1H), 8.23 (s, 1H), 8.19 (m, 1H), 8.10 (br s, 1H), 7.68 (m, 3H), 7.37 (d, 1H), 7.26 (m, 3H), 5.00 (s, 2H), 4.93 (s, 2H). ES-MS (m/z) 407 [M+1]+
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=3)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[C:38]([CH3:40])=[O:39].[C:41](OC(=O)C)(=[O:43])[CH3:42]>CN(C)C1C=CN=CC=1.O>[C:41]([O:1][CH:2]([C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([CH:23]([O:30][C:38](=[O:39])[CH3:40])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=3)[CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:43])[CH3:42]
Reactant: CC(C)=O
Reactant: OC(c1ccccc1)c1ccc2nc3ccc(C(O)c4ccccc4)cc3c(-c3ccccc3)c2c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC(=O)OC(c1ccccc1)c1ccc2nc3ccc(C(OC(C)=O)c4ccccc4)cc3c(-c3ccccc3)c2c1

Procedure:
1 pbw of 2,7-bis(α-hydroxybenzyl)-9-phenylacridine is suspended in 4 pbw of acetone and heated for 1 hour under reflux with 0.8 pbw of acetic anhydride and 0.001 pbw of 4-dimethylaminopyridine. Water is then added to the mixture and the product is filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=O)[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].O=P(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:26])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)cc(Cl)c2[nH]c1=O
Product: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step B from 6,8-dichloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester and POCl3. Light brown solid. MS (ESI): 366.0 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH3:7][CH2:8][CH2:9]CCC.[CH:13](Cl)(Cl)Cl>>[CH3:7][C@@H:8]1[CH2:9][CH2:6][C@@H:5]2[CH2:13][C@H:2]1[C:1](=[O:3])[O:4]2
Reactant: CCCCCC
Reactant: ClC(Cl)Cl
Reactant: CCOC(C)=O
Product: C[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2

Procedure:
A solution of 8 (26.8 g, 101 mmol), tributyltin hydride (29.8 mL, 111 mmol), and AIBN (200 mg) in benzene (300 mL) was refluxed overnight. After removing the benzene solvent in vacuo, diethyl ether (250 mL) and 10% aqueous KF (250 mL) was added. Stirring for 30 min precipitated a tributyltin flouride polymer. The polymer was filtered and the mother liquors were extracted with methylene chloride (3×100 mL). The combined organics were dried (MgSO4) and the volatiles were removed in vacuo to yield an oil which was purified by flash chromatography to give a yellowish solid (13.2 g, 94% yield). Rf 0.26 (ethyl acetate/hexane 1:9); m.p. 62-63° C.; 1H NMR (300 MHz, CDCl3) δ 4.76-4.80 (m, 1H), 2.43-2.46 (m, 1H), 2.12-2.25 (m, 2H), 2.01-2.05 (m, 1H), 1.89-1.98 (m, 2H), 1.62-1.70 (m, 1H), 1.41-1.47 (m, 1H), 1.13 (d, J=6.8, 3H); 13C NMR (75 MHz, CDCl3) δ 179.1, 78.1, 44.5, 31.0, 28.1, 24.8, 24.4, 17.5; MS (EI) m/z 140 (M+, 3), 112 ([M-CO]+, 3), 97 (28), 81(100), 70 (38), 55 (48); [α]D+31.3 (c=0.96°, CHCl3); Analysis calc'd for C8H12O2: C, 68.54; H, 8.63. Found: C, 68.15; H, 8.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([CH:4]([C:3]([O:2][CH3:1])=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 12.3 g (66.0 mmol) of BOC-piperazine. The reaction mixture was refluxed for 3.5 hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to yield 7.73 g (100%) of the desired mixture of isomers as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:12]([C@H:27]([NH2:31])[C:28]([OH:30])=[O:29])[CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][SH:19])=[O:15]>CC(C)=O.O.CC(C)=O>[NH2:31][C@H:27]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][S:19][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CC(=O)Cl
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Yield: 85 %

Procedure:
Using in the procedure of Example 1 acetyl chloride, in place of pivaloyl chloride, L-glutathione reduced (15.4 g) provides, after usual work-up, a crude white solid which is dissolved in warm acetone/water (2/1; 40° C.; 300 ml). The obtained solution is further diluted with more acetone (100 ml) and cooled on ice-water bath. After about two hours the white crystalline precipitate is collected, washed with the solvent (40 ml) and dried under vacuum affording γ-L-glutamyl-S-acetyl-L-cysteinyl-glycine (14.8 g yield=85%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([N:9]2[C:8]3[CH:15]=[CH:16][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=3[O:12][CH:11]([CH3:13])[C:10]2=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2C1CCCC1
Temperature: 70 °C
Yield: 51.5 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (4.0 g) in dimethylformamide (80 ml) were added 60% sodium hydride (in oil) (0.73 g) and cyclopentyl bromide (2.5 g) and the mixture was stirred at 70° C. for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using chloroform to give 4-cyclopentyl-7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.5 g) as an oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].O[CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:33]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32]1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc([N+](=O)[O-])c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
DIAD (0.309 mL, 1.495 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (Example 425B) (223 mg, 1.122 mmol), (+/−)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THE (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-20% ethyl acetate/dichloromethane). (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-nitrophenoxy)pyrrolidine-1-carboxylate (272 mg) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH3:12].[H][H].ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:29])[C:22]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12]
Reactant: [H][H]
Reactant: CC(c1oc2ccc(Br)cc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1cnc2c(N)ncnc21
Yield: 37.7 %

Procedure:
To a solution of example 21 (0.080 g, 0.173 mmoles) in methanol (10 ml), palladium on carbon (10% 16 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 24 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as light yellow solid (0.025 g, 38% yield). MP: 254-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.46(s, 1H), 8.03(s, 1H), 8.01(d, J=1.6 Hz, 1H), 7.83(dt, J=7.3,1.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.50 (m, 4H), 7.37(dd, J=8.1,1.7 Hz, 1H),7.22(s, 2H), 5.67(q, J=7.3 Hz, 1H),1.89(d, J=7.2 Hz, 3H).). Mass: 384.19(M+1).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].[Na].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C)C=O>[CH3:1][N:2]([C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[Cl:15])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.71 g (0.01 mole) of N-methylbenzenesulfonamide was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt was added 2.10 g (0.012 mole) of 2-chlorobenzoyl chloride, and the mixture was stirred at room temperature for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure. Cold water was added, and the resulting oil layer was extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate, and concentrated to afford almost pure N-methyl-N-(2-chlorobenzoyl)benzenesulfonamide in a yield of 92%. For further purification, this compound was subjected to chromatography or high vacuum distillation. This compound is designated as compound No. 16 in Table 2, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: NCCN1CCCC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCN2CCCC2)c1

Procedure:
3-Fluoro-4-nitro-benzoic acid methyl ester (xiv) (1.08 g, 5.41 mmol) and 2-pyrrolidin-1-yl-ethylamine (1.36 g, 11.9 mmol) in MeOH (19 mL) were stirred under microwave irradiation at 100° C. for 10 min. The RM was diluted with EtOAc and washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dry loaded on silica gel and purified by chromatography with DCM and MeOH to yield the title product as an orange solid (tR 2.45 min (conditions 8), MH+=294).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:18][C:19]([F:24])([F:23])[C:20]([NH2:22])=[NH:21]>C(Cl)(Cl)Cl.CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:2]2[NH:22][C:20]([C:19]([F:24])([F:23])[F:18])=[N:21][C:3]=2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: N=C(N)C(F)(F)F
Reactant: O=C(c1ccccc1)C(Br)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1ccc(-c2[nH]c(C(F)(F)F)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.7 %

Procedure:
A mixture containing impure 2-bromo-2-(4-fluorophenyl)-1-phenyl-ethanone (13.07 g) and trifluoroacetamidine (5.00 g) was heated at 60° under nitrogen and with stirring for 19 h. More trifluoroacetamidine (2.00 g) was added and after a further 3 h the mixture was allowed to cool to room temperature and dissolved in chloroform/methanol before purifying by FCC eluting with System A (1:9) to give the title compound (4.60 g) as a pale yellow solid. δ (DMSO-d6) 7.16 and 7.2-7.6 (t, J 9 Hz and m, aromatic protons), 13.90 (bs, NH).
Reaction SMILES: [C:1]1([O:7]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:10][C:11]1[CH:16]=CC(CC#N)=CC=1.I.CC[O:23]CC>>[OH:7][C:1]1[CH:2]=[CH:3][C:4]([CH2:16][C:11]([OH:10])=[O:23])=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: COc1ccccc1
Reactant: COc1ccc(CC#N)cc1
Agent: I
Product: O=C(O)Cc1ccc(O)cc1

Procedure:
A method in which anisole, which is a starting material, is subjected to chloromethylation and a cyanation to be thereby converted to 4-methoxyphenylacetonitrile (Organikum, Berlin, nine edit., p. 363); and the resultant 4-methoxyphenylacetonitrile is saponified to produce an acid, which is subsequently treated with hydriodic acid to eliminate an ether, whereby 4-hydroxyphenylacetic acid is obtained as the desired product (J. Org. Chem., Vol. 22, 1957, p. 1577).
Reaction SMILES: N1CCCC1.N1(CC(=C)C(=[O:16])C)CCCCC1.[N:18]1([CH2:24][CH:25]([CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([CH3:28])=[O:27])[CH2:23][CH2:22]C[CH2:20][CH2:19]1>>[CH2:19]([N:18]([CH2:24][CH:25]([CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([OH:16])[CH2:32][CH2:31]1)[C:26](=[O:27])[CH3:28])[CH2:23][CH3:22])[CH3:20]
Reactant: CC(=O)C(CN1CCCCC1)CN1CCCCC1
Reactant: C=C(CN1CCCCC1)C(C)=O
Solvent: C1CCNC1
Product: CCN(CC)CC(CN1CCC(O)CC1)C(C)=O

Procedure:
The intermediate olefinic ketone is prepared by the procedure of H. M. E. Carwell [J. Chem. Soc., 1058 (1950)]. The ketone obtained from A., 22.8 g., in 25 ml. of ethanol was added to a solution of 25 g. of anhydrous oxalic acid in 75 ml. of ethanol. The mixture was cooled to 0° C., filtered to remove diethylamine hydrogen oxalate and the mother liquor evaporated to dryness under reduced pressure. The residue was dissolved in a little water, treated with potassium carbonate and extracted with ether. The ether was dried over anhydrous sodium sulphate and the residue obtained by solvent removal was distilled. After re-distillation the product was obtained as an oil, b.p. 82° C./18 mm. Similarly, the other 1,1-bis-(disubstituted aminomethyl)acetones obtained as in A. can be converted to the corresponding 3-disubstituted aminomethylbut-3-en-2-ones. The disubstituted amino term as previously indicated also comprises pyrrolidine and piperidine alicyclic ring analogs. For example, 3-(piperidinomethyl)but-3-en-2-one boils at 135°-139° C./15 mm. and is synthesized following the same procedure from 1,1-bis(-piperidinomethyl)acetone.
Reaction SMILES: CC1N=CN([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)C=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)[CH2:21][CH2:20]1
Reactant: CN1CCC(O)CC1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Product: CN1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
for preparing the compound of examples 43 to 46 may be obtained analogously to a method as described in WO2004005281 for 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine, but using 1-methyl-piperidin-4-ol. ES-MS: 275.2 [M+H]+; tR=2.41 min
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH:26]([C:28]2[C:33]3[N:34]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=5[Cl:48])[C:35]4=[N:36][C:32]=3[CH:31]=[CH:30][CH:29]=2)[OH:27])[CH2:25][CH2:24]1>ClCCl.C(=O)([O-])O.[Na+]>[CH:23]1([C:26]([C:28]2[C:33]3[N:34]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=5[Cl:48])[C:35]4=[N:36][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24]1
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
Dess-Martin reagent (925 mg, 2.18 mmol) was added to a stirred solution of cyclopropyl[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a ]benzimidazol-6-yl]methanol (770 mg, 1.98 mmol) in dichloromethane (8.0 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (226 mg, 0.585 mmol, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1)O>CCOC(C)=O.CC(O)=O.[Pd]>[CH3:19][C:4]1[CH:5]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:20][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Reaction time: 5 h
Yield: 34.8 %

Procedure:
A degassed solution of crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-(4-methoxymethoxyphenyl)methanol (12.0 g, 26.84 mmol) and Pd/C (1.2 g) in EtOAc/HOAc (19/1) was stirred under an atmosphere of hydrogen (1 atm) at r.t. After 5 h, the catalyst was filtered through a pad of Celite, rinsed with ethyl acetate and the combined filtrates concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:9) to afford 4-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-methoxymethoxybenzene (4.0 g, 41.5% for two steps): 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 4H), 6.63 (s, 2H), 5.16 (s, 2H), 3.94 (s, 2H), 3.50 (m, 3H), 1.58 (s, 6H), 1.29 (m, 3H), 1.13 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:19); Rf=0.80.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:49]>CN(C=O)C>[Br:49][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCO)c(C)c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (1.39 g, 3.62 mmol) in DMF (15 mL) were added PPh3 (1.04 g, 3.98 mmol) and CBr4 (1.32 g, 3.98 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solids were dried and purified by the Simpliflash system, using 2% methanol in CH2Cl2, to give 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 940 mg (58%).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:15]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCOc1ccc(C=O)cc1
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(C=CC(=O)c2ccc(C(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of titanium(IV) chloride (13.88 g) in dichloromethane (100 ml) was added Ethyl 4-acetylbenzoate (11.53 g) and 4-n-pentyloxybenzaldehyde (12.68 g) in dichloromethane (50 ml) was added dropwise at 0° C. To the mixture was added triethylamine (12.44 ml) in dichloromethane (30 ml). The mixture was stirred at 0° C. for 30 minutes and diluted with ethyl acetate. The organic layer was washed with water (four times) and brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried to give 1-(4-n-Pentyloxyphenyl)-3-(4-ethoxycarbonylphenyl)-1-propen-3-one (13.45 g).