Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)([CH3:8])[O:5][C:4]1=[O:19].CN(C)C=O>C(OC(C)C)(C)C>[CH2:2]=[C:3]1[O:7][C:6]([C:9]23[CH2:16][CH:15]4[CH2:17][CH:11]([CH2:12][CH:13]([CH2:14]4)[CH2:18]2)[CH2:10]3)([CH3:8])[O:5][C:4]1=[O:19]
Reactant: CC1(C23CC4CC(CC(C4)C2)C3)OC(=O)C(CBr)O1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
A mixture obtained by dissolving 16.4 g (0.05 mol) of 5-bromomethyl-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one in 58 g of isopropyl ether was placed in a flask equipped with an agitator, a thermometer, a condenser and a dropping funnel. 36.5 g (0.5 mol) of N,N-dimethylformamide was added by drops thereto, followed by intensively stirring at room temperature for 4 hours. After completion of the stirring, insoluble products were removed from the reaction solution by filtration, and the obtained filtrate was transferred into a 500 ml separatory funnel. The solution was left at rest, so as to separate it into two layers, and the lower N,N-dimethylformamide layer was removed. The upper isopropyl ether layer washed with water to remove N,N-dimethylformamide dissolved therein. Thereafter, isopropyl ether was removed, so as to obtain white crystals. The obtained white crystals were recrystallized from hexane, so as to obtain 6.6 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (hereinafter referred to as AdMDO) (yield: 53%).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]2[C:17](=[CH:18][CH:19]=1)[C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][NH:11]2.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:42])([F:41])[CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.[BH4-].[Na+]>CCO>[F:7][C:8]1[CH:9]=[C:10]2[C:17]([C:13]([CH2:14][CH2:15][NH:16][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH2:31][C:30]([F:29])([F:41])[F:42])[CH:34]=3)=[CH:12][NH:11]2)=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Fc1ccc2c(CCNCc3cccc(OCC(F)(F)F)c3)c[nH]c2c1
Reaction time: 1 h

Procedure:
Combine 6-fluorotryptamine oxalate (350 mg, 1.3 mmol), N,N-diisopropylethylamine (506 mg, 3.9 mmol), 3-(2,2,2-trifluoroethoxy)benzaldehyde (266 mg, 1.3 mmol), and 4 Å molecular sieves (4 g) in EtOH (30 mL) and reflux for 7 hours. Decant the liquid into a separate flask and treat with NaBH4 (148 mg, 3.9 mmol). Stir 1 hour, concentrate the mixture in vacuo to give a residue. Partition the residue between 25 mL 5 N NaOH and 25 mL dichloromethane. Extract the aqueous layer with 25 mL dichloromethane, combine the organic layers, dry over MgSO4, and concentrate to approximately a 20 mL volume. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 mixed with conc. NH4OH to give the title compound. Combine an EtOAc solution of the title compound with an EtOAc solution of one equivalent of oxalic acid to give a solid, filter, and dry under vacuum to give the oxalate salt of the title compound: ISMS 367 (M+1); Analysis for C9H19ClF4N2O: calcd: C, 55.27; H, 4.42; N, 6.14. found: C, 55.17; H, 4.38; N, 6.09.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>C(O)(C)C>[C:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: C=CC=C
Solvent: CC(C)O
Product: CCC=CCc1ccccc1
Temperature: 110 °C
Yield: 77.2 %

Procedure:
The powdery catalyst that had been prepared in the same manner as in Example 1 was incorporated with 1000 g of toluene that had been dehydrated with molecular sieve, in a stream of nitrogen with heating to 110° C. Subsequently 70 g of 1,3-butadiene was introduced into the reaction system with vigorous stirring for one (1) hour to carry out the reaction. After cooling the system, the catalyst was deactivated by adding isopropyl alcohol thereto and then the reaction liquid was sampled for analysis by gas chromatography- As a result, the objective phenyl-2-pentene was obtained in a yield of 77.2%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1.O.C1COCC1>[Cl-].[NH4+].[Zn]>[CH3:1][N:2]1[C:6]([C:7]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 214.7 %

Procedure:
To a solution of 4-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-morpholine (1.913 g, 2.88 mmole), in saturated ammonium chloride solution (6 mL), water (6 mL) and THF (12 mL) was added zinc dust (1.123 g, 6 eq) at 0° C. The mixture was stirred at room temp for 1 hour and then filtered off through celite. The solution was dried in vacuo to give title compound as a yellow gummy solid (1.87 g, 99%). Exact mass calculated for C16H22N4O2 302.2. found 303.4 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1>>[NH2:16][C:17]1[NH:18][N:19]=[C:20]([S:22][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:15])[C:6]=2[CH2:12][CH2:13][CH3:14])[N:21]=1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: Nc1n[nH]c(S)n1
Product: CCCc1c(CSc2n[nH]c(N)n2)ccc(C(C)=O)c1O
Yield: 61.7 %

Procedure:
Using 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.18 g of 3-amino-5-mercapto-1,2,4-triazole as starting materials, 0.25 g of 4'-[[(5-amino-1,2,4-triazol-3-yl]thio]methyl]-2'-hydroxy-3'-propylacetophenone was obtained in a manner similar to Example 25.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[N:10]=[C:9]([CH3:15])[C:8]([CH3:17])([CH3:16])[NH:7][C:6]=2[N:5]=1.NC1N=C(O)C2N=C(CC)C(CCC)(CCC)NC=2N=1>C(O)(=O)C>[NH2:3][C:4]1[N:13]=[C:12]([OH:14])[C:11]2[N:10]=[C:9]([CH2:15][Cl:1])[C:8]([CH3:17])([CH3:16])[NH:7][C:6]=2[N:5]=1
Reactant: ClCl
Reactant: CC1=Nc2c(O)nc(N)nc2NC1(C)C
Agent: CCCC1(CCC)Nc2nc(N)nc(O)c2N=C1CC
Solvent: CC(=O)O
Product: CC1(C)Nc2nc(N)nc(O)c2N=C1CCl

Procedure:
A slight excess of chlorine was added with stirring to 2-amino-4-hydroxy-6-methyl-7,7-dimethyl-7,8-dihydropteridine, (II, X = Me, R1 =R2 =n-Pr) in glacial acetic acid, and the resulting precipitate was filtered off and washed with dry ether, and isolated analogously to the procedure described in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.CC([O-])(C)C.[K+].[C:19]([O:23][C:24]([N:26]1[C@@H:30]([CH3:31])[CH2:29]OS1(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24](=[O:25])[NH:26][C@@H:30]([CH3:29])[CH2:31][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C)n2C[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
5-Methoxy-2 methylindole (806 mg) was dissolved in DMF (25 mL) and cooled to 0° C. with an ice bath. Potassium tert-butylate (1M in THF, 6 mL) was added over 15 minutes and the resulting mixture was allowed to stir for further 30 minutes. (S)-4-Methyl-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester IV (1.42 g) was added in one portion and stirring was continued at RT until TLC analysis showed complete consumption of the starting material. The reaction mixture was partitioned between ether and saturated NH4Cl solution and the organic layer was separated, washed with sat. NH4Cl and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography (CH2Cl2). The appropriate fractions were combined and evaporated to give the product as an off-white solid (1.42 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][NH:7]1)=[O:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[N:7]2[C:12](=[O:17])[C:13]3[C:14]([C:15](=[O:16])[N:8]2[CH2:9][CH2:10][CH2:11]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)[C@@H]1CCCNN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Yield: 100 %

Procedure:
A solution of (S)-hexahydro-pyridazine-3-carboxylic acid methyl ester hydrochloride (Y. Nakamura, C. J Shin, Chem. Lett, 1991, 11, 1953-1956) (370 mg, 2.05 mmol), phthalic anhydride (318 mg, 2.15 mmol) and diisopropylethylamine (291 mg, 2.25 mmol) was heated in toluene (5 mL) for 2 h. The reaction mixture was then cooled and partitioned between ethyl acetate and dilute HCl. The organic phase was washed with saturated aq. NaHCO3, dried (MgSO4), filtered and evaporated. The residue was crystallised from hexane and filtered to afford the title compound as a white solid (562 mg, 82%): 1H NMR (400 MHz, CD3OD) δ 1.59 (1H, m), 1.96 (1H, m), 2.17 (1H, m), 2.55 (1H, m), 3.38 (1H, m), 3.70 (3H, s), 4.89 (1H, m), 5.74 (1H, m), 7.89 (2H, m), 8.16 (2H, m). 13C NMR (100 MHz, CD3OD) δ 21.2 (CH2), 25.7 (CH2), 46.0 (CH2), 53.8 (CH), 58.1 (CH3), 129.0 (CH), 129.1 (CH), 130.1 (C), 130.6 (C), 135.3 (CH), 135.7 (CH), 160.4 (C), 162.4 (C), 171.7 (C). Method N:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[O:17]1[CH2:21][CH2:20]OC1=O>CN(C=O)C>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:20][CH2:21][OH:17])[CH:6]=[O:7]
Reactant: O=C1OCCO1
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)ccc1OCCO
Temperature: 110 °C
Reaction time: 60 h

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (0.50 g, 3.67 mmol) in anhydrous DMF (8 mL) was added K2CO3 (1.01 g, 7.34 mmol) and 1,3-dioxolan-2-one (0.65 g, 7.34 mmol), and the mixture was stirred at 110° C. for 60 hours under nitrogen. DMF was removed under vacuum, the residue was diluted with water (50 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrate under vacuum to give 3-methyl-4-hydroxylethoxybenzaldehyde as a yellow oil. Yield: 0.60 g (91%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1Cl)[N:15]([NH:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25].[B:26]([F:29])([F:28])[OH:27]>CS(C)=O>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[N:15]([NH:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25].[B:26]([F:29])([F:28])[OH:27]
Reactant: CN1CCNCC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: OB(F)F
Solvent: CS(C)=O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 6.87 g of 4-methyl-piperazine and 7.26 g of an anhydride of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid formed with 36 ml of dimethyl sulfoxide is stirred at 110° C. for 3 hours. As the reaction proceeds yellow crystals precipitate gradually from the reaction mixture. The anhydride of 6-fluoro-1-methylamino-7-(4-methyl-piperazino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid thus formed is hydrolyzed without isolation from the reaction mixture as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(NC(C)=O)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.035 g, 0.103 mmol) in dimethylformamide (0.7 mL) was treated with N,N-diisopropylethylamine (0.018 mL, 0.103 mmol) followed by acetyl chloride (0.011 g, 0.134 mmol) and the reaction solution was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.52 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.74-7.78 (m, 2H), 7.65-7.67 (m, 1H), 7.62-7.67 (m, 2H), 7.43 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.71-4.76 (m, 4H), 3.16-3.21 (m, 2H), 2.04 (s, 3H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c(Cl)c1
Yield: 98.1 %

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (7.5 g, 50 mmol, 1.0 equiv), N-bromosuccinimide (9.14 g, 52 mmol, 1.1 equiv), and azobisisobutyronitrile (AIBN, 0.82 g, 5 mmol, 0.1 equiv) in carbon tetrachloride was heated to reflux temperature for 25 h. Water (50 mL) was added, and the product was extracted with CH2Cl2. The organic layers were washed with water, dried with MgSO4, and evaporated to provide 11.3 g of the title compound. This material was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C(O[Si](C)(C)C)(C#N)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:21]([C:20]([OH:23])=[O:22])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)OCCC2(C#N)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)OCCC2C(=O)O
Temperature: 130 °C
Yield: 78.1 %

Procedure:
To 7-methoxy-4-(trimethylsilyloxy)-3,4-dihydro-2H-chromene-4-carbonitrile (1.62 g, 5.84 mmol) in acetic acid (15 mL) and HCl (15 mL) was added SnCl2 dihydrate (5.27 g, 23.4 mmol). The reaction was heated at 130° C. for 1 day. The reaction was cooled, diluted with dichloromethane (50 mL) and washed with water (50 mL) and brine (50 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel using a gradient of 0.5% MeOH/CH2Cl2 containing 0.5% acetic acid to 10% MeOH/CH2Cl2 containing 0.5% acetic acid to provide the title compound (0.95 g, 78.1% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=O)[NH:22]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=[S:43])[NH:22]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=O)C2(C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=S)C2(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 1.189 g (2.71 mmol) of the 4-[3-(2-quinolinylmethoxy)benzyloxy]-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one obtained in Example 13, 1.076 g (2.71 mmol) of the Lawesson's reagent and 10 ml of toluene were added, followed by stirring at a bath temperature of 100° C. for 3 hours. After CHCl3 was added to dissolve the insoluble matter, the resulting solution was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from AcOEt, whereby 678 mg of the title compound were obtained as pale yellow powder (yield: 55.0%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[O:3]1.C(N(CC)CC)C.[Br:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[Br:34][CH2:35][C:36]([N:12]([CH2:11][C:10]1[C:4]2[O:3][C:2]([CH3:26])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:37]
Reactant: O=C(Cl)CBr
Reactant: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Cc2cccc(CN(C(=O)CBr)c3ccccc3Oc3ccccc3)c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine (0.20 g, 0.58 mmol) dissolved in DCM (2 mL) was added triethylamine (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) was added. The mixture was stirred at room temperature for 2 h. LC-MS indicated starting material and product (1:1). Further triethylamine (0.24 g, 2.32 mmol, 0.32 mL) and bromoacetyl chloride (0.18 g, 1.16 mmol, 0.10 mL) were added and stirred at room temperature for 2 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and EtOAc (B) (30% B, 80 g, 2.5 CV, 60 mL/min). The impure product was further purified by silica gel chromatography eluting with DCM (A) and EtOAc (B) (1-5% B, 80 g, 5 CV, 60 mL/min) to afford 170 mg (63%) of 2-Bromo-N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)acetamide as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:3]=1.[CH3:27]C(C)([O-])C.[K+].CI>CO>[CH3:27][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]1[C:12]1[CH:13]=[CH:14][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2nc(O)c3ccccc3n2)cc1)OCC
Agent: [K+]
Solvent: CI
Solvent: CO
Product: CCOP(=O)(Cc1ccc(-c2nc3ccccc3c(=O)n2C)cc1)OCC
Temperature: 40 °C

Procedure:
A 5.9 g quantity of diethyl 4-(4-hydroxyquinazolin-2-yl)benzylphosphonate, 1.8 g of potassium tert-butoxide and 2.3 g of methyl iodide were suspended in 100 ml of anhydrous methanol and stirred with heating at 40° C. for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol=100:1) and the crude crystals thus obtained were recrystallized from methylene chloride-n-hexane to provide 3.0 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].[BH4-].[Na+]>C(O)C.O>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[CH:4]([C:3]1[CH:15]=[C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:17]=[CH:18][C:2]=1[Cl:1])[OH:5]
Reactant: Cc1cc(C)c(C(=O)c2cc(-n3ccnc3)ccc2Cl)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2Cl)c(C)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
To a suspension of 10.9 g of 2-chloro-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 65 ml of ethanol is added a solution of 1.4 g of sodium borohydride in 14 ml of water. The mixture is stirred at 50° C. for 18 hours, and then the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 9.4 g of α-(2,4,6-trimethylphenyl)-2-chloro-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 206°-207° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[F:18][C:19]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:20]=1[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:18][C:19]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:20]=1[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Nc1cccc(Oc2c(F)c(F)c(F)c(F)c2F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Fc1c(F)c(F)c(Oc2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)c(F)c1F

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(2,3,4,5,6-pentafluorophenoxy)aniline (106 mg, 0.386 mmol) similar to Example 58 and isolated as a yellow solid (65 mg, 68%). 1H NMR (DMSO-d6): 10.46 (s, 1H), 9.24 (s, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.56–8.52 (m, 1H), 7.77 (s, 1H), 7.59–7.55 (m, 1H), 7.50–7.41 (m, 2H), 7.14 (s, 1H), 6.94–6.92 (m, 1H).
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7](=[CH2:12])[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: C=C(Cl)C(=O)OC
Reactant: NC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Cl)CSCC(N)=O
Yield: 85.8 %

Procedure:
2-Mercaptoacetamide (10.0 g) and methyl 2-chloroacrylate (13.24 g) were dissolved in warm acetone (100 ml), and potassium carbonate (7.58 g) was added in one portion. Heat was evolved. The mixture was heated to reflux for 2 hours. The red solution was filtered hot using a filter aid, and the residue washed with hot acetone (×2). The filtrate and washings were combined and evaporated to obtain the title compound as a red oil (19.92 g) 1H n.m.r. δ (CDCl3 /DMSO-d6) 3.05-3.18 (4H, overlapping s and d, CH2COR and CH2CH) 3.76 (3H,s,CO2Me), 4.67 (1H,t, J=7Hz, CHCH2), 6.92 (1H, br s, CONH), 7.43 (1H, br s, CONH).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[CH:2]1.[NH2:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[S:1]1[CH:5]=[C:4]([CH:6]=[N:8][CH:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[N:3]=[CH:2]1
Reactant: O=Cc1cscn1
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccccn1
Product: CC(C)(C)OC(=O)C(Cc1ccccn1)N=Cc1cscn1

Procedure:
Prepared in a similar manner to that described for Intermediate 1, replacing 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride with 2-amino-3-(2-pyridyl) propionic acid, tert-butyl ester.