Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[F:19][C:20]([F:24])=[C:21](F)[F:22]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:21]([F:22])=[C:20]([F:24])[F:19])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: FC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(OC(F)=C(F)F)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 10 g of p-(trans-4-n-propylcyclohexyl)phenol in a mixture of 40 ml of benzene and 10 ml of tetrahydrofuran is reacted with sodium hydride analogously to Example 1. After tetrafluoroethene has been condensed in, the mixture is heated at 140° C. for about 20 hours and treated as described in Example 1. p-(trans-4-n-propylcyclohexyl)trifluorovinyloxybenzene is obtained.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21][Cl:22])=[CH:14][CH:13]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:22][CH2:21][CH2:20]/[C:19](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:18](/[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][CH:16]=1)\[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
Z-1-[4-(2-benzyloxyethoxy)-phenyl]-4-chloro-1,2-diphenyl-but-1-ene (36 g, 0.08 mol) was dissolved in the mixture of ethyl acetate (350 ml) and ethanol (350 ml). Palladium on carbon (5%, 0.28 g) was added and the solution was flushed with hydrogen gas until there was not any starting compound left (thin layer chromatography). Palladium on carbon was filtered off through siliceous earth and the filtrate was evaporated. The residue was crystallized from the mixture of ethanol (155 ml) and water (65 ml). Yield 20 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>COCCOCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>[N:9]1([NH:8][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: Nn1cccc1
Reactant: Clc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: c1ccn(Nc2ccncc2)c1
Yield: 57.1 %

Procedure:
A solution of 4-chloropyridine (15 g) and N-aminopyrrole (18 g) in 225 ml of diglyme was stirred at 150° C. for one hour and thereafter cooled, diluted with water and basified with sodium carbonate. The mixture was extracted with ethyl acetate, and the organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. This oil was purified by high performance liquid chromatography (HPLC hereafter) using silica gel and ethyl acetate to give 12 g of a solid, m.p. 150° C. Five grams of the solid was recrystallized twice from benzene to give 2.8 g of crystals, m.p. 153°-154° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:28]=[CH:27][C:10]2[N:11]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:12]=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3].[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[CH2:1]([O:4][C:5]([C:7]1[CH:28]=[CH:27][C:10]2[N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[N:13][C:9]=2[CH:8]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc2c(c1)nnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)c1ccc2c(c1)nnn2C1CCNCC1

Procedure:
A solution of 1-(1-tert-butoxycarbonyl-piperidin-4-yl)-1H-benzotriazole-5-carboxylic acid allyl ester (1.40 g, 3.62 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 287.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 402.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][OH:22]>>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][O:22][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cccc(F)c1F
Product: CN1CCn2c1cc(OCc1cccc(F)c1F)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH:24][C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH:1]1([N:4]([CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:22]/[CH:23]=[CH:24]/[C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:2][CH2:3]1
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CC(=O)c1cccc(CNC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C2CC2)c1
Yield: 60.6 %

Procedure:
3′-(N-cyclopropylaminomethyl)acetophenone (0.35 g; 1.85 mmol) and potassium carbonate (0.36 g; 2.64 mmol) were added to N,N-dimethylformamide (15 ml). While the mixture was stirred in an ice bath, 1-bromo-6,6-dimethyl-2-hepten-4-yn (0.35 g; 1.76 mmol) in N,N-dimethylformamide (5 ml) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 18 hours at room temperature. The mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.33 g of the target compound (yield: 60.6%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])=[N:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=4)[N:18]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c(N3CCC[C@@H]3C)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[1-[(tert-butoxy)carbonyl]-1H-indazol-5-yl]-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (105 mg, crude) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (4 mL), The solution was stirred for 3 h at room temperature and concentrated under vacuum. The residue was quenched by the addition of water (50 mL) and adjusted pH to 9 with NaHCO3 (aq.), extracted with dichloromethane (3×30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a light yellow solid (69 mg, crude).
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][C@H:6](Cl)[CH2:5][N:4]1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:19][NH2:20]>CO>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([N:4]2[CH2:5][C@H:6]3[CH2:7][C@@H:3]2[CH2:2][N:20]3[CH3:19])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](Cl)C[C@@H]2CCl)cc1
Reactant: CN
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3C)cc1
Temperature: 110 °C
Yield: 90 %

Procedure:
A Parr bottle was charged with 0.5 g (1.29 :mmol) of (2R,4S)-2-chloromethyl-4-chloro-1-(4-toluenesulfonyl)pyrrolidine and 6 ml of methanol and the bottle was tared. Methylamine gas was then bubbled through the methanol solution until 0.4 g (12.9 mol) of the gas had dissolved. The bottle was then sealed and heated to 110° C. After heating for 16 hours, the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were partitioned between 50 ml of methylene chloride and 40 ml of 10% aqueous NaOH solution. The layers were separated and the organic layer was washed with 40 additional milliliters of 10% aqueous NaOH solution, and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 309 mg of the desired product which represents a 90% yield. M.P.=82°-87° C. [α]D =-16.8° (c=1.038, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:3]4[C:2]([Cl:1])=[CH:6][N:5]([CH2:7][CH3:8])[N:4]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1cc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n1
Temperature: 79 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A dry flask was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid (0.179 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.227 g, 0.560 mmol, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18].[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:7]1[C:2]([Cl:1])=[C:3]([C:17]#[N:18])[C:4](=[O:16])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:6]=1
Reactant: N#Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Cl)c(Br)cn(-c2c(F)cccc2F)c1=O
Temperature: 50 °C
Yield: 43.8 %

Procedure:
To a solution of 4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (670 mg) in N,N-dimethylformamide (5.0 mL) was added N-bromosuccinimide (548 mg) at room temperature. The reaction mixture was heated at 50° C. for 4 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)#[N:2].C(OCC)(=O)C>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CN)c1
Reaction time: 12 h
Yield: 99.2 %

Procedure:
The product of step B (100 mg, 0.201 mmol) was diluted with 7N ammonia/methanol (10 mL), followed by addition of ethyl acetate (10 mL). Once the material dissolved, Raney Nickel (1.72 mg, 0.0201 mmol) was added and the reaction was purged three times with a balloon of hydrogen. After stirring for 12 hours, the reaction mixture was filtered through a GF/F filter and concentrated. The residue was purified using a biotage 12i column eluting with methylene chloride:MeOH:NH4OH (90:9:1) to yield tert-butyl 2-(3-(aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (100 mg, 99.2% yield) as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:29]3[C:30]4[O:35][CH2:34][CH2:33][O:32][C:31]=4[CH:36]=[CH:37][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:38]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:29]3[C:30]4[O:35][CH2:34][CH2:33][O:32][C:31]=4[CH:36]=[CH:37][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:38]
Reactant: O=C1Nc2ccccc2C12COc1ccc3c(c12)OCCO3
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1ccc3c(c12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one was obtained (38%) as a colorless solid: mp 132-134° C.; 1H NMR (300 MHz, CDCl3) δ8.60 (d, J=1.2 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.38-7.13 (m, 4H), 7.01 (dd, J=7.2, 7.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 5.38 (d, J=16.2 Hz, 1H), 4.96-4.83 (m, 2H), 4.65 (d, J=8.7 Hz, 1H), 4.17-3.86 (m, 4H); 13C NMR (75 MHz, CDCl3) δ176.6, 156.0, 155.9, 149.4, 141.7, 139.6, 138.0, 136.7, 131.5, 128.6, 123.5, 123.2, 122.6, 121.4, 118.1, 115.7, 109.2, 102.4, 81.4, 64.5, 63.8, 57.2, 46.2; MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][CH3:26])[CH:18]=2)[C:12]([C:27]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)=[O:28])=[CH:11][N:10]=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([N:25]([S:41]([CH3:44])(=[O:43])=[O:42])[CH3:26])[CH:18]=2)[C:12]([C:27]([C:29]2[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=2)=[O:28])=[CH:11][N:10]=1
Reactant: CNc1cc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)ccc1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-pyridylmethoxy)-5-(3,4,5-trimethoxyphenyl-carbonyl)-4-(3-metylamino-4-methoxybenzylamino)pyrimidine (prepared in Example 48) 42 mg in methylene chloride 3 ml are added mesyl chloride 48 mg and triethylamine 69 mg, for three times at one hour intervals. The reaction mixture is stirred for 1 hour at room temperature. Ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution is added thereto. The organic layer is separated, washed with brine and dried over anhydrous sodium sulfate. After filtration of sodium sulfate the filtrate is concentrated in vacuo and the residue is purified by preparative thin-layer chromatograph (2 plates, solvent:ethyl acetate) to give 2-(2-pyridylmethoxy)-5-(3,4,5-trimethoxyphenylcarbonyl)-4-[4-methoxy-3-(N-methylmethansulfonylamino)benzylamino]pyrimidine as a colorless amorphous 20 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11](Cl)=[N:10]1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:22]2[CH:26]=[N:25][C:24]([C:27]#[N:28])=[N:23]2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(Cl)=NC1c1ccc(F)cc1Br
Reactant: N#Cc1nc[nH]n1
Product: CCOC(=O)C1=C(C)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 49.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-chloro-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3.77 g, 10 mmol) was reacted with 1H-1,2,4-triazole-3-carbonitrile (2.82 g, 30 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a pale yellow solid (2.16 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=C([CH:11]=[CH:12][CH:13]=1)C#N)=[O:5].S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([C:6]2[CH:7]=[C:31]([CH:11]=[CH:12][CH:13]=2)[C:30]([OH:33])=[O:32])=[O:5])=[C:2]([CH3:1])[CH:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(C)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(C)c1
Temperature: 0 °C

Procedure:
Anhydrous aluminium chloride (38.35 g) is added to a solution of the acid chloride prepared from 3-cyanobenzoic acid (36.3 g) as described in Example 26 and nitrobenzene (200 ml). A solution of 3-n-hexyloxytoluene (39.5 g) in nitrobenzene (50 ml) is added and the resulting mixture heated to 110°-120° C. for 3 hours. The reaction mixture is cooled and poured into a mixture of ice water (1,000 ml) and concentrated hydrochloric acid (100 ml). The mixture is extracted with ether (3×300 ml) and the combined extracts concentrated and the nitrobenzene removed by steam distillation. The resulting residue is dissolved in ether, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether; 70:30) to yield 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile (21.1 g) as a dark brown oil and 3-(2-hydroxy-4-methylbenzoyl)benzonitrile, which is recrystallized from ethanol to give 5.78 g as a yellow solid (m.p. 126°-128°C.). The 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile thereby obtained is heated under reflux in a mixture of acetic acid (160 g) and a solution of 75% sulfuric acid (160 g) for 1 hour. The cooled mixture is then poured into ice water (500 ml) and extracted with ether (3×200 ml). The extract is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether:acetic acid; 50:50:1). The main fraction is collected and concentrated in vacuo. The residual yellow solid is crystallized from heptane to yield 3-(4-n-hexyloxy-2-methylbenzoyl)benzoic acid (9.62 g) as yellow needles m.p. 136°-138° C.
Reaction SMILES: [C:1]1([S:7][CH:8]2[N:11]([CH2:12][C:13](=[O:22])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:23])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([S:7]([CH:8]2[N:11]([CH2:12][C:13](=[O:22])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:23])[CH2:9]2)=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 27 %

Procedure:
A solution of 4-phenylthio-N-(4-phenyl-2-oxobutyl)azetidin-2-one (2.3 g, 7 mmol) in dichloromethane (80 ml) was cooled to -50 to -60° C. and a solution of m-chloroperbenzoic acid (1.5 g, 9 mmol) in dichloromethane (60 ml) was added dropwise with stirring over 40 min. After a further 2 hr. at -50 to -60° C. another portion of m-chloroperbenzoic acid (61 mg, 0.35 mmol) was added and stirring continued for 30 min. The reaction mixture was then shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate and the organic layer collected, dried (MgSO4) and evaporated. Crystallisation from ether then dichloromethane/ether gave the product as a white crystalline solid, mp 125-6° C., 27% yield 1H NMR δ (CDCl3), 2.78 (2H, m, CH2CO), 2.87 (1H, dd, J=4.7, 15.0 Hz, H3a), 2.94 (2H, m, CH2Ph), 3.42 (1H, dd, J=2.0, 15.0 Hz, H3b), 3.85, 4.46 (each 1H, d, J=18.9 Hz, CH2N), 4.73 (1H, dd, J=2.1, 4.7 Hz, H4), 7.17-7.35 (5H, m, Ph--H), 7.55 (5H, s, SOPh--H). Found: C, 66.7; H, 5.7; N, 4.2%; C19H19NO3S requires: C, 66.8; H, 5.6; N, 4.1%
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]1=[O:21].[Cl:22][C:23]1[S:24][C:25]([CH:29]=[O:30])=[C:26]([Cl:28])[N:27]=1.CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C>C1COCC1.C(O)(=O)C>[Cl:22][C:23]1[S:24][C:25]([CH:29]([OH:30])[C:10]2[S:11][C:5]3[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3](=[O:21])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[C:9]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:26]([Cl:28])[N:27]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(O)c2sc(Cl)nc2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Yield: 18.9 %

Procedure:
To a solution of ethyl 3-methyl-1-(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-5-carboxylate (1.5 g), 2,4-dichlorothiazole-5-carboxaldehyde (1.75 g) and DMPU (1.2 ml) in THF (25 ml) at −78° C., was added LDA (10 mmol). Acetic acid (3 ml) was added and the mixture allowed to warm to ambient temperature. The mixture was then partitioned between ethyl acetate and water, the organics were collected, dried over magnesium sulphate and concentrated to dryness. The residue was purified by normal phase chromatography (3:1 i-hexane:ethyl acetate) to give the sub-title compound as a yellow foam (0.45 g).