Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1.Cl>CN(C)C=O>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[C:6](=[O:19])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:18])=[C:25]([F:31])[CH:24]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reactant: Fc1cc(Br)ccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of ethyl 2-(7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (176 g) in N,N-dimethylformamide (3.5 l) was added sodium hydride (60% in mineral oil, 32.3 g) at 0° C. and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added a solution of 4-bromo-2-fluorobenzyl bromide (200 g) in N,N-dimethylformamide (100 ml) below 20° C. over a 20-minute period and the resulting mixture was stirred at room temperature for 1 hour. 3N Aqueous hydrochloric acid (62.2 ml) was added to the mixture below 15° C. and the solvent was evaporated in vacuo. The residue was poured into a mixture of ethyl acetate (3 l) and water (3 l), and the resulting mixture was stirred for 15 minutes. The precipitates were filtered off and the organic layer was separated. The solution was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized with addition of isopropyl ether and the crystals were collected by filtration and washed with isopropyl ether. The crude crystals and the precipitates were mixed and recrystallized from a mixture of ethyl acetate (0.9 l) and n-hexane (0.9 l) to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (251 g).
Reaction SMILES: [CH:1](O)([OH:5])[C:2]#[C:3][CH3:4].[CH2:7]=[O:8].[CH:9]([OH:14])([OH:13])[CH2:10][CH2:11][CH3:12]>>[CH3:4][CH:3]([CH2:2][CH2:1][OH:5])[CH2:7][OH:8].[CH:9]([OH:14])([OH:13])[CH2:10][CH2:11][CH3:12]
Reactant: CC#CC(O)O
Reactant: C=O
Agent: CCCC(O)O
Product: CC(CO)CCO

Procedure:
As described in detail in copending application Ser. No. 924,212, filed July 12, 1978, (FDN-1113), the catalyst of the invention will produce high quality butanediol by a process involving a two-stage catalytic hydrogenation of a butynediol solution containing formaldehyde. During the first stage of the process, or low pressure, low temperature stage, a butanediol product having a much lower carbonyl number is obtained. The carbonyl number is the conventional measure of the undesired aldehyde and acetal content including residual formaldehyde. In the second or finishing stage, which is carried out at higher pressures and/or temperatures than the first stage, much less 2-methyl-1,4-butanediol byproduct (methylbutanediol) is produced concurrently with butanediol.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:18])[CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Yield: 78.6 %

Procedure:
1-([1,1′-Biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole (1.03 g, 3.3 mmol) was alkylated by treating with 0.31 mL (3.3 mmol) of methyl bromoacetate and 132 mg (3.3 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.0 g (79% yield) of [[1-([1,1′-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 99-102° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@@H:9]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH3:42])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[ClH:50].C(OCC)C>C(Cl)Cl.C(OCC)C>[NH2:8][C@@H:9]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH3:42])=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[ClH:50]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
150 ml TFA are added to 30 g BOC-(D)Trp-Lys(Z)-OMe in 150 ml methylene chloride pre-cooled to 0° C. The whole is stirred for 40 minutes at room-temperature and then added to 30 ml HCl/ethyl-ether (~5 N) in 4 l ethyl-ether. After thorough stirring the precipitate is filtered off, washed with ethyl-ether and dried to yield the title compound:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br-].[CH:20]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=3)=[CH:4][C:3]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: [Zn+]C1CCCC1
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cncc(C)c2)cnc1C1CCCC1
Temperature: 90 °C

Procedure:
To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate (6-1, 0.15 g, 0.57 mmol, 1.0 equiv, prepared in an analogous fashion to Examples 2 and 8) in dioxane (2.9 mL) at 25° C. was added cyclopentylzinc bromide (3.43 mL, 1.71 mmol, 3.0 equiv, 0.5 M in THF) and tetrakis(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol, 0.15 equiv). The reaction mixture was heated for 3 h at 90° C. The reaction mixture was cooled partitioned between water (10 mL) and EtOAc (30 mL), washed with water (3×30 mL) and brine (1×30 mL), and the organic phase was dried over magnesium sulfate. The residue was purified via normal phase chromatography (5 to 100% EtOAc in hexanes, silica) to afford the desired product (6-2) as an oil after concentration. ESI+MS [M+H]+ C18H20N2O2 calc'd 297.2, found 297.1
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:26])[NH:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[N:18]=2)=[O:16])[CH2:10]1.[C:27]1([N:33]2[CH:37]=[N:36][C:35]([C:38](O)=[O:39])=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([C:19]1[N:18]=[C:17]([C:15]([N:11]2[CH2:12][CH2:13][N:14]([C:38]([C:35]3[N:36]=[CH:37][N:33]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:34]=3)=[O:39])[C:9]([CH3:26])([CH3:8])[CH2:10]2)=[O:16])[CH:22]=[CH:21][CH:20]=1)([CH3:24])[CH3:25]
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: CC(C)c1cccc(C(=O)N2CCNC(C)(C)C2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)n1
Temperature: 25 °C

Procedure:
A mixture of 55 mg (0.15 mmol) (3,3-dimethyl-piperazin-1-yl)-(6-isopropyl-pyridin-2-yl)-methanone trifluoroacetate, 28 mg (0.15 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid, 52 mg (0.16 mmol) TBTU and 0.10 mL (0.61 mmol) DIPEA in 1.5 mL DMF was stirred at RT over the weekend. The reaction mixture was purified by HPLC.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O.CCOC(C)=O>C1COCC1.O>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:42][C:43]([F:46])([F:45])[F:44])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2c(C)cc3cn(CC(F)(F)F)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and NaH (60%) (67 mg, 1.6 mmol) in THF (5 mL) was stirred for 1 hour at ambient temperature, and was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 mg, 1.06 mmol). The resulting reaction mixture was stirred for 4 hours at 60° C. AcOEt and water was added. The phases were separated. The aqueous layer was extracted with AcOEt. The organic layers were washed with water, combined, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, Toluene/AcOEt 7:3) afforded the title compound as a colorless crystalline solid. M.p. 178-181° C., LC/MS: 550 (M+H)+, 572/574 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH:10]=[C:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1.[H][H].C(OCC)C>C(OCC)(=O)C.[Pt]>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH2:10][CH:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3c2nc(C)cs2)c1

Procedure:
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate M) (100 mg, 0.24 mmol) was dissolved in ethyl acetate (20 mL) and the resulting solution was hydrogenated using the H-Cube® (10% platinum on carbon CatCart®), at atmospheric pressure of hydrogen and 20° C., for 6.5 hours. The solvent was removed under vacuum. The crude material was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to obtain a gum. Diethyl ether was added and removed under vacuum to give the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH2:45]Cl)[CH:42]=[CH:41][C:40]=1[Cl:47])[CH:36]=[CH2:37]>>[CH2:35]([O:38][C:39]1[CH:44]=[C:43]([CH:42]=[CH:41][C:40]=1[Cl:47])[CH2:45][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH:36]=[CH2:37]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: C=CCOc1cc(CCl)ccc1Cl
Product: C=CCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl

Procedure:
Analogously to Method D, 2.00 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 2-allyloxy-1-chloro-4-chloromethylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.18 (1:4 EtOAc-heptane); Rt=6.44.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.C[N:27]1[C:31](=[O:32])C[CH2:29][CH2:28]1.N1C=CC=CC=1.N(CC)=C=O>O.C(#N)C>[Br:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:31]([NH:27][CH2:28][CH3:29])=[O:32])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: CCN=C=O
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCNC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.150 g, 0.366 mmol; Example 98, Step A) was placed in 1:1 NMP:pyridine (2 mL total volume). Isocyanatoethane (0.146 mL, 1.83 mmol) was then added, and the reaction was stirred at room temperature for 30 minutes and then concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 5:95 ACN in water) to give (R)-tert-butyl 1-(5-bromo-3-(3-ethylureido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.130 g, 74% yield).
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH:1]([OH:3])=[O:2].[CH2:44]([N:11]([C:10]1[C:5]([NH2:4])=[N:6][C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:8][C:9]=1[NH2:16])[C:12](=[O:15])[O:13][CH3:14])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.22 mmol) of methyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate were initially charged in THF (0.94 ml), and 44.4 mg (0.24 mmol) of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After 30 min at 0° C., 52 μl (0.44 mmol) of benzyl bromide were added and the mixture was stirred at 20° C. for 20 hours. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 105 mg of the target compound (87% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][O:23][CH3:24])=[C:6]([CH:20]=1)[CH:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[CH:12][N:11]=1)C#N.C(=O)([O-])[O-:26].[K+].[K+].CN(C=O)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][O:23][CH3:24])=[C:6]([CH:20]=1)[C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:26]
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(Br)cc1C(C#N)c1ncccc1OCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1C(=O)c1ncccc1OCOC
Temperature: 25 °C
Reaction time: 38 h
Yield: 87 %

Procedure:
A mixture of 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (2.40 g), potassium carbonate (2.53 g), tetrabutylammonium hydrogensulfate (0.41 g) and DMF (24 ml) was stirred for 38 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous sodium sulfate), and concentrated to leave an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (2.03 g) as an oily product, whose spectrum data are shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Al+3].[Cl-].[Cl-].[Cl-].ClC1C=C2C(=CC=1Cl)N(CC(O)=O)C(=O)C=C2>>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:9][C:10](=[O:19])[CH:11]=[CH:12]2
Reactant: Cc1ccc(NC(=O)/C=C/c2ccccc2)cc1C
Agent: O=C(O)Cn1c(=O)ccc2cc(Cl)c(Cl)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc2ccc(=O)[nH]c2cc1C
Reaction time: 2 h

Procedure:
A mixture of (2E)-N-(3,4-dimethylphenyl)-3-phenyl-2-propenamide (5.86 g, 23.3 mmol) and AlCl3 (15.6 g, 116.57 mmol) was heated slowly until the mixture became liquefied and then subsequently congealed to form a solid cake. Ice was slowly added to break up the hardened material. The mixture was vigorously stirred for 2 h. The solid material was collected and washed with 2 N HCl solution, water, and ether to obtain a white mixture of product A and B above (3.8 g, 94%), MS (ES) m/e 176 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[CH:9]2)=[CH:4][C:3]=1[F:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1(C(F)(F)F)C=CC=CC=1>[C:14]([NH:18][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Reactant: CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)Nc1nccc2cc(F)c(Cl)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 4.3 %

Procedure:
A solution of 5.0 g (25.3 mmol) of 7-chloro-6-fluoro-isoquinoline 2-oxide (9) in 120 mL of benzotrifluoride was treated with 15.9 mL (11.1 g, 152 mmol) of tert-butylamine and cooled to 0° C. Then, 17.3 g (53.1 mmol) of p-toluenesulfonic anhydride were slowly added portionwise with temperature control (<10° C.). The reaction mixture was stirred at room temperature for 16 h, before being cooled to 0° C. and another 8.0 mL (76.1 mmol) of tert-butylamine and 8.26 g (25.3 mmol) of p-toluenesulfonic anhydride were added. The reaction mixture was stirred for 24 h at room temperature, then concentrated and partitioned between 120 mL of water and 150 mL of dichloromethane. The phases were separated and the organic phase was washed eight times with 3N aqueous sodium hydroxide, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified twice by silica gel chromatography (dichloromethane:methanol) to give 277 mg of pure desired product (61) and 714 mg of the product slightly contaminated with p-toluenesulfonic acid. Rt=2.35 min (Method C). Detected mass: 253.1 (M+H+).
Reaction SMILES: BrC1SC=C(CCl)N=1.CNC.Br[C:13]1[S:14][CH:15]=[C:16]([CH2:18][N:19]([CH3:21])[CH3:20])[N:17]=1.[CH2:22]=[O:23]>C(O)C>[CH3:20][N:19]([CH2:18][C:16]1[N:17]=[C:13]([CH2:22][OH:23])[S:14][CH:15]=1)[CH3:21]
Reactant: C=O
Reactant: CN(C)Cc1csc(Br)n1
Agent: CNC
Agent: ClCc1csc(Br)n1
Solvent: CCO
Product: CN(C)Cc1csc(CO)n1

Procedure:
When 2-bromo-4-chloromethylthiazole [prepared according to the procedure described in Rev. Roumaine Chim., 10, 897 (1965) (C. A., 64, 8164b 1966)] is reacted with an ethanol solution of dimethylamine and the resultant 2-bromo-4-dimethylaminomethylthiazole is treated with a strong base and formaldehyde according to the general procedure described in Acta Chem. Scand., 20, 2649 (1966) there is produced 4-dimethylaminomethyl-2-hydroxymethylthiazole. When that compound is reacted with thionyl chloride to produce 2-chloromethyl-4-dimethylaminomethylthiazole, and the latter compound is reacted according to the general procedure of Example 15, the title compound is thereby produced.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16]
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc(C)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-methylbenzothiazole (4.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.1 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.CO.[NH3:32]>>[I:11][C:9]1[N:10]=[C:2]([NH2:32])[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=1)[C@@H:12]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 90 %

Procedure:
6.0 g of 6-chloro-2-iodo-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine was added to 60 ml of methanol/ammonia (saturated at 0° C.) to cause reaction at a temperature of 60° C. for 17 hours in a sealed tube. The reaction solution was cooled, then degassed, and concentrated under reduced pressure. Crystallization of the residue from water afforded 3.94 g of 2-iodoadenosine (90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[F:9])[NH2:5].[CH3:11][O:12][C:13](=[O:20])[C:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>>[CH3:11][O:12][C:13](=[O:20])[C:14]([CH3:16])([CH3:15])[NH:17][C:18](=[O:19])[NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([F:9])=[C:7]([Cl:10])[CH:6]=1
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Reactant: COC(=O)C(C)(C)N=C=O
Product: COC(=O)C(C)(C)NC(=O)Nc1cc(Cl)c(F)c(Cl)c1

Procedure:
3-(3,5-dichloro-4-fluoro-phenyl)-5,5-dimethylhydantoin, which melts at 175°-176°, is obtained in the manner indicated in Example 1 from 3,5-dichloro-4-fluoro-aniline and 2-isocyanato-2-methylpropionic acid methyl ester and after crystallizing from ether/petroleum ether. The N-[(3,5-dichloro-4-fluorophenyl)-carbamoyl]-2-methylalanine methyl ester intermediately formed is not isolated.