Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[C:16]=2[F:25])[CH2:11][CH2:10]1)[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:17]([F:24])[C:16]=2[F:25])[CH2:13][CH2:14]1)[CH3:8]
Reactant: Brc1ccc[se]1
Reactant: CCC1CCC(c2ccc(B(O)O)c(F)c2F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC1CCC(c2ccc(-c3ccc[se]3)c(F)c2F)CC1

Procedure:
A mixture of 8.9 g (42.4 mmol) of 2-bromoselenophene, 16.0 g (59.7 mmol) of 4-(4-ethylcyclohexyl)-2,3-difluorophenylboronic acid, 3.93 g (3.40 mmol) of tetrakis(triphenylphosphine)palladium(0) and 125 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium chloride soln., and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from n-heptane:EtOH=1:1 and IPA. 2-[4-(4-Ethylcyclohexyl)-2,3-difluorophenyl]selenophene is obtained as a pale-yellowish solid.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(OC)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:17]1([CH2:16][N:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(OC)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1cc(NCC2CCCC2)ccc1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1cc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)ccc1F

Procedure:
The title compound was prepared via {2-[3-(4-fluoro-3-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-fluoro-3-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].O.[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([O:9]C)=[O:8].Cl>C(O)C>[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([OH:9])=[O:8]
Reactant: COC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 g. (12.5 mmol) of sodium hydroxide in 4 ml. of water was added to a solution of 1.0 g. (3 mmole) of methyl 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoate in 10 ml. of absolute ethanol. The mixture was stirred at 45° C. for 4 hours. The solution was cooled to room temperature, acidified with 3N hydrochloric acid and filtered. The crude orange solid was purified by silica gel chromatography, eluted with hexane-ethyl acetate (3:5 parts by volume) and crystallized from hexane-ethyl acetate (1:1 parts by volume) to give 600 mg. (62% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid orange crystals, m.p. 217°-223° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C@H:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH3:2].[NH:8]1[CH2:9][CH2:10][C@H:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OCCC#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N
Product: N#CCCO[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %
Yield: 120 %

Procedure:
To a stirred solution of (3S)-3-(2-cyanoethoxy)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (Example 107(a)) (1 g) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 30 minutes and then concentrated. Purification (Varian SCX cartridge, using methanol and then 10% ammonia in methanol as eluant) gave the sub-title compound (350 mg).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:32][N:33]([CH3:35])[CH3:34]>C(O)C>[CH3:30][S:27]([O-:29])(=[O:28])=[O:26].[CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][N+:33]([CH3:35])([CH3:34])[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCCCCCCCCCCC)COCCCCOS(C)(=O)=O
Reactant: CN(C)C
Solvent: CCO
Product: C=C(COCCCCCCCCCCCCCCCC)COCCCC[N+](C)(C)C
Product: CS(=O)(=O)[O-]

Procedure:
1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (from Preparation 7) (1.77 g) was refluxed with 33% trimethylamine in ethanol at 50° C. for 4 hours. Excess trimethylamine and ethanol were removed in vacuo. The product was recrystallized from chloroform/acetone.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH2:27][CH2:28][OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[CH3:30][NH2:31]>C(O)C>[ClH:25].[CH3:30][NH:31][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH2:27][CH2:28][OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCC(OCCO)c2cccc(Cl)c2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)COc1ccc(CC(C)NCC(OCCO)c2cccc(Cl)c2)cc1
Product: Cl

Procedure:
A mixture of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine (4.0 g) and 33% methylamine in ethanol (50 ml) was heated under reflux for 1.5 h. The mixture was evaporated under reduced pressure and the residue converted to its hydrochloride by addition of ethereal hydrogen chloride. Recrystallisation from ethyl acetate-methanol gave the title compound, mp. 117°-121° C. as a 56:44 mixture of diastereoisomers.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N+:15]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)([O-:17])=[O:16].O>CN(C=O)C>[CH2:1]([N:19]1[CH:20]=[CH:21][N:22]=[C:18]1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1nccn1Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Benzylbromide (3 mmol) and K2CO3 (6 mmol) were added to a solution of 2-nitroimidazole (2 mmol) in DMF (6 mL). The mixture was stirred at 60-70° C. for 4 h or overnight. The contents were cooled to room temperature, and water (30 mL) was added. The mixture was extracted with EtOAc (3×15 mL). The combined extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo to afford 1-benzyl-2-nitro-1H-imidazole. The product used for further transformation without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O>N1CCCCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60° C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M−1]+., 100).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([O:30]CC)=O)=[N:22][C:21]=2[S:20][CH:19]=1.Cl.N1C=NC(SCCOC2C=C(CN)C=CN=2)=N1.[C:51]1([C:57]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[N:58]2[CH:62]=[N:61][C:60]([S:63][CH2:64][CH2:65][O:66][C:67]3[CH:72]=[C:71]([CH2:73][NH2:74])[CH:70]=[CH:69][N:68]=3)=[N:59]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH3:17][C:18]1[C:26]2[C:25](=[O:27])[NH:24][C:23]([C:28]([NH:74][CH2:73][C:71]3[CH:70]=[CH:69][N:68]=[C:67]([O:66][CH2:65][CH2:64][S:63][C:60]4[N:61]=[CH:62][N:58]([C:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)([C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=5)[C:81]5[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=5)[N:59]=4)[CH:72]=3)=[O:30])=[N:22][C:21]=2[S:20][CH:19]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: NCc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: Cl
Agent: NCc1ccnc(OCCSc2nc[nH]n2)c1
Product: Cc1csc2nc(C(=O)NCc3ccnc(OCCSc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 19, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 and using, instead of 1-(2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridin-4-yl)methanamine hydrochloride, 1-{2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridin-4-yl}methanamine obtained in Reference Example 20, 5-methyl-4-oxo-N-({2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridin-4-yl}methyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide was obtained as a white powder (85 mg, 20%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using a similar procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (0.1 g) was reacted with oxalyl chloride (0.093 ml) and DMF (3 drops) in methylene chloride (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 2-(4-benzyloxy-2-methoxyphenyl)acetyl chloride. A mixture of the material so obtained, 3-amino-4,5-dimethylisoxazole (0.062 g), diisopropylethylamine (0.065 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml) was stirred at ambient temperature for 14 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained N-(4,5-dimethylisoxazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.77 (s, 3H), 2.28 (s, 3H), 3.55 (s, 2H), 3.74 (s, 3H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.09 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 367.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41].C(Cl)CCl>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:20]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 75 (0.270 g, 0.83 mmol) and Intermediate 3 (0.192 g, 0.75 mmol) in ACN (2 mL) was added EDC (0.201 g, 1.05 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2 mL) and heated at 150° C. under microwave irradiations for 45 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.43 (1H, d, J=1.8 Hz), 8.21 (1H, d, J=1.7 Hz), 8.17 (1H, dd, J=7.9, 1.9 Hz), 8.08 (1H, dd, J=8.0, 1.7 Hz), 7.72 (1H, d, J=8.0 Hz), 7.35-7.21 (4H, m), 7.13 (1H, d, J=7.4 Hz), 4.29-4.17 (2H, m), 3.90 (2H, s), 3.33 (3H, s), 3.29 (2H, s), 2.46 (3H, s), 2.08 (3H, s), 1.50 (9H, s).
Reaction SMILES: [C:1]([C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[C:7](=[O:20])[C:6]3=[CH:5][CH:4]=1)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].CN(C)C=O>C(O)(=O)C.O>[CH3:16][CH:11]1[N:10]2[C:15]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]4[NH:23][N:22]=[N:21][N:2]=4)[C:14]=3[CH2:13][CH2:12]1)[C:7](=[O:20])[C:8]([C:17]([OH:19])=[O:18])=[CH:9]2
Reactant: CC1CCc2c(C#N)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1CCc2c(-c3nnn[nH]3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C

Procedure:
A mixture of 1.4 g (5 mmole) of 8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.75 g (11 mmole) of sodium azide, 0.6 g (11 mmole) of ammonium chloride and 50 ml of N,N-dimethylformamide was heated at 120° C. for three days in a sealed vessel followed by decantation into 100 ml of water. To this mixture was added 2 ml of glacial acetic acid, and the mixture was cooled. The solid was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide white needles of 6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 270° C. (dec.). Analysis: Calculated for C15H13N5O3 : %C, 57.9; %H, 4.2; %N, 22.5; Found: %C 57.8; %H, 4.0; %N, 22.7. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(OCC)C>[CH3:2][CH:1]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(O)c1ccccc1
Reaction time: 48 h
Yield: 72 %

Procedure:
Following the set-up of Example 5 and under a nitrogen atmosphere, acetophenone (2.9 g, 3.0 mL, 25 mmol) was added to a solution of (+)-B-chlorodiiso-2-ethylapopinocampheylborane (9.6 g, 27.5 mmol) in EE (ethyl ether, 20 mL) at -25° C. The reaction was complete in 48 h (followed by 11B NMR after methanolysis of an aliquot). The reaction was worked up following the procedure of Example 3 to obtain 2.2 g, 72% of α-phenethyl alcohol which was found to be of ≥99% ee by capillary GC analysis of its MTPA ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:14][NH2:15].[CH3:16][C:17]([CH:19]([C:21]([CH3:23])=O)[CH3:20])=O.C(O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:21]([CH3:23])=[C:19]([CH3:20])[C:17]([CH3:16])=[N:15]1
Reactant: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Reactant: CC(=O)C(C)C(C)=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1C

Procedure:
A mixture of (2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)hydrazine (25.5 g) of the formula: ##STR53## 3-methylpenta-2,5-dione (CH3COCH(CH3)COCH3) (11.4 g), ethanol (100 ml) and water (100 ml) was heated to reflux for one hour. After the reaction mixture was cooled, toluene was added thereto to form two layers. The toluene layer separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (29.3 g) as a pale yellow crystalline solid. Recrystallization of this solid from a mixture of n-hexane and ethyl acetate afforded a white crystalline solid. m.p. 123°-125° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:18][NH2:19].O>C(OCC)(=O)C>[NH2:10][C:11]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:19][CH3:18])=[O:8]
Reactant: CN
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(C)c1N
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
A mixture of 8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (PCT Patent Publication WO 00/27831) (18 g, 0.1 mol) and acetic acid (1.2 g, 0.02 mol) in ethyl acetate (200 mL) was warmed to 35° C., and aqueous methylamine (40%, 9.0 g, 0.12 mol) was added dropwise over 50 minutes at 35-37° C. Then more aqueous methylamine (40%, 0.9 g, 12 mmol) was added, and the mixture was stirred an additional 2.5 h at 36° C. Then water (20 mL) was added, the layers were separated, and the organic layer was washed with water, dried (MgSO4), and evaporated to afford the title compound, 15.45 g (92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Br)[CH3:27]>>[ClH:23].[ClH:23].[CH3:1][C:2]1([CH3:24])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)CC2C1=O
Reactant: CCN(CC)CCCBr
Agent: Br
Product: CCN(CC)CCCC1C(=O)C2=NC(c3ccc(Cl)cc3)=NC2=C2C=NC(C)(C)C(=O)C21
Product: Cl

Procedure:
Prepared analogous to Example 23 from 3.8 gm of 7,7-dimethyl-2-(4-chloro-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 3.1 gm of 3-diethylamino-propyl bromide hydrobromide.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH:36]2[CH2:38][CH2:37]2)(O)[CH3:34])=[C:29]([F:39])[CH:28]=1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(F)=CC=2)C)CC1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:34])=[C:29]([F:39])[CH:28]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: CC(O)(c1ccc(Cl)cc1F)C1CC1
Agent: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared starting from 3.00 g (16.92 mmol) of the compound from Example 8 and 4.00 g (18.62 mmol) of the compound from Example 79A in analogy to the synthesis of the compound from Example 95. As a difference, the reaction mixture was stirred at 0° C. for 2 h and then warmed to RT. 1.54 g (24% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH4+:18].[OH-]>C1COCC1>[Cl:8][C:6]1([NH2:18])[N:7]=[CH:2][N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[NH:5]1
Reactant: C[C@H](Nc1nc(Cl)nc(Cl)n1)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC1=NC=NC(N)(Cl)N1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 4,6-Dichloro-N2-[(1S)-1-phenylethyl]-1,3,5-triazine-2-amine, (Compound of Example 14), in THF (500 mL) was added conc. NH4OH (50 mL). The reaction mixture was stirred at ambient temperature for 48 h then was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500 mL) and was washed with H2O (2×250 mL). The organic layer was filtered through a cotton plug then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-Chloro-N2-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4-diamine as a white solid (29.7 g, 90%) MP 163-164° C., 1H (CDCl3) δ 7.78 (m, 5H), 6.1-6.2 (m, 4H), 1.52 (d, 3H), MS (ESI+) (M+) 249.7 obs.