Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:12]([N:17]([CH3:37])[C:18]2[C:19]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)(=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:12]([N:17]([CH3:37])[C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CN(Cc5ccccc5)CCC4C)ncnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A mixture of 50% sodium hydroxide (10 mL) and N-(1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.80 mmol, 1.00 equiv.) was stirred at about 60° C. for about 16 hours, and then was cooled to ambient temperature. Following standard extractive workup with ethyl acetate (4×10 mL), the crude residue was then purified by silica gel column chromatography (dichloromethane/methanol (10:1)) to give the title product as a yellow solid (0.25 g; yield=88%). 1H NMR (300 MHz, CDCl3) δ: 11.35 (br s, 1H), 8.30 (s, 1H), 7.20-7.40 (m, 5H), 7.06 (d, J=3.6 Hz, 1H), 6.60 (d, J=3.6 Hz, 1H), 5.20-5.30 (m, 1H), 3.66 (s, 3H), 3.48-3.65 (m, 2H), 2.85-2.98 (m, 1H), 2.60-2.85 (m, 2H), 2.30-2.45 (m, 1H), 2.12-2.30 (m, 1H), 1.60-1.92 (m, 2H), 0.98 (d, J=6.0 Hz, 3H). LC-MS: m/z=336 (M+H)+.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].C(N(CC)CC)C.C1(C)C=CC=CC=1>CCCCCC>[CH3:3][Si:2]([CH3:5])([CH3:4])[N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1CCCC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Chlorotrimethylsilane (TMSCl, 56.0 mL, 441 mmol) is added dropwise to a solution of 2-pyrrolidinone (30.4 mL, 400 mmol), triethylamine (70.0 mL, 502 mmol) and toluene (400 mL) at room temperature. After stirring at room temperature with a mechanical stirrer for 20 minutes, the mixture is heated at 50° C. for 4 hours. After cooling, the mixture is diluted with hexane (300 mL) and stirred for 30 minutes at room temperature. The mixture is filtered and the filtrate concentrated. Distillation of the residue (1 mm, 68+-74° C.) gives 50.0 g (94%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:30])[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: BrBr
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Br)cc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (108 mg, 0.26 mmol, 1.0 equiv) and sodium acetate (64 mg, 0.78 mmol, 3.0 equiv) were dissolved in 2 mL of acetic acid. A 1 mL solution of Br2 (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and was stirred for 3 hours at ambient temperature, after which the vessel was heated at 50° C. for 18 hours. An additional 1 mL solution of Br2 (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and stirred at 50° C. for 90 minutes. An additional 1 mL solution of Br2 (82 mg, 0.52 mmol, 2.0 equiv) was added and the vessel was heated for 30 more minutes. The reaction mixture was partitioned between ethyl acetate and aqueous saturated NaHCO3, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 496.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36](O)=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>ClCCl>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][C:36]([C:33]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:35][CH2:34]1)=[O:37]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CN(C)CCN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN(C)C)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid (0.2566 g, 0.4 mmol), N,N-dimethylethylene-diamine (0.05 mL, 0.48 mmol), HOBt (65 mg, 0.48 mmol), EDC (92 mg, 0.48 mmol), DIEA (0.08 mL, 0.48 mmol) were combined in dichloromethane (20 mL). The mixture was stirred for 72 h at ambient temperature. The mixture was extracted with H20. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed using a Vydac (25×250 mm) C-18 HPLC column to give the title compound:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.62 g, 4.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (1.0 g, 4.1 mmol) and K2CO3 (0.6 g, 4.3 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with EtOAc (20 mL×3). The combine organic layers were concentrated in vacuo to give 4-chloro-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, yield 80%) as brown solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:7](=[O:31])[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:17]=[C:16]2[CH3:29])=[CH:11][C:10]1=[O:30])C>C(O)C>[CH3:1][N:2]([CH3:3])[C:7](=[O:31])[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:17]=[C:16]2[CH3:29])=[CH:11][C:10]1=[O:30]
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Reactant: CNC
Solvent: CCO
Product: Cc1cccc(C#Cc2cn(-c3ccn(CC(=O)N(C)C)c(=O)c3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2 ml of a 5.6M solution of dimethylamine in ethanol were added 70 mg (0.19 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 2 days at room temperature. The solution was then evaporated to dryness, the residue was triturated with a small amount of ethyl acetate and the product was filtered off, yielding 59 mg of the title compound as a white solid, MS: m/e=375.3 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O-])(=O)[CH2:4]C.[OH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(I)C>CN(C)C=O>[CH2:3]([O:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:4]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl(propionate of the formula (10) (40 g) obtained according to the procedure described in step (iii) above in dimethylformamide (105 ml) at 5–10° C. over a period of 15–30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1–3 h. Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25–30° C. over a period of 2–3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47–48 g, 98–99%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:28]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCc2ccccc2)C3)nc1
Temperature: 75 °C
Yield: 29 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Part E, 112.9 mg, 0.40 mmol), K2CO3 (110.1 mg, 0.80 mmol), and phenethyl bromide (82 uL, 0.60 mmol) in DMF (2.0 mL). Heat at 70-80° C. overnight. Remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:19:6 EtOAc/CH2Cl2/2.0 M NH3 in MeOH and then with 60:30:10 EtOAc/hexanes/2.0 M NH3 in MeOH. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (44.9 mg, 27% from Step D): MS ES+ 284.0 (M−H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.85 min, 100% purity; Anal. Calcd for C24H25N3O2.0.1H2O.0.1MeOH: C, 73.75; H, 6.57; N, 10.71. Found: C, 73.45; H, 6.62; N, 10.72.
Reaction SMILES: CC1C(=O)NC(=O)NC1=O.N1C=C(C)C(=O)NC1=O.N1C=CC(=O)NC1=O.[C@@H:28]1(N2C=C(C)C(=O)NC2=O)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[CH2:29]1.[NH:45]1[C:54](=[O:55])[C:53]2[NH:52][CH:51]=[N:50][C:49]=2[N:48]=[C:46]1[NH2:47]>>[C@@H:28]1([N:50]2[C:49]3[N:48]=[C:46]([NH2:47])[NH:45][C:54](=[O:55])[C:53]=3[N:52]=[CH:51]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[CH2:29]1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC1C(=O)NC(=O)NC1=O
Agent: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=c1cc[nH]c(=O)[nH]1
Product: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 75 %

Procedure:
FIG. 1 shows formation of 5-methyl barbituric acid. Since the acid is decomposed so as to disappear, it has been clarified that uracil thymine dehydrogenase and barbiturase are present in the uracil·thymine decomposing enzyme. In the case of FIG. 1, thymidine disappeared substantially completely, though the starting material guanine was found to remain only slightly. Deoxyguanosine was formed in an amount of 14.9 mM (yield of 75%). Compared with FIG. 2 covering the case where uracil·thymine decomposing enzyme solution was not present, FIG. 1 supports that the desired product of deoxyguanosine was formed in a very large amount.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11]C2=O)=[CH:5][CH:4]=1.FC1C=CC(CO)=CC=1OC1C=CC=CC=1>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:13]([C:12]([OH:17])=[O:11])[CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: OCc1ccc(F)c(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2, 5-dione is reacted with 4-fluoro-3-phenoxybenzyl alcohol to give the 4-fluoro-3-phenoxybenzyl ester of N-(4-trifluoromethylphenyl) valine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([NH:9][CH3:10])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[C:4]=1[NH2:11]
Reactant: CNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1cccc(OC)c1N
Reaction time: 4.5 h
Yield: 95.4 %

Procedure:
7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml of ethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psi and ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 5.9 g of the product are obtained as an oil.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36]O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.S(Cl)([Cl:41])=O>ClCCl.CN(C=O)C>[F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH2:36][Cl:41])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CO)C3)cs2)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CCl)C3)cs2)CC1

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(hydroxymethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.55 g) in dichloromethane (10 ml) were added, at room temperature, thionyl chloride (0.24 g) and one drop of DMF, and the mixture was then refluxed for 2 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. This gave, without further purification, 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.59 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].C1(C)C=CC(S(Cl)(=O)=[O:23])=CC=1>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([CH2:6][C:7]#[N:12])=[C:9]([CH:10]=1)[C:8]([OH:11])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1Br)C(=O)C(=NO)C2
Product: COc1cc(CC#N)c(C(=O)O)cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-5-methoxy-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 5-Bromo-2-cyanomethyl-4-methoxy-benzoic acid. LC-MS: m/e 268 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9]
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2,6-dichlorotoluene (200 g) is added dropwise fuming nitric acid (d=1.52, 206 ml) at 25° to 30° C. After stirring for 30 minutes at room temperature, the mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with an aqueous sodium hydrogen carbonate solution and then dried. The solvent is distilled off under reduced pressure to give 2,6-dichloro-3-nitrotoluene as yellow crystals (253.2 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(Cl)Cl.CO>O1CCCC1>[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Yield: 5.5 %

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 174 mg of 2,4-difluorobenzoyl chloride in 4 ml of tetrahydrofuran. After two successive purifications by silica chromatography (eluent: CH2Cl2/MeOH, gradient of 100/0 to 98/02 then 99/01), 24 mg of (8S)-9-[(2,4-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetra-hydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a colourless lacquer, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH2:43][CH2:42][CH2:41][CH2:40]2>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=4[CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: ClCc1ccc2c(c1)CCCC2
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc4c(c3)CCCC4)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]propoxy}benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)-propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH:4]([OH:32])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:31])[O:28][C:29](=O)[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[NH3:34]>>[CH3:33][N:2]([CH3:1])[CH2:3][CH:4]([OH:32])[CH2:5][N:6]1[C:18]2[C:17]3[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[C:15]3[C:27](=[O:31])[NH:34][C:29](=[O:28])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)OC3=O
Reactant: N
Product: CN(C)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5n(C)c4c21)C(=O)NC3=O

Procedure:
750 mg (1.7 mmol) (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxoindolo[2,3-a]furano[3,4-c]carbazole are heated in an autoclave with 50 ml ammonia-saturated ethanol for 20 hours at 140° C. The undissolved product is filtered off and again crystallised from ethanol. (±)-12-(3-Dimethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of a yellow amorphous powder; m.p. 260-270° C.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:14]=[C:13]([C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:17][CH:16]=3)[S:1][C:2]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: COc1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: COc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Yield: 46.3 %

Procedure:
2-Mercapto-4-methoxybenzoic acid (1.26 g, 6.8 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.21 g, 5.2 mmol) were dissolved in pyridine (10 ml), and the reaction mixture was refluxed for 24 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (0.96 g, 46%).
Reaction SMILES: [CH2:1]([C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([N+:28]([O-])=O)=[C:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:28][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)=[CH:18][C:17]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1N
Yield: 88.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-benzylphenoxy)-2-nitrophenyl]-N-methylcarbamate (12.2 g), palladium on carbon (10%, 0.91 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (10.1 g).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:3]([CH3:4])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH2:11]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH:11][CH:3]([CH3:4])[CH2:2][C:1]([OH:5])=[O:6]
Reactant: CC1CC(=O)O1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: CC(CC(=O)O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
86 g (1.00 mole) of β-butyrolactone was added to 162 g (1.00 mole) of 3,4-dichloroaniline, and this mixture was stirred at 110°-120° C. for 1 hour and then allowed to cool to room temperature. To the resulting reaction solution was added 1000 ml of ether. This mixture was filtered to remove any insoluble matter, and the filtrate thus obtained was extracted with 750 ml of a 2N aqueous solution of sodium hydroxide. This extract was acidified with 130 ml of concentrated hydrochloric acid and then extracted with 1000 ml of ether. The ether layer was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. Thus, there was obtained 128 g (51.6% yield) of 3-(3,4-dichloroanilino) butyric acid in the form of pale-yellow crystals.