Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]2[N:10]=[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH3:13][N:12]1[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:30]=[CH:29][C:9]=2[N:10]=[C:11]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CCOC(=O)c1ccc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)O)cc21
Yield: 95.4 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (2.5 g) was prepared by following General Procedure E starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid ethyl ester (2.8 g) and 2 N NaOH (6 mL) in methanol:THF (1:1, 12 mL).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:36])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16](S(C)=O)[N:15]=3)[CH:8]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)[N:15]=3)[CH:8]=2)=[O:36])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
To the solution of N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide (100 mg) in THF (10 mL) was added 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (195 mg) at r.t. The reaction mixture was heated at reflux for 4 h. The solution was then evaporated in vacuo and the residue was purified by column chromatography to provide the title compound as a white solid. LC-MS m/z 648.4 (M+H)+, 2.16 min (ret. time).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Cc1ccc(N)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 26.2 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methylbenzoic acid (2.06 g 15.0 mmole), DMF (60 ml), TEA (4 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (5.52 ml, 17.7 mmole), 1.50 g (27.0% yield) of 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O[CH:8]=[N:9][C:10]1[S:18][C:17]2[CH2:16][CH2:15][N:14]([CH2:19][CH3:20])[CH2:13][C:12]=2[C:11]=1[C:21](OCC)=[O:22])C>C(O)C>[OH:2][CH2:1][CH2:3][N:4]1[C:21](=[O:22])[C:11]2[C:12]3[CH2:13][N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][C:17]=3[S:18][C:10]=2[N:9]=[CH:8]1
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Reactant: NCCO
Solvent: CCO
Product: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Yield: 63 %

Procedure:
5.0 ml (81 mM [sic]) of ethanolamine were added to 17.0 g (55 mM [sic]) of 2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 130 ml of ethanol and then refluxed for 2 h. The mixture was then concentrated to a volume of about 50 ml and stirred in an ice bath. The precipitated fine solid was filtered off with suction and washed with cold ethyl acetate. 10.5 g (63%) of pale brown product were isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(O)C>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(3-Aminopropyl)imidazole (2.39 ml, 0.02 mol) was added to a solution of 4-bromobenzoyl chloride (4.0 g, 0.218 mol) in ethanol (250 ml). The mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was purified by chromatography eluting with hexane/dichloromethane (50:50) increasing in polarity to dichloromethane/methanol (80:20) to give the title compound. NMR: 1.95 (m, 2H), 3.20 (q, 2H), 4.0 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.64 (d, 2H), 7.68 (s, 1H), 7.78 (d, 2H), 8.58 (t, 1H); m/z: 308 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C=Nc1ccccc1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2Br)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 103.9 %

Procedure:
2-Bromophenyl isocyanate (10.2 g, 51.5 mmol) was dissolved in N,N-dimethyl-formamide (40 mL) with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.36 g, 51.5 mmol). The reaction mixture was stirred at 50° C. for 20 hours before being concentrated under reduced pressure. The crude was taken up in dichloromethane (200 mL) and washed with water (2×150 mL) and brine (1×150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (21.36 g). MS m/z: [M+H+] calcd for C17H23BrN2O4 399.08; found 399.3.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30](/[C:34](/[CH3:39])=[CH:35]/[C:36](O)=[O:37])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][CH:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30](/[C:34](/[CH3:39])=[CH:35]/[C:36]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:37])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(C)c2ccccc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(C)c2ccccc2)c1

Procedure:
111 mg of compound 38 was obtained in a similar manner to those described in the Examples 1 and 2 using 393 mg of ethyl 4-(2-aminophenoxy)butyrate and 268 mg of 3-[1-(α-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH2:1][O:8][C:17](=[O:18])[CH:16]([CH3:15])[CH2:20][CH:21]=[CH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of 4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylene chloride is added, dropwise, a solution of 29.5 g of racemic 2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. The mixture is stirred at room temperature for 4 hours, followed by successive washing with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation to give 35.2 g of the desired product as a colorless oil; bp 70°-75° C. at 0.10 mm Hg.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH:32]=O.[BH4-].[Na+]>CO>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH2:32][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(F)cc1OCC=O
Reactant: COc1ccc(CCN)cc1S(N)(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1OCCNCCc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A suspension of 1.50 g of 5-(2-aminoethyl)-2-methoxybenzenesulfonamide hydrochloride and 0.8 ml of triethylamine in 50 ml of methanol was heated for 30 minutes at 75° C. To the reaction mixture was added 1.00 g of 2-(5-fluoro-2-methoxyphenoxy)acetaldehyde and the reaction mixture was heated for 10 minutes at 75° C. To the solution was added 0.45 g of sodium borohydride under ice cooling and the solution was stirred for 1 hr at room temperature. The reaction mixture was evaporated, acidified with 10% hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was solidified with a mixture of methanol and ether and the precipitate was filtered to give 0.46 g of the desired compound as pale brown crystals which were recrystallized from N,N-dimethylformamide as pale yellow crystals, m.p. 201°-205° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)c1ccc(C)c(N)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.0093 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (1.49 g, 0.0084 mol, see preparation 10) and N,N-diisopropylethylamine (4.79 g, 0.0372 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 8.87 g, 0.028 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (2.80 g, 80%). Mass spectrum (m/z): 376.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][OH:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN(CC)CC.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([O:29][CH2:28][CH2:27][C:22]2[C:21]3[C:25](=[C:17]([C:14]4[N:13]=[C:12]([C:4]5[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=5)[O:16][N:15]=4)[CH:18]=[CH:19][CH:20]=3)[N:24]([CH3:26])[CH:23]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCO)cn(C)c34)no2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 242.5 %

Procedure:
To a stirred solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethanol (D126) (30 mg), Et3N (0.1 mL) and DMAP (10 mg) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (42 mg) in DCM (5 mL). The reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched with water, partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, saturated aqueous sodium carbonate and brine, dried over sodium sulphate and evaporated to give the crude product 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl 4-methylbenzenesulfonate (D127) (100 mg). MS (ES): C29H28ClN3O5S requires 565; found 566.2 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:31][CH3:32])=[C:13]([O:29][CH3:30])[C:14]=2[CH2:15][NH+:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[C:17]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[OH-:34].[Na+]>O>[CH2:1]([C:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:31][CH3:32])=[C:13]([O:29][CH3:30])[C:14]=2[C:15](=[O:34])[N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]4[O:28][CH2:27][O:26][C:21]=4[CH:22]=3)[C:17]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2Cc1ccccc1)OCO4
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(Cc3ccccc3)c3n(c(=O)c2c1OC)CCc1cc2c(cc1-3)OCO2
Yield: 22 %

Procedure:
A mixture of 13-benzyl-9,10-dimethoxy-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (0.9 g, 1.8 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 16 h. The precipitate was collected and treated with hot 3% hydrochloric acid. The residue was re-crystallized from ethanol to afford 13-benzyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (180 mg. 22%) LC/MS m/e calcd for C27H23NO5 (M+H)+: 442.49, observed: 442.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31](I)[CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH2:31][CH3:32])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2F)CC1
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Yield: 71.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[2-fluoro-4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (2.20 g) described in Preparation Example 156 and ethyl iodide (972 mg), the title compound (1.67 g) was obtained.
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][CH2:20][C:11]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:11]12([CH2:20][CH2:21][CH2:22][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12]2
Reactant: [H][H]
Reactant: c1ccc(CN2CCCC3(CC2)OCc2ccccc23)cc1
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)COC21CCCNCC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of (RS)-1-benzyl-3′H-spiro[azepane-4,1′-[2]benzofuran] (4.00 g, 13.6 mmol) in methanol (50 ml) in an autoclave was purged with argon. After addition of the palladium catalyst (10% Pd on activated charcoal, 1 g) the autoclave was pressurized with 5 bar of hydrogen gas. The mixture was stirred over night at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium hydroxide solution (pH 14). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound as white solid (2.5 g, 90%).
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19]([CH2:21]N)[OH:20]>C1C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[O:20]1[CH2:19][CH2:21][N:2]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: c1ccc2c(c1)C1CC(C3=NCCO3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethanolamine (1.8 g) and zinc acetate (250 mg) is stirred at 130° C. for 5 hours. The reaction mixture is dissolved in benzene and passed through a column of 10% hydrated alumina. The eluate is evaporated to remove the solvent, and the residue is recrystallized from ether to give 11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (3.3 g) as crystals melting at 155 to 156° C. IR (KBr), 1655 cm-1 (O--C=N).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>>[Cl:25][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of methyl [4-hydroxy-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (4.0 g, 13.19 mmol), phosphorus oxychloride (6.15 mL, 65.95 mmol) and N,N-dimethylaniline (2.51 mL, 19.78 mmol) was stirred at 150° C. for 3 hours. After the removal of the excess phosphorus oxychloride, the residue was dissolved with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (hexane:ethyl acetate, 7/3) to give methyl [4-chloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.70 g, 64%) as orange solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:9]=1[O:10][CH3:11])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30]Br>CN(C=O)C>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][C:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:8][C:9]=1[O:10][CH3:11])=[O:2]
Reactant: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1NC=O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(=O)OC(C)(C)C)ccc1NC(=O)CC(OC)OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
tert-Butyl (E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylate synthesized according to the method in Examples 168 and 169 (4 g) was dissolved in DMF (60 mL). Cesium carbonate (9.38 g) was added and the reaction solution was heated to 60° C. Bromoacetaldehyde dimethylacetal (2.08 mL) was added to the reaction solution. The reaction solution was stirred for two hours, heated to 110° C. and stirred for 10 hours. The reaction solution was left to cool. Ice water was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=7:1→heptane:ethyl acetate=1:2) to obtain the title compound (3.99 g). The property values of the compound are as follows.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (3,4-methylenedioxyphenyl)acetic acid (4.64 g, 25.74 mmol) in dry DMF (40 mL), cesium carbonate (9.2 g, 25.74 mmol) and methyl iodide (3.7 g, 26.0 mmol) in dry DMF (40 mL) was stirred at room temperature for 3h. At the end of this period, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO3, water, brine and then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide pure methyl (3,4-methylenedioxyphenyl)acetate as an oil (4.38 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9].O.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[S:8]([OH:11])(=[O:10])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Nc1ccc(S(=O)(=O)O)cc1
Temperature: 200 °C

Procedure:
651.7 g (7.0 mol) of aniline in 1400 ml of o-dichlorobenzene were introduced into a 4 enamel stirring autoclave and 686.7 g (7.0 mol) of 100% sulphuric acid were added with stirring. The autoclave was then closed and the reaction mixture was heated to 200° C. with stirring. After 21/2 hours reaction time, the reaction mixture was cooled, poured into 1000 ml of water with stirring and neutralized with sodium hydroxide solution. Two liquid phases were obtained. After replenishing the aniline to the abovementioned value, the organic phase was added to a further batch. Pure p-sulphanilic acid was obtained from the aqueous phase by acidification using sulphuric acid. The yield amounted to 64.2%.
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[CH2:3][O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([NH:27][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH2:3][C:2]([CH3:1])=[CH2:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 78.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-[(2-methyl-2-propen-1-yl)oxy]-4-oxopiperidine-1-carboxylate obtained in Example (117b) (3.43 g, 17.1 mmol), benzylamine (1.5 g, 14 mmol), sodium (triacetoxy)borohydride (4 g, 18.9 mmol) and 1,2-dichloroethane (30 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 3.97 g of the title compound as a colorless oily substance (86%).