Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][C:15](N)=[O:16].C(=O)(O)[O-]>>[NH2:5][C:4]1[C:3]2[C:2](=[C:9]([Br:10])[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:1]=[C:15]([OH:16])[N:14]=1
Reactant: NC(N)=O
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Agent: O=C([O-])O
Product: Nc1nc(O)nc2c(Br)cc([N+](=O)[O-])cc12
Yield: 89.4 %

Procedure:
2-Amino-3-bromo-5-nitro-benzonitrile (1.9003 g, 7.85 mmol) was heated with urea (1.8862 g, 31.4 mmol) at 180–185° C. for 3 hrs. The cooled mixture was powered and treated with bicarbonate solution, filtered and washed with water. The solid was the collected and washed with ethanol, ether, and used for the next step reaction without further purification. 2.0 g product was obtained. Yield 89%; 1H NMR (500 MHz, DMSO-d6): δ 8.44455–8.45011(d, J=2.78 Hz, 1H), 8.87071–8.87544(d, J=2.365 Hz, 1H), 9.39866–9.40333(d, J=2.335 Hz, 1H), 9.50740–9.51282(d, J=2.71 Hz, 1H); ESI-MS: 285, 287 (M++1)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Product: O=S(=O)(Nc1nc(-c2ccc(Cl)s2)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (24.0 mg) with purity >90%. MS (pos) m/z 461.0, 463.0.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1.[CH3:42][N:43]=[C:44]=[S:45]>O1CCCC1>[CH3:42][NH:43][C:44]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[C:31]([F:41])[CH:30]=2)[CH3:28])[N:26]=1)=[S:45]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: CN=C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CNC(=S)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
The lithium diisopropylamide in tetrahydrofuran prepared with diisopropylamine (0.187 g, 1.85 mmol) and n-butyllithium (1.9 mmol) was added 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.68 mmol) in tetrahydrofuran at -70° C. After the mixture was stirred for 20 min, methylisothiocyanate (0.131 g, 1.8 mmol) in tetrahydrofuran was added to the mixture. After the mixture was stirred at room temperature for 3.5 h, the mixture was evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were washed with water, dried over, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.233 g, 35% yield) as crystalline material: mp 180.5°-181.0° C.
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.C12C(=[O:24])C(CCC1)CCC2.N1CCOCC1>C1(C)C=CC=CC=1>[O:24]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: O=C1C2CCCC1CCC2
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 8.29 g (0.06 mole) of bicyclo[3,3,1]nonan-9-one and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure and the remaining chromanone compound was recrystallized from acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° C. to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.8 g of a chromene compound represented by the following formula: ##STR162##
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=S)[NH:8][C:7]=2[CH:18]=1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>C(O)CCC>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:25][C:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:18][C:7]=2[N:8]=1
Reactant: COC(CN)OC
Reactant: FC(F)(F)c1ccc2c(c1)NC(=S)c1ccccc1N2
Solvent: CCCCO
Product: COC(CNC1=Nc2cc(C(F)(F)F)ccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino] acetaldehyde dimethyl acetal.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[C:13](C(OCC)=O)[C:12]2=[O:30])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2ccc(F)cc2F)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 3.7 %

Procedure:
A solution of the compound (0.099 g, 0.24 mmol) of Example 53 in N,N-dimethylformamide (1.0 mL) was refluxed for 4 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 4%).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([Br:7])=[N:4][N:3]=1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH2:10]([N:6]1[C:5]([Br:7])=[N:4][N:3]=[C:2]1[Br:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1nnc(Br)[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1nnc(Br)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 3,5-dibromo-4H-1,2,4-triazole (3.0 g, 13.3 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil, 0.58 g, 14.5 mmol) (CAUTION: NaH and DMF can become a runaway reaction. All necessary safety precautions were performed). After the mixture was stirred at 0° C. for 30 minutes, benzyl bromide (1.57 mL, 13.2 mmol) was added. The mixture was stirred at 0° C. for 2 hours, then the mixture was partitioned between EtOAc (150 mL) and water (30 mL). The organic layer was washed with brine (2×30 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 50:1 to 10:1) to yield 3.71 g (89%) of the title compound as a white solid. m/z (ES+) 316, 318, 320 (M+H)+.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](O)(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].B(F)(F)F.CCOCC>O>[C:12]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11])(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCC(=O)O
Reactant: Oc1cccc2ccccc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCC(=O)c1ccc2ccccc2c1O

Procedure:
1-Naphthol (72.1 g, 500 mmol) and pentadecanoic acid (121.2 g, 500 mmol) were mixed with boron trifluoride etherate (400 ml) and heated on a steam bath for 4 hours. Then 400 ml water was carefully added and heating was continued to remove as much of the ether as possible. The precipitated solid was filtered off, washed well with water and air dried. The crude product was recrystallized from ethanol to give the pentadecanoylnaphthol as light yellow plates. Yield: 110 g (60 percent).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]>O.C(O)C>[CH2:12]([C:14]1[N:15]([CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[N:2][OH:3])=[CH:27][CH:26]=2)[C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[CH3:13]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(C=NO)cc1
Temperature: 95 °C
Yield: 89.9 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143.0 mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100 ml) at 30° C. was added a hot solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (5.72 g, 20.0 mmol) (obtained from preparation 3) in ethanol (100 ml). The reaction mixture was immersed in a preheated oil bath (95° C.) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and concentrated to a volume where crystals of oxime started separating out and the mixture was kept aside for 30 min. to 1 h at 25° C. The resultant crystals were filtered and washed with water and dried to obtain the title compound (5.42 g, 90%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13](=[N:21]O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:24]1([CH2:34][NH2:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:35][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[N:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Reactant: NCc1cccc2ccccc12
Product: CC(=O)OCc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)OC(C)(C)C)cc1
Yield: 39.7 %

Procedure:
tert-Butyl 3-(4-acetoxymethylphenyl)-2-hydroxyimino-3-oxopropionate (19.2 g) and 1-naphthylmethylamine (11.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give tert-butyl 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)-imidazole-4-carboxylate (10.5 g), melting point 162-164° C. (2) tert-Butyl 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)imidazole-4-carboxylate (10.5 g) was reacted and treated in the same manner as in Example 31 to give 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)imidazole-4-carboxamide (6.62 g), melting point 197-199° C.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccc(Br)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccc(Br)cc1)Sc1ccc(Cl)cc1

Procedure:
1-chloro-1-[(4-bromophenyl)hydrazono]-2-propanone is reacted with 4-chlorothiophenol and triethyl amine in ethanol as Example 11 to yield 1-[(4-chlorophenyl)thio]-1-[(4-bromophenyl)hydrazono]-2-propanone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1.CN(C=O)C.C1(C)C=CC=CC=1.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>[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:33]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: OB(O)c1cccs1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccs2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of 2-thienylboronic acid (1.135 g) and anhydrous K2CO3 (2.23 g) in toluene/DMF (75 mL/7.5 mL) under N2 was added a solution of N-(tert-butoxycarbonyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (3.42 g) in 5 mL of toluene. Pd(PPh3)4 (1.4 g) was added and the mixture was heated at 80° C. for 24 h. After usual work-up as shown in Example 1 the crude material was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to yield N-(tert-butoxycarbonyl)-4-(2-thienyl)-L-phenylalanine methyl ester(1.81 g). ESMS: m/z 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=O)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:18][CH2:17][CH:13]([C:14]#[N:16])[CH2:12][CH2:11]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 33 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (0.50 g, 2.7 mmol), isonipecotamide (0.30 mg, 2.7 mmol), NMP (15 mL) and triethylamine (0.76 mL, 5.5 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound as a white solid (228 mg, 33%), m/z (ESI) C11H12Cl2N3 requires 256.0403 found [M+H]+ 256.0409.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[C:4]([NH:6][O:7]CC1C=CC=CC=1)=[O:5].[CH3:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)[C:18]([OH:20])=O>>[CH3:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)[C:18]([NH:2][C@H:3]([CH3:15])[C:4]([NH:6][OH:7])=[O:5])=[O:20]
Reactant: C[C@@H](N)C(=O)NOCc1ccccc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: Cl
Product: CC(C)Cc1ccc(C(C)C(=O)N[C@H](C)C(=O)NO)cc1

Procedure:
This compound was synthesized by coupling 2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with (R/S)-α-methyl-4-isobutylphenylacetic acid followed by hydrogenation using the procedures as described in Example 42. MS (ESI): (M−H)−=291.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)OC)c(N)c1

Procedure:
23.9 g (0.1 mol) of dimethyl 2-nitroterephthalate are hydrogenated in a mixture of 100 ml of methanol and 200 ml of tetrahydrofuran with palladium/charcoal at 5 bar and 20° C. After the catalyst has been removed by suction filtering the solvent is evaporated off and the residue is recrystallised from methanol. Yield 18-19 g, yellowish crystals m.p. 130-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2.[Li]CCCC.[C:28](=[O:30])=[O:29]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]([C:28]([OH:30])=[O:29])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]1=2
Reactant: O=C=O
Reactant: Cc1cccc(C)c1N1c2ccccc2Cc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1c2ccccc2C(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
A solution of 4.28 g of N-(2,6-dimethylphenyl)acridan (15 mmol) in 100 mL of THF under argon was cooled to −78° C. After 10 min, 7.6 mL of n-BuLi (18.7 mmol) was added. The black solution stirred 30 min and then the temperature was raised to 0° C. for 40 min. The reaction was again cooled to −78° C. and 270 g of crushed dry ice was added to the reaction mixture to form a yellow solution with a white precipitate that dissolved once the reaction was warmed to room temperature. The reaction was stirred for 16 h at room temperature, and then concentrated and taken up in a mixture of water and diethyl ether. The aqueous portion was acidified with HCl to afford a white precipitate, which was filtered and dried to give 4.8 g of N-(2,6-dimethylphenyl)acridan-9-carboxylic acid as a white solid (97%).
Reaction SMILES: [C:1]([O:4][C:5]1([C@@:9]2([C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:13][C@H:12]([N:14]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C@@H:15]3[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]3)[CH:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt].[Pd]>[C:1]([O:4][C:5]1([C@:9]2([C:29]([OH:31])=[O:30])[CH2:10][CH2:11][C@@H:12]([N:14]([C:23](=[O:28])[C:24]([F:27])([F:25])[F:26])[C@@H:15]3[C@H:20]([O:21][CH3:22])[CH2:19][O:18][CH2:17][CH2:16]3)[CH2:13]2)[CH2:6][CH2:7][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(OC(C)=O)CCC2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)O)(C2(OC(C)=O)CCC2)C1
Yield: 102.6 %

Procedure:
A mixture of 2.62 g (4.86 mmol) of 3-[{(1S,4R)-4-[1-(acetyloxy)cyclobutyl]-4-[(benzyloxy)carbonyl]cyclopent-2-en-1-yl}(trifluoroacetyl)amino]-1,5-anhydro-2,3-dideoxy-4-O-methyl-D-erythro-pentitol and 750 mg each of 5% Pt/C and 5% Pd/C in 10 mL of acetic acid was stirred rapidly under 50 psi hydrogen gas for 18 h, then filtered through diatomaceous earth to remove catalyst. The filtrate was concentrated under reduced pressure, with added toluene to azeotropically remove acetic acid, to provide 2.25 g (103%) of the title compound as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.71 (m, 3H) 1.74-1.84 (m, 1H) 2.02 (s, 3H) 2.04-2.17 (m, 1H) 2.34-2.55 (m, 5H) 2.60 (dd, J=14.3, 8.5 Hz, 1H) 2.66-2.81 (m, 2H) 3.30 (d, J=13.0 Hz, 1H) 3.35-3.39 (m, 1H) 3.42 (s, 3H) 3.47-3.56 (m, 1H) 3.83-3.91 (m, 1H) 4.13 (dd, J=11.6, 4.4 Hz, 1H) 4.16-4.23 (m, 1H) 4.26-4.38 (m, 1H). LC-MS ES+452.1
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:9]([O:16][CH2:17][CH3:18])=[N:10]2.CO.[OH-].[Li+]>O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:8]2[C:9]([O:16][CH2:17][CH3:18])=[N:10][C:11]3[C:6]([C:7]=2[CH3:27])=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[CH:14]=[C:13]([CH3:15])[CH:12]=3)=[CH:25][CH:24]=1
Reactant: CCOc1nc2cc(C)cc(CC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1nc2cc(C)cc(CC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-2-ethoxy-4,7-dimethylquinolin-5-yl]acetic acid methyl ester (0.10 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.20 mL) and water (0.4 mL) was stirred at 50° C. for 5 hours. The methanol was removed under reduced pressure and the residue acidified by the addition of trifluoroacetic acid. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid, 0.095 g.
Reaction SMILES: [CH2:1]([C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH2:11]1[O:14][CH:12]1[CH3:13]>Cl.[Cl-].[Li+].CN(C)C=O>[OH:14][CH:12]([CH3:11])[CH2:13][N:7]1[C:3]([CH2:1][CH3:2])([CH3:10])[C:4](=[O:9])[N:5]([CH2:11][CH:12]([OH:14])[CH3:13])[C:6]1=[O:8]
Reactant: CC1CO1
Reactant: CCC1(C)NC(=O)NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC1(C)C(=O)N(CC(C)O)C(=O)N1CC(C)O
Temperature: 50 °C
Yield: 99.7 %

Procedure:
A mixture of 256.3 g of 5ethyl-5-methylhydantoin (1.805 mols), 675 ml of dimethylformamide and 4.51 g of lithium chloride is stirred at 50° C. 288.0 g of propene oxide (4.96 mols) are slowly added dropwise over the course of 2 hours. Thereafter the temperature is gradually raised to 90° C. over the course of 10 hours. The reaction mixture is brought to pH = 7 with 4 drops of 2 N hydrochloric acid, filtered and concentrated on a rotational evaporator at 90° C. bath temperature, under a waterpumpvacuum. It is then treated at 90° C. under 0.1 mm Hg until the weight remains constant. 465 g of a clear pale yellow product (99.5% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:14][CH3:13])[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (6.54 g) in methanol (31.5 mL) was added sodium methoxide (28% methanol solution, 6.05 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 1.5 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=9/1) to give the title compound (5.7 g).
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([NH2:2])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)CCCCCCl
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.5 ml of a 28% aqueous solution of ammonium hydroxide were added dropwise at 0° to +5° C. under an inert gas atmosphere to a solution of 2.5 g of 5-chloropentane sulfonyl chloride (preparation described in: Bull. Soc. Chim. Belg. (1965) Vol. 74, p. 21) in 30 ml of tetrahydrofuran. The temperature was allowed to rise from 3° C. to 16° C., and the mixture was stirred at ambient temperature for 2 hours. The tetrahydrofuran was evaporated under reduced pressure and the residue was taken up in water, extracted with methylene chloride, washed with water, then with an aqueous solution of sodium chloride,. dried and evaporated under reduced pressure to obtain 2.01 g of the expected product melting at 62° C.