Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1ccccc1-3
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(NCCN(C)C)COc1ccccc1-3
Reaction time: 0.08 h

Procedure:
To a solution of methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (from Step 4) in 1,2-dichloroethane (0.08 M), were added 1.0 eq of N,N-dimethylethane-1,2-diamine and 1.5 eq acetic acid, followed by 1.5 eq. of solid sodium triacetoxyborohydride. NaOH (20 eq, 1 N) was added after 2 h, and after stirring for 5 min the mixture was taken into EtOAc and washed with water and brine. Drying over sodium sulfate and concentration in vacuo gave the crude product, which was used without further purification; MS (ES+) m/z 476 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([O:16]CC)=O.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[C:14]([NH:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])=[O:16]
Reactant: CCOC(=O)C(=O)Nc1cc(C(=O)OC)ccc1Cl
Reactant: COC(CN)OC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)c(NC(=O)C(=O)NCC(OC)OC)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of methyl 4-chloro-3-{[ethoxy(oxo)acetyl]amino}benzoate (Example 330b, 11.2 g) dissolved in ethyl acetate (80 mL) was treated with aminoacetaldehyde dimethyl acetal (5.08 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 3 h. The reaction mixture was diluted with diethyl ether (100 mL) and stirred at room temperature overnight. The solid formed was filtered off and dried under vacuum to afford the subtitle compound (12.64 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[C:27]([CH2:33][CH3:34])[NH:28][C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:25]1[N:26]=[C:27]([CH2:33][CH3:34])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (197 mg, 0.573 mmol), 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (100 mg, 0.573 mmol) and HATU (218 mg, 0.573 mmol) in DMF (4.0 ml) was added diisopropylethyl amine (0.200 ml, 1.146 mmol) and the mixture was stirred for 1 hr at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-ethyl-1H-imidazole-5-carboxamide (135 mg, 0.269 mmol, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (s, 2H), 7.80 (s, 1H), 7.74 (s, 1H), 7.50 (dd, 1H), 7.36 (t, 1H), 4.52 (d, 2H), 2.58 (q, 2H), 1.16 (t, 3H). LC-MS (ES+) m/z 501.10, [M+H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O-:14])([O-:13])=O.[K+].[K+].[SH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>C(O)C>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=[CH:6][CH:7]=1)([OH:14])=[O:13]
Reactant: O=C(O)c1ccccc1S
Reactant: O=C([O-])[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)CSc2ccccc2C(=O)O)cc1

Procedure:
To bromoacetophenone (394.09 mg, 1.62 mmole) and anhydrous K2CO3 (896 mg, 6.48 mmole) in ethanol (20 ml), 250 mg (1.62 mmole) 2-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The aqueous layer was acidified to yield a precipitate which was filtered and dried (487 mg). m/z 315 (M−1)+1HNMR (DMSO) δ 4.75 (s, 2H, —CH2-), 7.22 (1H, t, ArH), 7.47 (2H, t, 2×ArH), 7.87 (1H, d, ArH), 8.06 (2H, d, 2×ArH), 8.15 (2H, d, 2×ArH).
Reaction SMILES: [CH3:1][S-:2].[Na+].CC1C=CC(S(O[CH2:15][C:16]2(C)[CH2:21][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C@@H:19]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=3[O:45][CH3:46])[C:17]2=[O:47])(=O)=O)=CC=1.[CH3:49]N(C=O)C>O>[Cl:28][C:24]1[CH:23]=[C:22]([C@@H:20]2[C@@H:19]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=3[O:45][CH3:46])[C:17](=[O:47])[C@@:16]([CH3:15])([CH2:1][S:2][CH3:49])[CH2:21]2)[CH:27]=[CH:26][CH:25]=1
Reactant: C[S-]
Reactant: CN(C)C=O
Reactant: COc1ccc(CN2C(=O)C(C)(COS(=O)(=O)c3ccc(C)cc3)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@](C)(CSC)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: 50 °C

Procedure:
Sodium thiomethoxide (0.193 g, 2.76 mmol) was added to a solution of ((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidin-3-yl)methyl 4-methylbenzenesulfonate (Example 88, Step C) (0.738 g, 1.104 mmol) in anhydrous DMF (5.52 mL) at rt under nitrogen. The reaction mixture was heated at 50° C. for 8 hours before being cooled to rt, diluted with water and extracted with ether three times. The organics were pooled, washed with water three times, sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a 40 g SiO2 column and eluting with 15 to 40% EtOAc/hexanes provided the title compound as a colorless foam.
Reaction SMILES: O[C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-:18].[K+].[K+].[CH2:23]([O:25][C:26](=[O:29])CBr)[CH3:24]>CN(C=O)C.O>[CH2:23]([O:25][CH2:26][O:29][C:17]([C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1)=[O:18])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c2oc3ccccc3c12
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOC(=O)c1ccc(C=O)c2c1oc1ccccc12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Intermediate 19 (500 mg, 2.358 mmol) was dissolved in dry DMF (5 ml). Anhydrous potassium carbonate (650 mg, 4.716 mmol) was added to the above solution and was stirred for 10 min. at 80° C. To this was added ethylbromoacetate (2.0 eq.) and the reaction mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (50 ml) and brine solution (25 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave the product as a white solid (550 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:38])([F:37])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:45]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:35]([F:37])([F:38])[F:36])[CH:6]=[C:7]([NH:9][C:10](=[O:34])[N:11]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)=[C:22]([Cl:45])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:12])[CH:8]=1
Reactant: ClCCl
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4cc(OC)cc(C(F)(F)F)c4)ncn3)cc2Cl)CC1
Temperature: 0 °C

Procedure:
Portions of 0.4 mL of a 1 M solution of SO2Cl2 in DCM are added repeatedly over a period of 27 h to an ice-cooled suspension of 3-(5-methoxy-3-trifluoromethyl-phenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (105 mg, 0.20 mmol) (Example 26) in acetonitrile (6 mL). The reaction is followed by HPLC analysis. The reaction mixture (still containing starting material) is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated. Reversed phase MPLC (H2O/CH3CN+0.1% TFA) yields, after neutralization of the product containing fractions with NaHCO3, partial concentration and extraction with DCM, the title compound: API-MS: 564/566 [MH]+; TLC: Rf=0.28 (DCM/MeOH+1% NH3aq, 95:5); 1H-NMR (DMXO-d6) δ 1.02 (t, H3C), 2.37 (q, H2C), 2.51 (m, 4H), 2.92 (m, 4H), 3.33 (s, H3C), 3.82 (s, H3C), 6.48 (s, 1H), 6.90 (s, 1H), 7.12 (d, 1H), 7.43 (m, 2H), 7.59 (s, 1H), 7.82 (s, 1H), 8.55 (s, 1H), 9.66 (s, HN), 12.33 (s, HN).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(O)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
4-Chlorophenylboronic acid (501 mg) was combined with 4-iodobenzoic acid (795 mg), cesium carbonate (5.22 g), toluene (16 mL), water (8 mL) and n-butanol (4 mL). The mixture was degassed under vacuum with argon purging after which, tetrakis-triphenylphosphine palladium (40 mg) was added. The reaction was heated to 80° C. for 20 hours after which, it was cooled to room temperature and diluted with ethyl acetate (16 mL). The solids were collected on a Celite pad and washed with hot methanol. The methanol filtrate was concentrated to dryness giving 4′-chloro-4-biphenylcarboxylic acid (305 mg). Yield=41%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH:13]([CH3:21])[C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:14]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:8][C:13]=1[CH3:21]
Reactant: COc1ccc(C(N)=O)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: ClCCl
Product: COC(=O)Cc1nc(-c2ccc(OC)cc2)oc1C
Temperature: 120 °C
Yield: 15.1 %

Procedure:
A mixture of 725 mg (4.80 mmol) of 4-methoxybenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate was heated neat at 120° C. for 2 h. The resulting dark slurry was cooled to RT, diluted with 2 mL of DCM and purified by silica gel flash column chromatography using hexane/EtOAc (3/1) as eluent to afford 189 mg of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ7.92 (d, 2H, J=8.9), 6.93 (d, 2H, J=8.9), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (s, 2H), 2.34 (s, 3H); low resolution MS (FAB)m/e 285 (MH+), 284 (M+).
Reaction SMILES: [C:1]([O-])(=O)C.[NH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([C:13]#[N:14])=[CH:8][NH+:7]=1.C(O)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29]>CC(C)=O>[S:28]([OH:31])(=[O:30])(=[O:29])[CH3:27].[NH2:5][C:6]1[N:7]=[CH:8][C:9]2[C:13]([NH:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)=[N:14][CH:1]=[N:12][C:10]=2[CH:11]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Reactant: N#Cc1c[nH+]c(N)cc1N
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: O=CO
Product: Nc1cc2ncnc(NCc3ccc(Cl)cc3)c2cn1

Procedure:
The free base (56 mg, 0.20 mmol)(prepared from 2,4-diamino,5-cyanopyridinium acetate, formic acid and 4-chlorobenzylamine at 200° C. as described in a previous example is precipitated from acetone solution with methanesulfonic acid (105 μL, 0.23 mmol) to give a polymesylate salt. 1H NMR (DMSO) δ 10.59 (1H, t, J=5.6 Hz), 9.24(1H, s), 8.69 (1H, s), 7.42 (4H, s), 6.42 (1H, s), 5.8 (6H, vbrs), 4.89 (2H, d, J=5.8 Hz), 2.41 (˜7.5H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:5][CH2:4]1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[N:13]=[C:14]([NH:16][C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:29])[S:15][C:11]=1[C:9]([CH:6]1[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]1)=[O:10]
Reactant: COC1CCC(C(=O)c2sc(N)nc2-c2ccco2)CC1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
Compound 441 (579 mg, 1.89 mmol) was dissolved in THF (9.0 mL), and isonicotinic acid (931 mg, 7.57 mmol), EDC hydrochloride (1.45 g, 7.57 mmol) and 1-hydroxybenzotriazole monohydrate (1.16 g, 7.57 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 442 (664 mg, 85%).
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4](Cl)(=[O:8])[C:5](Cl)=[O:6].[C:10]1([C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[OH:11]>O1CCOCC1>[NH:1]1[C:5](=[O:6])[C:4](=[O:8])[NH:3][C:2]21[O:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[O:11]2
Reactant: N#CN
Reactant: Oc1ccccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Product: O=C1NC2(NC1=O)Oc1ccccc1O2
Reaction time: 2 h

Procedure:
0.155 mol (6.5 g) of dehydrated cyanamide were put into 500 ml of anhydrous dioxane and 0.155 mol (19.65 g) of oxalyl chloride were added dropwise at 20° C. After 2 hours' stirring, 0.155 mol (17.1 g) of pyrocatechol, dissolved in 50 ml of dioxane, were added dropwise. The reaction mixture was stirred overnight, suction filtered to remove precipitate and washed with dioxane and water. The solid product was dried and stirred up with about 200 ml of acetone, filtered with Tonsil and evaporated to dryness under reduced pressure at a bath temperature of about 35° C. 13.2 g, which is 41.4% of the theoretical yield, of spiro-[1,3-benzodioxol-2,2'-imidazolidine]-4',5'-dione were obtained. The melting point was 202° C with decomposition.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].O>CC(C)=O.CCOCC>[CH:2]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1sccc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)CSc1sccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a solution of methyl [3-(2-dioxolanyl)-thiophene-2-ylthio]acetate (23.36 g) in acetone (100 mL) was added p-toluenesulfonic acid (0.25 g) and the reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate (4 mL) was added with stirring followed by the addition of water (50 mL). After stirring for 10 minutes, the acetone was evaporated in vacuo to leave a gum and water. The gum was dissolved in ether (500 mL) and extracted with water (4×50 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo to leave 19.77 g of oily methyl (3-formylthiophene-2-ylthio)acetate which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)C>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: CCO
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Yield: 28.7 %

Procedure:
7-Fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 9 g of 4-(4-fluorophenyl)piperazine in 30 cm3 of pyridine for 28 hours. After concentrating the reaction mixture to dryness under reduced pressure (20 kPa) at approximately 60° C., the residue was taken up twice in 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid was taken up into 50 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. 20 cm3 of water and approximately 10 cm3 of 10% acetic acid were added to the precipitate formed. The suspension was extracted 3 times with 50 cm3 of trichloromethane. The trichloromethane was concentrated under reduced pressure (20 kPa) and the solid obtained was taken up in 2 times 20 cm3 of ethanol. After crystallizing once from 42 cm3 and then recrystallizing once from 15 cm3 of dimethylformamide, 1.33 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid were obtained in the form of a brown solid melting at about 304-305° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]CCl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][NH:15][CH2:1][CH:27]([O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[CH2:28][CH3:29])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: NCCc1ccccc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(CNCCc1ccccc1)Oc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and phenylethylamine (0.4 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to oily compound which was later crystallized by benzene hexane to get N-(2-phenylethyl)-(2-(naphthalen-2-yloxy)butyl)amine, solid, m.p. 139° C., (yield 0.656 gm, 95.6%).
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
420 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C. under a nitrogen atmosphere, 350 ml of THF are added, then, dropwise, a solution of 57.6 g of 4-chlorophenylacetic acid in 70 ml of THF is added and the mixture is left stirring at −60° C. for one hour. 66 g of methyl 2,4-dichlorobenzoate are subsequently added dropwise at −60° C., the mixture is left stirring at −60° C. for 40 minutes and then the temperature is allowed to rise to 0° C. The reaction mixture is poured onto an ice/1 liter of 2N HCl mixture and extracted with ether, the organic phase is dried over Na2SO4, the solvent is concentrated under vacuum to a volume of 150 ml, 200 ml of pentane are added and the crystalline product formed is filtered off. 60 g of the expected compound are obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([OH:19])C.O>[OH-].[K+]>[CH:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([CH3:16])([CH3:15])[C:13]([NH2:14])=[O:19])=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C#N)c1ccc(C(=O)C2CC2)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionitrile (100 mg) in aqueous ethanolic potassium hydroxide (2 mL) (prepared from ethanol (5 mL), water (5 mL) and solid potassium hydroxide (1.5 g). Stir overnight at room temperature, then heat at reflux for 6 hours. Cool and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: C1[O:8][C:6](=[O:7])[CH2:5][O:4]C1=O.[Sn]>>[C:6]([OH:8])(=[O:7])[CH:5]([CH:5]([C:6]([OH:8])=[O:7])[OH:4])[OH:4]
Reactant: O=C1COC(=O)CO1
Agent: [Sn]
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 0.83 h

Procedure:
The L(+)-tartaric acid was previously dried over silica gel (Riedel-de Haen, Seelze, Germany) in an Abderhalden drying apparatus for about 10 hours. The reactor (connected to a pump via a liquid nitrogen trap) was then put under vacuum (0.04 mbar) with stirring for about 50 minutes to remove toluene. The reactor, under an atmosphere of oxygen-free nitrogen (BOC gases, Dublin, Ireland, moisture content of 8 VPM), was then immersed in an oil bath (Temperature=˜180° C.) and stirring was increased to 125 rpm. Prior to immersion, a heating tape (Thermolyne type 45500, input control setting=4) was placed on the reactor lid. The time taken to completely melt the reactor contents was noted, typically about 15 minutes for a load of 300 g at about 180° C. Samples were taken every hour during synthesis and analyzed by GPC to determine the percentage residual monomer and to obtain values for average molecular weight by number (Mn) and by weight (Mw) distributions. Typical reaction times were of the order of about 15 hours. The final polymer was also analyzed by titration to determine an acid number in meq/g and by OC to determine residual unreacted monomer content. Further analyses include IR (detection of characteristic C═O peak); NMR (determination of lactide and glycolide content in polymer) and residual tin (determination of residual tin due to use of stannous 2-ethyl hexanoate as catalyst).