Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH2:9].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31](SC)=[N:32][CH:33]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH:9][C:31]1[NH:30][C:29](=[O:36])[C:28]([CH2:27][C:24]2[CH:25]=[N:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[CH:33][N:32]=1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Reactant: CCN(CC)Cc1ccc(OC)c(CSCCN)c1
Solvent: c1ccncc1
Product: CCN(CC)Cc1ccc(OC)c(CSCCNc2ncc(Cc3ccc(C)nc3)c(=O)[nH]2)c1

Procedure:
2-Methoxy-5-(diethylaminomethyl)benzyl alcohol (British Patent Specification No. 594624) is treated with thionyl chloride to give the benzyl chloride and this is reacted with cysteamine and sodium ethoxide in ethanol to give 2-(2-methoxy-5-(diethylaminomethyl)benzylthio)ethylamine. This amine is heated under reflux for 40 hours in dry pyridine with 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone to give 2-[2-(2-methoxy-5-(diethylaminomethyl)benzylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[OH-].[Na+].ClCCl.[CH3:16][C:17]([CH3:19])=[O:18]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:16]/[C:17](=[O:18])[CH3:19])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)/C=C/c1ccc(Cl)cc1F
Yield: 76 %

Procedure:
To a mechanically stirred solution of 4-chloro-2-fluorobenzaldehyde (23.8 grams (g), 0.15 mole (mol)) in acetone (100 milliliters (mL)) at room temperature was added over 20 minutes (min) a solution of sodium hydroxide (NaOH, 6.6 g, 0.165 mol) in water (H2O, 400 mL). After stirring the reaction mixture overnight, dichloromethane (CH2Cl2, 100 mL) was added. The aqueous layer was separated and extracted with CH2Cl2 (100 mL), and the combined organic extracts were washed with brine and dried over magnesium sulfate (MgSO4). Solvent removal followed by Kugelrohr distillation gave 4-(4-chloro-2-fluorophenyl)-3-buten-2-one (1; 22.5 g, 76%) as a colorless liquid, which solidified upon standing: by 70-80° C., 0.1 mmHg (13.33 pascals (Pa)); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=16.5 Hz, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.22-7.12 (m, 2H), 6.76 (d, J=16.5 Hz, 1H), 2.39 (s, 3H); HRMS-ESI (m/z): calcd for C10H8ClFO, 198.024. found 198.025.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:13])[CH2:11]Cl)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:9][C:10](=[O:13])[CH2:11]2
Reactant: O=C(CCl)Nc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(F)c(F)cc2N1
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
A mixture of N-(3,4-difluorophenyl)chloroacetamide (14 mmol) and aluminum chloride (54 mmol) was stirred and heated to 200-210 deg C. in a silicon oil bath for 4.5 h. On cooling, 40 mL of ice cold hydrochloric acid was added to the reaction mixture. The solid residue was removed by vacuum filtration and purified by column chromatography with hexane-ethyl acetate (1:1) as eluting solvent. The yield for this step was 40.7%. 1HNMR (300 MHz, in DMSO-d6) δ 10.46 (s, 1H, NH), 7.33 (t, J=8.7 Hz, 1H, Ar—H), 6.82 (q, J=6.9 Hz, 1H, Ar—H), 3.47 (s, 2H, ArCH2CO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:35])[C:10](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.O.[OH:37]OS([O-])=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:35])[C:10](=[O:37])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C(C(=O)c1ccc(OC)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.510 g, 1.1 mmol) in THF (10 ml) was added water (10 ml) followed by oxone (0.974 g, 1.6 mmol) in portions and the resulting mixture was stirred at room temperature overnight. The solid was removed by filtration and filtrate concentrated in vacuo and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford crude ethyl 3-(4-methoxyphenyl)-2,3-dioxopropanoate as a yellow oil (0.500 g) as a mixture with triphenylphosphine oxide which was used without further purification. LCMS (2) 2.38 min; m/z 237.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(NC(C)C)(C)C.[OH:48][NH:49][C:50](=[NH:59])[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>CN(C)C=O>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[C:14](=[O:16])[NH:59][C:50](=[N:49][OH:48])[C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: COc1ccc(C(=N)NO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=NO)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
23 mg (0.1 mmol) of Boc-D-Pipecolic Acid were treated with 0.1 mmol [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate (HATU) and Diisopropylamine (DIPEA) in 1 ml Dimethylforamide (DMF) for 10 min. 17 mg (0.1 mmol) of N-Hydroxy-4-methoxy-benzamidine were added and the reaction stirred at room temperature for 20 min. The product was not further characterized.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:22][CH3:23])[C:9]3[C:14]([Br:15])=[CH:13][N:12]=[C:11]([CH2:16][O:17]C(=O)C)[C:10]=3[N:21]=2)=[N:4][O:5][N:6]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:22][CH3:23])[C:9]3[C:14]([Br:15])=[CH:13][N:12]=[C:11]([CH2:16][OH:17])[C:10]=3[N:21]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(COC(C)=O)ncc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(-c2nonc2N)nc2c(CO)ncc(Br)c21
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a suspension of the product of step 2 (312 mg, 0.74 mmol) in methanol (10 ml) was added a 2M aqueous solution of sodium hydroxide (1.1 ml, 2.21 mmol) and the reaction heated at reflux for 1 hour. The reaction was then diluted with water (20 ml) and aged at room temperature for 2 hours. The resulting precipitate was collected, washed with water and dried in vacuo at 45° C. for 16 hours to afford the title compound (220 mg, 88%); MS (ES+), m/e 339/341 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([OH:14])=O)=[C:9]([CH3:11])[N:10]=1)=[O:4].COC(NC1SC(C(Cl)=O)=C(C)N=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:36][CH:37]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:38]#[N:39]>C(N(CC)CC)C>[C:38]([CH:37]([NH:36][C:12]([C:8]1[S:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:10][C:9]=1[CH3:11])=[O:14])[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)#[N:39]
Reactant: COC(=O)Nc1nc(C)c(C(=O)O)s1
Reactant: N#CC(N)c1cccs1
Agent: COC(=O)Nc1nc(C)c(C(=O)Cl)s1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc(C)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 32.1 %

Procedure:
1.7g of 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.8g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.5g of amino-thiophen-2-yl-acetonitrile hydrochloride and 2.4ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.85g (Yield 32%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:44]=[CH:43][C:32]3[N:33](C(OC(C)(C)C)=O)[CH:34]=[N:35][C:31]=3[CH:30]=2)O1.CC1(C)C(C)(C)OB(C2C=CC3N=CN(C(OC(C)(C)C)=O)C=3C=2)O1>>[NH:33]1[C:32]2[CH:43]=[CH:44][C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:30][C:31]=2[N:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: CC(C)(C)OC(=O)n1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]cnc4c3)ccn2c1=O

Procedure:
Methyl 8-(1H-benzo[d]imidazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and a mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (141.5 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title BOC-deprotected compound as a yellow solid (69.9 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35](O)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:41]2)=[CH:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:41]2)=[CH:28]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Product: Cc1ccc(OC(C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c2ccccc2)cc1
Yield: 48.9 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.32 g of (2RS)-2-(4-methylphenoxy)-2-phenylacetic acid and 0.61g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 0.42 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N#Cc1c(N)cccc1OC1CCOCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCOCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (Example 118b) and ethyl 3-oxobutanoate as a pale yellow solid (51%). MS 331 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.[CH2:23]([O:25][C:26](=[O:54])[CH:27](CC)[CH2:28][CH2:29][N:30]1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2[C:31]1=[O:51])[CH3:24].N(CCCC(OCC)=O)=C=O.C(N(CC)CC)C.N(CCCC([O-])=O)=C=O>C(OCC)(=O)C.CCCCCC>[CH2:23]([O:25][C:26](=[O:54])[CH2:27][CH2:28][CH2:29][N:30]1[C:31](=[O:51])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])[CH3:24]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Agent: CCOC(=O)CCCN=C=O
Agent: O=C=NCCCC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)CCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
2-(4-Nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (25 mg, 0.087 mmol, 1 molequivalent), prepared as described hereinabove (see, preparation of Compound 1), ethyl 4-isocyanatobutyrate (135 mg, 0.87 mmol) and triethylamine (214 μl, 1.74 mmol) were stirred overnight at room temperature. Additional 4-isocyanatobutyrate (130 μl) was added and the mixture was heated to 50° C. and was stirred at this temperature overnight. Once TLC analysis, using a 2:1 hexane:ethyl acetate mixture as eluent, indicated a complete conversion, the crude mixture was purified by column chromatography using a gradient of hexane to hexane:ethyl acetate (9:1) as eluent to give pure Compound 30 (26 mg, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[CH:4][C:3]=1[F:22].[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([N+:37]([O-])=O)[CH:29]=1)[CH2:24][CH2:25][CH3:26]>>[NH2:37][C:30]1[CH:29]=[C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(N)c(F)c2)C1
Reactant: CCCCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(CNC(=O)OC(C)(C)C)C3)cc2F)c(N)c1

Procedure:
tert-Butyl [1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed by hydrogenation. This resulted in the product with the molecular weight of 500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+).
Reaction SMILES: [S:1]1[C:5]2S[CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([OH:11])=[O:10].O[O:13][S:14]([O-:16])=O.[K+]>O>[S:1]1[C:5]2[S:14](=[O:16])(=[O:13])[CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([OH:11])=[O:10]
Reactant: O=S([O-])OO
Reactant: O=C(O)c1cc2c(s1)SCC2
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc2c(s1)S(=O)(=O)CC2
Temperature: 60 °C
Yield: 68 %

Procedure:
4,5-Dihydrothieno[2,3-b]thiophene-2-carboxylic acid (88.3 g, 0.474 mol) was added to a solution of Oxone® (730 g, 1.18 mol) in water (3.0 L), and the resulting suspension heated on a steam bath for 1 hour. During this time the solids dissolved to give a clear yellow solution. The reaction was cooled to 60° C. and filtered. The filtrate was extracted four times with ethyl acetate (6 L total) and the combined extracts washed with saturated brine and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the title compound as a yellow solid (70 g, 68%). Recrystallization from dichloroethane gave an off-white powder, mp=227°-230° C. Anal. Calc. for C7H6O4S2 : C, 38.52; H, 2.77. Found: C, 38.53; H, 2.61.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18].ClCCl>ClCCCl>[N+:17]([C:20]1[CH:21]=[C:22]([S:26]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Indole (17.09 mmol, 2.0 grams) was taken in 1,2-dichloroethane (20 mL) in 100 mL three necked round-bottomed flask. Triethylamine (34.19 mmol, 3.45 grams) was added to it at 25° C. The above mixture was added to solution of 3-nitrobenzenesulfonyl chloride (25.64 mmol, 5.68 grams) (obtained from step (i)) and dichloromethane (25 mL), while maintaining the temperature below 10° C. The reaction mixture was then stirred for a period of 24 hours at 25° C. After the completion of reaction, the reaction mixture was poured onto ice-water mixture under stirring and the product was extracted with ethyl acetate (2×30 mL). The combined ethyl acetate extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 5.4 grams of thick syrupy mass, which was purified by column chromatography using silicagel (100-200 mesh), eluent being ethyl acetate and n-hexane (5:95),
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4]CC=1.C.OO.[C:11]([OH:14])(=[O:13])[CH3:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(=O)C=CC(=O)C=C1>[C:11]([O:14][CH:5]1[CH2:6][CH2:7][CH:1]=[CH:4]1)(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: C1=CCCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)C=C1
Product: CC(=O)OC1C=CCC1
Reaction time: 2 h
Yield: 62 %

Procedure:
Acetoxylation of cycloheptene A 500 ml three-neck flask is charged with 15 g of cycloheptene (0.15 moles), 150 g of acetic acid, 0.77 g of benzoquinone (7 mmoles), 1 g of charcoal and 80 mg of palladium acetate (0.35 mmoles). The temperature is taken to 50°, then 8 g (0.17 moles) of 70% by weight hydrogen peroxide are introduced in 8 h, and the reaction is allowed to proceed for a further 2 h while maintaining the temperature at 50°. The acetic acid is then distilled (35°, 20×102Pa). The residue is distilled under vacuum (75°-80°, 15×102Pa) to provide cyclopent-2-en-1-yl acetate (14 g, yield 62%). cyclopent-2-en-1-yl acetate
Reaction SMILES: C([C:3]1[N:4]([CH:27]2[CH2:29][CH2:28]2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[CH:9][C:8]([F:17])=[C:7]([C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25]Cl)[CH:19]=1)[CH:6]=2)C.[CH3:30][O-:31].[Na+]>CO>[CH:27]1([N:4]2[C:5]3[C:10](=[CH:9][C:8]([F:17])=[C:7]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH2:25][O:31][CH3:30])[CH:19]=4)[CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)[CH2:29][CH2:28]1
Reactant: C[O-]
Reactant: CCc1c(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(CCl)c3)cc2n1C1CC1
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)cc(C)n1
Yield: 65 %

Procedure:
A solution of 1.52 g ethyl-1-cyclopropyl--7-[2-(chloromethyl)-6-methyl-4-pyridinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 18b) in 125 ml methanol was treated with 1.5 g of powdered sodium methoxide, and the reaction mixture was heated at reflux for about 16 hours. The mixture was quenched in ice containing acetic acid and extracted with methylene dichloride. The extracts were concentrated and the residue treated with water. The solid product was collected and dried (1.11 g) and was recrystallized from ethyl acetate/hexane to give 0.91 g 1-cyclopropyl-6-fluoro-7-[2-(methoxymethyl)-6-methyl-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 192°-193° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].C(O)=[O:12].OO.S([O-])([O-])=O.[Na+].[Na+]>O>[OH:12][CH:5]1[CH:6]2[CH:1]3[CH:2]([CH2:3][CH:4]1[CH2:7]3)[C:8](=[O:10])[O:9]2
Reactant: O=CO
Reactant: O=C(O)C1CC2C=CC1C2
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1OC2C(O)C3CC1C2C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
With 328.2 g of 5-norbornene-2-carboxylic acid was mixed 240.6 of formic acid. Below 50° C., 254.5 g of 35% aqueous hydrogen peroxide was added dropwise to the mixture over 6 hours. After the completion of addition, the reaction mixture was poured into a mixture of 1.5 liters of water and 0.8 kg of sodium sulfite. After three times of extraction with 1 liter of ethyl acetate, the organic phase was washed with water, dried, and concentrated in vacuum. The residue was dissolved in 1.2 liters of methanol, to which a catalytic amount of potassium carbonate was added. This was agitated for one hour at room temperature. The methanol was distilled off under vacuum, followed by conventional extraction and washing. There was obtained 247.6 g of 2-hydroxy-4-oxatricyclo[4.2.1.03,7]nonan-5-one. The yield was 65.5%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:42])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cc(OC2CCCC2)c2c(=O)[nH]cnc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [9] in Example 15, 7-acetoxy-5-cyclopentyloxy-3,4-dihydroquinazolin-4-one (5 g) was reacted with carbon tetrachloride and triphenylphosphine to give 7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline (5.3 g); NMR Spectrum: (CDCl3) 1.65-1.8 (m, 2H), 1.8-2.05 (m, 4H), 2.1 (m, 2H), 2.4 (s, 3H), 4.95 (m, 1H), 6.78 (d, 1H), 7.35 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 307 and 309.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].F[C:9]1[C:14]([F:15])=[C:13]([N:16]2[CH2:21][CH:20]([CH3:22])[CH2:19][CH:18]([CH3:23])[CH2:17]2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[C:14]([F:15])=[C:13]([N:16]2[CH2:21][CH:20]([CH3:22])[CH2:19][CH:18]([CH3:23])[CH2:17]2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC1CC(C)CN(c2ncnc(F)c2F)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
0.09 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.3 ml of tetrahydrofuran solution of 0.15 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.3 ml of tetrahydrofuran solution of 0.40 g of 4,5-difluoro-6-(3,5-dimethylpiperidino)pyrimidine (cis/trans diastereomer=about 5/1) at room temperature, and stirred for 20 minutes at 0° C. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.46 g of 4-(2-butynyloxy)-5-fluoro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (50)). Compound (50) had the cis/trans diastereomer originated two methyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]([CH2:8][C:9]([CH3:11])=O)=O.[N+:12]([N:15]=[C:16]([NH:18][NH2:19])[NH2:17])([O-:14])=[O:13]>O>[CH3:5][C:6]1[CH:8]=[C:9]([CH3:11])[N:18]([C:16](=[N:15][N+:12]([O-:14])=[O:13])[NH2:17])[N:19]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNC(N)=N[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)n(C(N)=N[N+](=O)[O-])n1
Yield: 89 %

Procedure:
2.7 ml of acetic acid and 2,4-pentadione (0.785 mg, 7.83 mmol) are added to a mixture heated under reflux containing the N′-nitrohydrazinecarboximidamide compound isolated previously (0.5 g, 4.20 mmol) in 15 ml of water. The reaction medium is returned to ambient temperature then filtered. The solid obtained is washed with dichloromethane. A white solid in the form of white powder is obtained with a yield of 89%.