Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=C)[CH:20]=[C:19]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:8]=1)=[O:5].C[OH:27]>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([CH:23]=[O:27])[CH:22]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]2[CH2:17][CH2:18]2)=[O:15])[CH:8]=1)=[O:5]
Reactant: CO
Reactant: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-vinylbenzamide (750 mg, 1.99 mmol) was dissolved in a solution of MeOH (14 mL) and DCM (28 mL). The resulting mixture was cooled to −78° C., O3 was bubbled into the solution for 7 min, N2 was bubbled for 10 min, and then Me2S (14 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 20 min. The mixture was concentrated under reduced pressure to provide 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-formylbenzamide (0.70 g, yield: 86%). LCMS (ESI) m/z: 378.1 [M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:57])([F:56])[F:55])[CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]([F:56])([F:57])[O:53][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=1)[CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccc(OC(F)(F)F)c2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-3-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (65%) as a white solid: mp 88-91° C.; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][N:1]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[CH:10]=[CH:9][S:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2sccc12
Temperature: 90 °C
Reaction time: 48 h
Yield: 14.5 %

Procedure:
To a solution of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (188 mg, 0.59 mmol), TFA (0.37 mL, 4.75 mmol) in TFE (2.5 mL) was added 4-aminobenzonitrile (280 mg, 2.37 mmol) in a scaled tube. The reaction was stirred at 90° C. for 2 d. Reaction-mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC afforded the product as white solid (34 mg, 14%):
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.FC1C=CC(C2(CCO)[O:36]C(=O)NCC2)=CC=1>>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:36])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reactant: O=C1NCCC(CCO)(c2ccc(F)cc2)O1
Product: C[C@H](N1CCC(CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C

Procedure:
(S)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 2] (500 mg, 1.57 mmol) was converted to (R)-3-(S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 2] (300 mg, 59%) following a procedure analogous to that described immediately above. LC-MS Method 1 tR=1.112, min, m/z=324.2; 1H NMR (CDCl3): 0.85-0.99 (m, 12H), 2.09-2.18 (m, 1H), 2.19-2.34 (m, 3H), 2.73-2.84 (m, 1H), 3.12-3.28 (m, 1H), 3.48-3.57 (m, 1H), 3.69-3.76 (m, 1H), 4.26-4.35 (m, 1H), 7.02-7.08 (m, 2H), 7.24-7.32 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].C[O-].[Na+].CS(O)(=O)=O.N[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17]#[N:18]>CO.O>[Cl:1][CH2:2][C:3]1[N:22]([CH2:23][C:24](=[O:32])[NH:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[N:4]=1
Reactant: N#CCCl
Reactant: N#Cc1ccc(NCC(=O)NC2CCCCC2)c(N)c1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of chloroacetonitrile (3.9 ml) in methanol (166 ml) was added sodium methoxide (3.29 g), and the mixture was stirred at room temperature for 40 min under a nitrogen atmosphere. Methanesulfonic acid (7.91 ml) and 3-amino4-(cyclohexylcarbamoylmethylamino)benzonitrile (8.3 g) were added, and the mixture was stirred for 3 hours. After completion of the reaction, water (166 ml) was added and the precipitated solid was collected by filtration, and washed with a small amount of water. The obtained solid was stirred in a mixture of hexane and tetrahydrofuran, collected by filtration and dried under reduced pressure to give the title compound (9.30 g).
Reaction SMILES: [C:1]1(=[N:10]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([NH:10][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: ON=C1CCc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1=CCc2ccccc21
Reaction time: 2.5 h

Procedure:
1-Indanone oxime (7.02 g, 0.048 moles), pyridine (250 ml) and acetic anhydride (170 ml) were stirred and heated under nitrogen at reflux for 16.5 hours. The cooled mixture was evaporated in vacuo and the residue agitated thoroughly with 1N sodium carbonate solution and ether (250 ml each). The liquid was filtered through filter-aid and the black solid treated again with sodium carbonate/ether and filtered. The combined ether extracts and washes were dried (MgSO4) and evaporated to a black-orange oil (8.6 g). This was applied to a column of basic alumina, allowed to stand for 2.5 hours and eluted with ethyl acetate/hexane 1:2 v/v. The appropriated fractions were evaporated to leave a crude solid (3 g). This was recrystallized from ethyl acetate/hexane to give the title product, mp. 139° C., (1.44 g, 17%) with the same IR spectrum as in Example 1.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[C:9](=O)[N:8]([C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([NH2:22])=[O:21])[C:7]2=[O:23]>C1COCC1.CO>[Cl:13][C:12]1[C:4]([Cl:3])=[CH:5][C:6]([C:7]([OH:23])=[O:1])=[C:10]([C:9]2[NH:22][C:20](=[O:21])[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[N:8]=2)[CH:11]=1
Reactant: [OH-]
Reactant: NC(=O)c1sccc1N1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH2:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34])([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Yield: 99.2 %

Procedure:
Into a 1-neck round-bottom flask was added tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and tetrahydrofuran (20 mL) and triethylamine (1.0 mL, 7.2 mmol). The mixture was cooled in an ice bath and (3-nitrophenyl)methanesulfonyl chloride (1.1 g, 4.8 mmol) was slowly added. The resultant mixture was warmed to rt. The solvent was removed under vacuum and EtOAc and water added. The aqueous phase was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4 and the solvent removed under vacuum to give the desired product (1.94 g, 99%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 9.37 (s, 1H), 8.98 (s, 1H), 8.19 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.71 (dt, J=7.7, 1.3 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.10 (m, 1H), 6.81 (t, J=8.0 Hz, 1H), 6.78 (br, 1H), 6.75 (ddd, J=7.4, 2.2, 1.6 Hz, 1H), 1.46 (s, 9H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([S:37]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(F)c1)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-(3-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (104 mg, 0.3 mmol), NEt3 (0.14 mL, 1.1 mmol), and 3-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the free base product (90 mg, 70% yld) as an off-white solid. MS (ES+) 433.2(M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C

Procedure:
The 3-acetoxy-2-methylbenzoic acid (3) is then reacted, for example with thionyl chloride, to give 3-acetoxy-2-methylbenzoyl chloride (4) ##STR4##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1.O[C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([O:52][C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice cooling, 72 mg of triphenylphosphine were dissolved in 1 ml of dry tetrahydrofuran, and 47 mg of diethyl azodicarboxylate were added. After 15 min, 80 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol were added, followed by 32 μl of triethylamine and 44 mg of tert-butyl alpha-hydroxyisobutyrate. The reaction mixture was then stirred at room temperature for 16 hours, and another 72 mg of triphenylphosphine and 47 mg of diethyl azodicarboxylate were added with ice cooling. After a further 4 h at room temperature, the reaction was concentrated and purified by preparative HPLC. This gave 60 mg (53%) of the title compound.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[SH:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.Cl.[Cl:26][CH2:27][C:28]1[C:33]([CH3:34])=[C:32]([S:35][CH2:36][C:37]2[O:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][N:29]=1>C(O)(C)C>[ClH:26].[ClH:13].[O:38]1[CH:39]=[CH:40][CH:41]=[C:37]1[CH2:36][S:35][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:27][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:33]=1[CH3:34]
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 90 %

Procedure:
The compound of Example 1 can also be prepared via the corresponding dihydrochloride, by refluxing 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 30 ml of isopropanol with 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride (10 mmol) for 5 h, cooling, removing the precipitated solid by filtration and recrystallizing this from isopropanol/water. This gives the title compound (yield 90%) as a colorless solid of m.p. 208° C. (decomp.).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN(C1C=CC=CN=1)C.[OH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@H:34]2[CH2:51][C@@:49]3([CH3:50])[C@@H:45]([CH2:46][CH2:47][C:48]3=[O:52])[C@H:44]3[C:35]2=[C:36]2[C:41]([CH2:42][CH2:43]3)=[CH:40][C:39](=[O:53])[CH2:38][CH2:37]2)=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C@H:34]3[CH2:51][C@@:49]4([CH3:50])[C@@H:45]([CH2:46][CH2:47][C:48]4=[O:52])[C@H:44]4[C:35]3=[C:36]3[C:41]([CH2:42][CH2:43]4)=[CH:40][C:39](=[O:53])[CH2:38][CH2:37]3)=[CH:30][CH:29]=2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCOCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOc2ccc([C@H]3C[C@]4(C)C(=O)CC[C@H]4[C@@H]4CCC5=CC(=O)CCC5=C43)cc2)cc1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
320 mg of tosyl chloride and 70 mg of dimethylamino-pyridine are added to 690 mg of the product obtained in Stage D in 5 cm3 of pyridine, then two lots of 115 mg of tosyl chloride is added again. Agitation is carried out for 2 hours and 30 minutes, followed by acidifying with 6N hydrochloric acid, extraction with ethyl acetate, washing with an aqueous solution of sodium bicarbonate, with salt water, drying and evaporating the solvent under reduced pressure, the residue is chromatographed on silica (eluant: ethyl acetate-essence G 7-3 then ethyl acetate). 710 mg of expected product is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH3:23])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH3:23]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(CC)sc1N
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 180 °C
Yield: 17.3 %

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.0 g (0.040 mol) of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 180° C. for two hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 1.8 g of 2-ethyl-4-oxo-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 278°-280° C. after recrystallization from pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(C)[CH:19]=CC=C(S(O)(=O)=O)[CH:15]=1.C(O)C=C>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:19][CH:14]=[CH2:15])=[O:6]
Reactant: Cc1cccc(S(=O)(=O)O)c1
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Solvent: C=CCO
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1cc(F)cc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
3-Fluoro-5-nitrobenzoic acid (3 g, 16.2 mM), m-toluenesulfonic acid (1.54 g, 8.1 mM), and allyl alcohol (50 ml) were heated to reflux, passing the distillate through 3å molecular sieves, for 16 hours. After cooling, the mixture was neutralised with triethylamine, and solvent removed. The residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, aqueous NaHCO3, and brine, and dried over MgSO4. Crude product was purified by chromatography on silica, using a gradient elution from dichloromethane to ethyl acetate/dichloromethane (3:1), to give allyl 3-fluoro-5-nitrobenzoate. Nmr (CDCl3): δ4.89 (dt, 2H); 5.33-5.49 (m, 2H); 5.95-6.15 (m, 1H); 8.11 (m, 2H); 8.70 (t, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(Br)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 45.1 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (200 mg, 1.06 mmol) and methyl 2-(5-bromo-1H-indol-3-yl)oxoacetate (300 mg, 1.06 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.06 mL, 1.06 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.12 mL, 2.12 mmol) was added. The resulting dark red solution was heated up to 50° C. overnight. The mixture was cooled to room temperature, quenched with 1N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to an orange solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (201 mg, 45%) as an orange solid, mp 270–290° C. dec.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH3:8][C:9]([CH3:11])=[O:10].C1OC1C>C[Si](C)(C)N[Si](C)(C)C.Cl.O.C(O)C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:9]([OH:10])([CH3:11])[CH3:8])(=[O:7])[OH:6]
Reactant: CC(C)=O
Reactant: NCCCP(O)O
Agent: CC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(O)P(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml of hexamethyldisilazane is heated to reflux under an inert gas for 20 hours. After this time a clear solution results and the reaction mixture is cooled to room temperature under inert gas and 50 ml of anhydrous acetone is added and an exothermic reaction results. The reaction mixture is allowed to cool to room temperature and the volatile components removed invacuo to afford a clear oil. This oil is dissolved in 50 ml of a 2.0M hydrochloric acid solution in water and washed with 2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer is evaporated to dryness to give a semi-solid residue which is co-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml) yielding3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloride m.p. 159°-161° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid affords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p. 243°-244°.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([CH2:18][CH2:17][C:14]([OH:16])=[O:15])[CH:20]=3)[NH:24][C:23]2=[O:28])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(CCC(=O)O)cc21
Yield: 65.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 102.6 mg 5-carboxyethyl-2-oxindole and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by chromatography a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 121 mg (66%) of the title compound as a yellow solid.