Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][CH:18]=O)[C:14]3[CH:20]=[C:21]([C:24]([N:26]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:37][CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:64]CCl>CO.C(O)(=O)C.O>[ClH:64].[ClH:64].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][CH2:18][NH:37][CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[C:14]3[CH:20]=[C:21]([C:24]([N:26]([CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH:22]=[CH:23][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: NCC1CCCCC1
Reactant: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNCC2CCCCC2)cc1
Product: Cl

Procedure:
A solution of 2-[(4-acetylphenyl)amino]-N,N-bis(3-methylbutyl)-1-(3-oxopropyl)-1H-benzimidazole-6-carboxamide (100 mg, 1 eq) and aminomethylcyclohexane (46 mg, 2 eq) is stirred for 4 hours at a temperature of approximately 20° C. The mixture is diluted with methanol (1 ml), then sodium triacetoxyborohydride (86 mg, 2 eq) and a few drops of acetic acid are added to produce a pH of 5. After 1 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce the expected dihydrochloride compound (83 mg, 62% yield).
Reaction SMILES: C[O:2][P:3]([O-:6])[O:4]C.[CH2:7]=O.[CH2:9]([CH2:11][NH2:12])[OH:10]>>[OH:10][CH2:9][CH2:11][NH:12][CH2:7][P:3](=[O:6])([OH:4])[OH:2]
Reactant: NCCO
Reactant: COP([O-])OC
Reactant: C=O
Product: O=P(O)(O)CNCCO
Temperature: 80 °C
Yield: 0 %

Procedure:
Dimethylphosphite (36 g, 0.3227 mole) was added dropwise over a period of 1 hour to a stirring solution of paraformaldehyde (9.8 g, 0.32 mole) and ethanolamine (20 g, 0.32 mole) below 20° C. under nitrogen. The solution was heated to 80° C. for 1 hour and then cooled to room temperature. The solution was extracted with 350 ml of benzene as described in the paper. The benzene solution was then passed through a column containing 1 kg of alumina and the column was eluted with 1 liter of benzene. The benzene solution was concentrated under vacuum to dryness and 250 mL of Conc. HCl was added. The solution was heated to 110° C. for 6 hours. Analysis of the reaction mixture by 31P-NMR showed 0% yield of N-(2-hydroxyethyl)aminomethylphosphonic acid. This Example demonstrates that contrary to what is disclosed in the Barsukov et al reference, the process taught in the Barsukov et al reference produces no N-(2-hydroxyethyl)aminomethylphosphonic acid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: NCc1cccnc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCc4cccnc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-pyridin-3-ylmethyl-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 3-(aminomethyl)-pyridine (0.82 mL, 8.1 mmol) in a manner analogous to Example 406. Product isolated as a light yellow powder (163 mg, 53%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64 (d, J=6.5 Hz, 1H), 8.62 (s, 1H), 8.44 (m, 1H), 8.38 (d, J=8.0 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.47 (t, J=12.8, 6.4 Hz, 1H), 7.35 (m, 1H), 7.04 (t, J=14.2, 7.2 Hz, 1H), 4.50 (d, J=6.2 Hz, 2H), 3.28 (s, 3H). MS=380 (MH)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[OH:6].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:4]([F:3])([F:18])[F:19])[N:24]=[CH:23][N:22]=1
Reactant: OC(c1ccccc1-c1ccco1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccco1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
Sixty percent NaH (12 mg, 0.3 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-furan-2-yl-phenyl)-ethanol (55 mg, 0.2 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, after which 4,6-dichloro-pyrimidine (29 mg, 0.2 mmol) was added. The mixture was then heated at 110° C. until the reaction was complete. After cooling, 5 ml of water was added, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 60 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-furan-2-yl-phenyl)-ethoxy]-pyrimidine (yield 80%).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH3:43]>CC(C)=O>[CH2:42]([C:25]1([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])[CH3:43]
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)C1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)c2ccccc2C1=O
Temperature: 20 °C

Procedure:
The intermediate 2-(1-Trityl-1H-imidazole-4-yl)indan-1,3-dione (79.4 g, 0.175 mol), potassium carbonate (72.5 g, 0.875 mol) and ethyl iodide (71 mL, 0.522 mol) were added to stirred acetone (1300 mL) in a 4-liter glass reactor, fitted with a mechanical stirrer, a thermometer and a reflux condenser. The reaction mixture was heated to reflux for 7 hours, then cooled to 20° C. and filtered. The inorganic residue on the filter was washed with acetone. The filtrate was concentrated in vacuo and poured into water.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6]([Cl:13])=[O:7])[CH3:3]
Reactant: CC(C)(C)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCC(=O)Cl
Yield: 52.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (1,1-dimethylethoxy)acetic acid (24.00 g, 0.182 moles) and 300 ml of toluene under nitrogen. Oxalyl chloride (46.10 g, 0.363 moles) was then added dropwise and to this mixture was added N,N-dimethylformamide (0.25 g, 0.003 moles). This solution was heated at 30°-40° C. for 5 hours and then concentrated in vacuo to give 14.5 g of the product as a brown oil.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
cis-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (22.3 g, 95.59 mmol) was dissolved in CH2Cl2 (240 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (25.42 g, 114.7 mmol) was added and the mixture was stirred for 30 minutes. NEt3 (19.99 mL, 143.4 mmol) was added and the mixture was slowly warmed to ambient temperature over 2 hours and stirred overnight. The mixture was diluted with CH2Cl2 and washed with 1N KHSO4 (2×100 mL) followed by washing with saturated aqueous NaHCO3 (100 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude orange solid was dissolved in minimal hot CH2Cl2 and hexanes were added with stirring until the solution became persistently cloudy. The warm mixture was cooled to ambient temperature and allowed to stand undisturbed for 1 hour. The solids were collected by filtration and the solid was successively washed with hexanes followed by 50% Et2O/hexanes and finally with hexanes again to provide the clean cis isomer of the product as a pale yellow solid (27.05 g, 68%).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C)=O)C=C(F)C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1>ClCCl>[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1d) (300 mg) in dichloromethane (40 mL) at 0° C. under nitrogen was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (238 mg), HOBt-hydrate (330 mg), EDAC-HCl (282 mg) and NMM (165 mg). The reaction mixture was stirred 1 h at 0° C., concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, and brine, dried, filtered and evaporated to yield a mixture of the title compound and N2-[(3,5-difluorophenyl)acetyl]-N1-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-alaninamide. The crude product (500 mg) was purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound (180 mg, 69%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ1.22 (d, 3H), 3.48 (s, 2H), 4.29 (m, 1H), 4.93 (t, 1H), 5.68 (d, 1H), 6.01 (d, 1H), 6.50 (d, 1H), 6.73-6.80 (m, 3H), 6.93-7.02 (m, 2H), 7.15 (d, 1H), 7.30 (t, 1H), 7.43 (t, 1H),7.5-7.6 (m, 1H), 7.73 (d, 1H), 7.74 (s, 1H). MS APCI, m/z=532 (M+1). LC/MS: 2.53 min.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-].[Na+].IC>C(O)C>[NH2:1][C:2]1[N:7]([CH3:13])[C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(N)[nH]c(=O)c1CCO
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: Cc1nc(N)n(C)c(=O)c1CCO
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 67.7 parts of 2-amino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone and 800 parts of ethanol were added 80 parts of a sodium methoxide solution 30%. The reaction mixture was heated to reflux temperature and 62.5 parts of iodomethane were added dropwise. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was suspended in 400 parts of water. The precipitated product was filtered off, washed with 40 parts of ethanol and dried, yielding 58.3 parts (79.6%) of 2-amino-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 12).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:34][NH2:35]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:34][N:35]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: NN
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-4-trifluoromethoxy-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-trifluoromethoxy-phenyl)-amine as brown solid in 33% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:19].O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][Br:19])=[CH:4][CH:3]=1
Reactant: OCC#Cc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: Clc1ccc(C#CCBr)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 141.3 %

Procedure:
A suspension of p-iodochlorobenzene [formula (VII), 7.15 g, 30.0 mmol], propargyl alcohol (1.75 mL, 30 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.21 g, 0.3 mmol), copper (I) iodide (29 mg, 0.15 mmol) and diethylamine (50 mL) was stirred under a N2 atmosphere at room temperature and dissolution occurred within 20 min. After 5 h, the diethylamine was removed, and the crude product was partitioned between water and ether. The ether phase was dried (brine), concentrated and flash chromatographed (4:1 petroleum ether: ethyl acetate) to provide 3-(4-chlorophenyl)-prop-2-yn-ol (compound of formula VIII, 4.09 g, 82%). This compound of formula (VIII) (3.47 g, 20.83 mmol) was suspended in dry ether (12 mL) and pyridine (0.42 mL) was added. The reaction mixture was cooled in an ice bath and a solution of phosphorus tribromide (1.0 mL, 10.42 mmol) in dry ether (6 mL) was added dropwise over a 15 min period. The reaction mixture was then stirred at room temperature for 2.5 h, cooled in an ice bath and crushed ice was added. The reaction mixture was added to water (200 mL) and extracted with ether (200 mL). The ether phase was washed with water, sat. aqueous NaHCO3 and brine. The extract was concentrated and flash chromatographed (9:1 petroleum ether:ethyl acetate) to provide the product as a white solid (3.38 g, 86%): mp 41°-43 ° C.; NMR (CDCl3): δ 7.37 (d, J=8.7 Hz, 2H, ArH), 7.27 (d, J=8.7 Hz, 2H, ArH), 4.16 (s, 2H, CH2).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12>Cl.CC(C)=O.O>[C:4]1(=[O:16])[N:5]([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 81.2 %

Procedure:
Methyl 7-phthalimidohept-5-ynoate (1.45 g) was dissolved in a mixture of concentrated hydrochloric acid (7.3 ml), acetone (30 ml) and water (14.6 ml) and the resulting solution was heated at reflux for 3.5 hours. The solution was cooled and then poured into water (175 ml). The precipitate was collected by filtration and recrystallised from ethanol-water to give the title compound (1.12 g) m.p. 120°-122° C.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)C=[CH:24]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7][C:9]2[C:26]3[C:31](=[N:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CS(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: c1ccc(Sc2c[nH]c3ncccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl phenyl sulfoxide (8.33 g, 59.4 mmol) in CH2Cl2 is chilled to −78° C. and treated dropwise with trifluoroacetic anhydride (4.1 mL, 5.3 mmol). After stirring for 30 min at −78° C., a solution of 7-azaindole (5.2 g, 44.0 mmol) in CH2Cl2 is added. After 30 min at −78° C., triethylamine (74 mL, 534 mmol) is added and the reaction is allowed to reach ambient temperature. After stirring for 3.5 days, the reaction is concentrated in vacuo, treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts are combined and concentrated in vacuo. The resultant residue is crystallized from methanol/H2O and recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid, 1.26 g, mp 188-189° C., characterized by mass spectral analyses and HNMR analyses.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32](O)=[O:33])[C:20]3=[O:38])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:37]=[CH:36][CH:35]=[C:31]([C:32]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[O:33])[CH:30]=4)[C:20]3=[O:38])[CH2:18]2)=[CH:13][CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Product: CC(C)N1CCN(C(=O)c2cccc(CN3C(=O)[C@@]4(C[C@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 1-isopropylpiperazine, (3-bromomethyl)-benzoate (commercially available), (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C31H32ClN3O2: 513, observed (M+H)+: 514.2 1H NMR (400 MHz, CDCl3) δppm 1.37 (d, J=6.32 Hz, 6 H) 2.04 (dd, J=7.71, 4.67 Hz, 1 H) 2.28 (dd, J=9.22, 4.67 Hz, 1 H) 2.86 (br. s., 2 H) 3.35 (t, J=8.46 Hz, 1 H) 3.61 (br. s., 6 H) 4.96 (d, J=15.92 Hz, 1H) 5.18 (d, J=16.17 Hz, 1 H) 6.02 (d, J=7.33 Hz, 1 H) 6.71-6.82 (m, 2 H) 7.06-7.19 (m, 3 H) 7.31 (s, 1 H) 7.33-7.39 (m, 1 H) 7.39-7.51 (m, 3 H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=N)C1C=CC=CC=1>>[OH:24][CH2:17][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15].[C:26]1([N:25]=[C:17]([O:24][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:8](=[O:15])[CH3:9])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: N=C(Cl)c1ccccc1
Product: CC(=O)c1ccccc1OC(=Nc1ccccc1)c1ccccc1
Product: O=C(CO)c1ccccc1

Procedure:
In a third method the 1,2-diphenylquinolones (IV, m = O) are prepared by acylation of an appropriate aniline with an appropriate benzoyl chloride, chlorination of the resulting benzanilide, reaction of the benzimidoyl chloride so obtained with an appropriate 2-hydroxyacetophenone and rearrangement of the resulting 2-acetylphenyl N-phenylbenzimidate. The sequence of reactions is illustrated by the following equations: ##STR9##
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:31][CH:32]=2)[O:3]1.[OH-].[Na+]>CO.O>[OH:3][CH:4]([C:28]1[N:29]=[C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31][CH:32]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2csc(-c3ccccc3)n2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of tert-butyl (4RS,5RS)-2-oxo-5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (3.17 g, 5.74 mmol) in methanol (60 ml) was added 1N sodium hydroxide (6.9 ml, 6.9 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give tert-butyl (1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (1.72 g, 57%) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].[BH4-].[Na+]>CO>[CH2:6]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)CO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of (2R)-2-amino propanol (1.2 equivalents), benzaldehyde (1 equivalent), NaHCO3 (1.5 equivalents), and MeOH, (˜1 M) was heated at reflux for 4 hours and then cooled to 0° C. Sodium borohydride (4.8 equivalents) was added portionwise to the stirred reaction mixture during a period of 2 hours at ca. 10° C. The whole was stirred at room temperature for 4 hours. The insoluble materials were filtered off and then the filtrate was concentrated to dryness. The residue was dissolved in CH2Cl2, and the solution was washed successively with water (2×) and brine (1×). The organic extracts were collected and dried (Na2SO4). The solvent was evaporated to give the desired product as a colorless oil, which solidified on standing and was used in the next step without further purification. GC/MS: 134 (100%, M+-CH2OH), Rt 11.57 minutes.