Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][C:13]2[N:14]=[N:15][C:16]([Cl:22])=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=2)=[C:7]([CH3:23])[CH:6]=1.[OH-].[Na+]>CO>[Cl:22][C:16]1[N:15]=[N:14][C:13]([O:12][C:8]2[C:9]([CH3:11])=[CH:10][C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:6][C:7]=2[CH3:23])=[CH:18][C:17]=1[CH:19]([CH3:21])[CH3:20]
Reactant: COC(=O)Cc1cc(C)c(Oc2cc(C(C)C)c(Cl)nn2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CC(=O)O)cc(C)c1Oc1cc(C(C)C)c(Cl)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid methyl ester (8a) (1.66 g, 4.75 mmol, contains a minor amount of isomer) in methanol (50 mL) at room temperature was treated dropwise with a 1N aqueous sodium hydroxide solution (9.5 mL, 9.50 mmol). The reaction was stirred at room temperature for 24 h. At this time, the reaction mixture was concentrated under vacuum. The resulting solid was diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate layer was discarded. The water layer was acidified to pH=4 by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford a solid. The solid was dried overnight under high vacuum to afford [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid (9a) (1.58 g, 100%, contains a minor amount of isomer) as an off-white solid; EI(+)-HRMS m/z calcd for C17H19ClN2O3 (M+) 334.1084, found 334.1083. Molecular Weight=334.8056; Exact Mass=334.1084
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[CH:26]([F:32])[O:27][C:28]([F:31])([F:30])[F:29])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[O:43])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[CH:26]([F:32])[O:27][C:28]([F:31])([F:29])[F:30])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.22 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.46 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])=[O:4].O>ClCCl>[NH2:1][S:3]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:5])=[O:4]
Reactant: CCOc1ccc(C(=O)OC)c(S(=O)(=O)Cl)c1
Reactant: N
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Liquified ammonia (4.4 mL, 180 mmol) was added to a stirred solution of methyl 2-(chlorosulfonyl)-4-ethoxybenzoate (22.1 g, 79.3 mmol) in dichloromethane (221 mL) at -70° C. The reaction mixture was allowed to warm to -10° C. and was held at this temperature for 30 minutes. The mixture was then poured into water (221 mL). More water and dichloromethane were used for rinsing, and tetrahydrofuran (ca. 40 mL) was also added. The layers were shaken and separated, and the aqueous layer was extracted with dichloromethane (2×221 mL). The combined dichloromethane solutions were washed with water (221 mL), and the aqueous wash was back-extracted with dichloromethane (ca. 120 mL). The combined dichloromethane solutions were dried (Na2SO4), and filtered. Rotary evaporation of the solvent left crude product as an off-white crystalline solid (18.1 g). This was dissolved in hot methanol (ca. 200 mL) and hot filtered. The solution was boiled down to a volume corresponding to 3 mL/g methanol. After seeding and cooling with the aid of an ice bath, the crystals were collected, rinsed with ice-cold methanol and hexanes, and dried. Methyl 2-(aminosulfonyl)-4-ethoxybenzoate (15.3 g) was obtained as white crystalline needles melting at 146°-148° C. PMR (CDCl3, 200 mHz): δ7.91 (d, 1H, H ortho to CO2CH3); 7.68 (d, 1H, H ortho to SO2NH2); 7.04 (dd, 1H, H para to SO2NH2); 5.91 (broad s, 2H, NH2); 4.14 (q, 2H, OCH2CH3); 3.95 (s, 3H, CO2CH3); 1.45 (t, 3H, OCH2CH3). IR (Nujol): 3348 (m, NH); 3241 (m, NH); 1692 (s, C=O) cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[N:23][C:24]#[N:25])[N:14]([C:15]4[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:28])[C:13](=[N:23][C:24]#[N:25])[N:14]([C:15]4[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(-n2c(=NC#N)[nH]c3cnc4ccc(Br)cc4c32)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(Br)cc4c32)cn1
Reaction time: 0.25 h

Procedure:
To a solution of N-(8-bromo-1-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (compound of step 4, 0.674 mmol) in 5 ml of dry DMF at 0° C. was added NaH (60% dispersed in mineral oil, 1.011 mmol). The reaction mixture was stirred for 15 minutes followed by addition of methyl iodide (1.011 mmol). Reaction mixture was stirred at 0° C. for another 1 h and quenched with water. The solvent was removed; aqueous layer was extracted with DCM. Organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.62 (d, J=3 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.18 (dd, J=9 Hz, 3 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.80 (dd, J=9 Hz, 3 Hz, 1H), 7.21 (d, J=9 Hz, 1H), 7.03 (d, J=3 Hz, 1H), 4.01 (s, 3H), 3.83 (s, 3H); MS (m/z): 409 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>C(O)C.[Pd]>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:1]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(C(=O)O)c1N
Yield: 91 %

Procedure:
2-Nitro-3-methoxybenzoic acid (10 g, 0.051 mol) was suspended in ethanol with palladium/charcoal 10% (1 g). The mixture was placed under hydrogen (50 psi) and shaken on a Parr until theoretical uptake had been achieved. The suspension was then flushed with nitrogen, the charcoal filtered off, and the filtrate evaporated in vacuo to give 3-methoxyanthranilic acid (7.76 q, 91%) m.p. 172°-175°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](OC)=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1>[O-2].[Mn+2]>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2snnc2c1
Agent: [Mn+2]
Agent: [O-2]
Product: O=Cc1ccc2snnc2c1

Procedure:
This was prepared from methyl benzo[1,2,3]thiadiazole-5-carboxylate (0.291 g) by the method of Example 16c, (except that the alcohol was stirred with manganese (II) oxide overnight) and used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19](I)[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[O:4].C([O-])(=O)C.[K+]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)c2ccccc12
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A suspension of 40.0 g (83.9 mmol) of methyl-4-[(2-Butyl-5-formyl-4-iodo-1H-imidazol-1-yl)methyl]naphthalene-1-carboxylate, 9.07 g (92.4 mmol) of potassium acetate, and 6.0 g of 10% palladium on carbon in 1.2 liters of ethyl acetate was hydrogenated for 2 hours. The solids were removed by filtration and an additional 8.0 g of 10% palladium on carbon and 9.01 g (92.4 mmol) of potassium acetate was added. After hydrogenating the reation mixture an additional 2 hours, the solids were removed by filtration and the solution was concentrated to about 1/3 volume. The ethyl acetate solution was washed with aqueous sodium carbonate solution, dried over magnesium sulfate, and concentrated under vacuum to give an oil which crystallized. Recrystallization from methylene chloride-hexane gave 25.77 g (87.6%) of colorless crystals; mp 95.5°-97° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7]>CC#N.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:1]
Reactant: Cc1cc(CO)cc(C(=O)O)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: Cc1cc(C=O)cc(C(=O)O)c1
Reaction time: 4 h
Yield: 53.9 %

Procedure:
To a solution of 3-bromomethyl-5-methyl-benzoic acid (3.90 g, 17 mmol) in water (30 mL) and MeCN (30 mL), Cu(NO3)2 hemipentahydrate (12.77 g, 68 mmol) followed by water (50 mL) was added. The turquoise mixture was refluxed for 2 h before it was concentrated to about half of the original volume. The dark green solution was extracted three times with EA (150 mL). The org. extracts were washed twice with water (2×50 mL), combined, dried over Na2SO4, filtered and concentrated. The white residue was separated by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 95% MeCN in water containing 0.5% of formic acid) to give 3-hydroxymethyl-5-methyl-benzoic acid as a white solid (897 mg; LC-MS*: tR=0.17 min; [M−1]−=164.86), along with the title compound as a white solid (160 mg). To a solution of the above 3-hydroxymethyl-5-methyl-benzoic acid (947 mg, 5.70 mmol) in MeCN (40 mL), MnO2 (1.49 g, 17.1 mmol) was added and the resulting mixture was stirred at 80° C. for 16 h before another portion of MnO2 (1.21 g, 13.9 mmol) and acetonitrile (40 mL) was added and stirring was continued at 80° C. for 4 h. The mixture was filtered over a glass fibre filter, the colourless filtrate was concentrated and purified by prep. HPLC (as above) to give the title compound (504 mg) as a white solid. LC-MS*: tR=0.26 min; [M−1]−=162.88; 1H NMR (D6-DMSO): δ 2.47 (s, 3H), 7.96 (s, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 10.06 (s, 1H), 13.28 (m, 1H).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.CN(C)CCCN(C)C.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:30]1([S:36]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]([NH2:13])=[O:12])=[O:10])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Agent: CN(C)CCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 91 %

Procedure:
Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:20][C:19](=[O:21])[CH:18]([C:11]1[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:22]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-benzyloxy4-nitrophenyl)propionic acid(1.89 g), methanol(30 mL) and concentrated sulphuric acid(1 mL) was heated at reflux for 3 h, cooled to ambient temperature and the mixture was extracted with ether. The extract washed with brine, dried and evaporated to dryness to give methyl-2-(3-benzyloxy-4-nitrophenyl)propionate(1.8 g). [m/e316(MH+)].
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:15][OH:16])[N+:11]([O-])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:16][CH2:15][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1)(=[O:19])[CH3:18]
Reactant: [O-][n+]1ccc(Oc2ccccc2)cc1CO
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(Oc2ccccc2)ccn1
Yield: 88 %

Procedure:
All of the 4-phenoxypyridine-2-methanol-N-oxide was added to 45.0 g of acetic anhydride and the mixture was refluxed for 15 minutes to react them. After the reaction, acetic anhydride and the by-product of acetic acid were distilled off under a reduced pressure and the resulting crude product was distilled under a reduced pressure to obtain 40 g of the object compound (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:13][CH:14]([N-]C(C)C)[CH3:15].C(I)C=C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:14]=[CH2:13])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)[N-]C(C)C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C=CCI
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
3,4-Dichlorophenylacetonitrile (5 g, 26.87 mmol, 1 eq) in THF (50 mL) was cooled to −78° C. under Ar. LDA (2 M in THF, 16.1 mL, 32.2 mmol, 1.2 eq) was added and the reaction was warmed to 0° C. over 1 h. The reaction was re-cooled to −78° C. and allyl iodide (2.67 mL, 26.87 mmol, 1 eq) was added then the reaction was stirred at −78° C. for a further 2 h. The reaction was diluted with EtOAc (150 mL) and washed with aqueous HCl (1 M, 100 mL), saturated aqueous Na2S2O3 (100 mL) and saturated aqueous NaCl (100 mL). The organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to afford 2-(3,4-dichlorophenyl)-pent-4-ene-nitrile (6.3 g, ˜28 mmol) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([OH:33])=[O:23])[CH2:2][CH2:3]2)=[CH:8]1
Reactant: c1csc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4cccs4)c4ccccc34)CC2)c1
Yield: 176.2 %

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 4.35 mmol (15 mmol) of 3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 4.58 g (20 mmol) of 3-bromomethyl-benzoic acid methyl ester. After the standard work-up, 3.3 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 0.64 g (10% of yield) of the pure acid.
Reaction SMILES: O.[CH2:2]([NH2:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])([O:14]C)=[O:13].[OH-].[Na+]>CCOCC>[CH2:2]([NH:11][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCNC(=O)CCCCC(=O)O

Procedure:
A two liter beaker fitted with a mechanical stirrer, ice bath, and pH electrode, was charged with 700 mL of water and 89.4 g (0.624 mol) of nonylamine in 200 mL of ether. To this stirred mixture was added dropwise over a 30 minute period a solution of the above 5-carbomethoxyvaleryl chloride in 100 mL of ether. Concurrent with addition of the ether solution was added 50% sodium hydroxide solution at a rate such as to keep the pH of the aqueous layer between 10 and 12. Following addition of the acid chloride and sodium hydroxide the reaction mixture was added to a two L separatory funnel and extracted with 300 mL methylene chloride. The methylene chloride layer was separated, washed with 300 mL saturated sodium chloride solution, and dried over magnesium sulfate. Removal of the methylene chloride on a rotary evaporator yielded a yellow oil which solidified upon standing. Recrystallization from hexane afforded the methylester of 6-nonylamino-6-oxocaproic acid as colorless crystals, mp 56°-57° C., weight 155.1 g. Upon cooling to -15° C. the filtrate deposited an additional 11.0 of product. Total yield was 166.1 g (93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: ClCCCBr
Product: ClCCCOc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([CH3:9])=[N:3]1.C([O:12][CH:13]=[C:14]([C:18]#[N:19])[C:15]([O-])=O)C>C(O)C>[C:18]([C:14]1[C:13](=[O:12])[N:3]2[CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=[N:1][CH:15]=1)#[N:19]
Reactant: CC1=NC(N)CCCC1
Reactant: CCOC=C(C#N)C(=O)[O-]
Solvent: CCO
Product: CC1CCCCc2ncc(C#N)c(=O)n21
Temperature: -5 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2.52 g. of 2-amino-7-methyl-3,4,5,6-tetrahydro-2H-azepine are dissolved in 25 ml. of ethanol and the solution is added dropwise to a solution of 3.38 g. of ethoxy-methylene-cyanoacetate in 25 ml. ethanol at -5° C. The reaction mixture is stirred for 1 hour at -5° C. and allowed to warm up to room temperature and boiled for 1 hour. The solvent is evaporated. The residual oil is dissolved in 40 ml. of benzene and the solution is shaken out once with 10 ml. of 5% by W/V sodium carbonate solution and twice with 10 ml. of water. The benzene layer is dried above sodium sulphate and evaporated after filtration. The residual oil is crystallized from acetone. 1.26 g. (31%) 3-cyano-6-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine is obtained melting at 154° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[O-:30][CH2:31][CH3:32].[Na+]>C(O)C>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([O:30][CH2:31][CH3:32])=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: CC[O-]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 56 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and sodium ethoxide (5 mL of a 0.5M solution in ethanol). Yield 0.1 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), phenylboronic acid (80.5 mg, 0.660 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.6 mL) and DME (2.4 mL). Purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid) afforded the product (33.7 mg, 38%) as a white solid.