Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:2].[Cl:26][C:27]1[C:32]([O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:31][C:30]([NH:40][N:41]=[CH:42][C:43](=O)[C:44]([F:47])([F:46])[F:45])=[C:29]([F:49])[CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:32]([O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:31][C:30]([N:40]2[C:1](=[O:2])[CH:6]=[C:43]([C:44]([F:47])([F:46])[F:45])[CH:42]=[N:41]2)=[C:29]([F:49])[CH:28]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=NNc1cc(Oc2ncccn2)c(Cl)cc1F)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)cnn1-c1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 76.9 %

Procedure:
Carboethoxymethylenetriphenylphosphorane (0.235 g) was added to a suspension of 3,3,3-trifluoro-2-oxopropanal 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazone (0.122 g) in toluene (15.0 ml) and the mixture was heated at reflux for 1 hour. The solvent was removed under reduced pressure and the residue chromatographed on silica gel to give the titled compound (0.10 g) mp=156-60° C. 1H NMR (CDCl3, TMS): 7.11(1H, br t), 7.32(1H, m), 7.42(1H, d, J=6.9 Hz), 7.43(1H, d J=9.0 Hz), 8.05(1H, br d), 8.58(2H, br d).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([O:10]CC)=[O:9])=[N:5][CH:4]=1.C1COCC1>>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[N:5][CH:4]=1
Reactant: CCOC(=O)c1ncc(OC)s1
Solvent: C1CCOC1
Product: COc1cnc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-methoxythiazole-2-carboxylate (73 mg, 0.39 mmol) in THF (1 ml) 1 M LiOH-solution (0.78 ml, 0.78 mmol) was added. Reaction mixture was stirred at RT for 1 h. Reaction was quenched by adding 1 M HCl solution until pH was about 5. Solvents were evaporated and thus obtained crude title compound was used without purification. 1H-NMR (400 MHz; d6-DMSO): δ 3.88 (s, 3H), 7.12 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:32]([N:34]=C=NCCCN(C)C)[CH3:33].O.ON1C2C=CC=CC=2N=N1.O1CCCC1.C(N)C>CN(C)C=O>[CH2:32]([NH:34][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1)[CH3:33]
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg), 1-hydroxybenzotriazole monohydrate (214 mg), 2M ethylamine tetrahydrofuran solution (0.7 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/70/30 to 8/92/0, volume ratio) to give a pale yellow amorphous solid. The amorphous solid was crystallized from acetonitrile to give white crystals. The crystals were recrystallized from acetonitrile to give the title compound (222 mg, 70%) as colorless crystals. MS 455 (MH+). mp 130-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@H:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C(OC1C=CC(C#N)=C(F)C=1)C)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[C@H:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[C:12]([F:18])[CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Agent: CC(Oc1ccc(C#N)c(F)c1)C(=O)OC(C)(C)C
Product: C[C@@H](Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.20) was prepared in a manner analogous to that described in Preparation 10, substituting (R)-2-(4-Cyano-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding (+)-2-(4-cyano-3-fluoro-phenoxy)-propionic acid tert-butyl ester material.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([C:3]1[C:4]2[C:9](=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Product: O=C(c1c(F)ccc(F)c1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12

Procedure:
N-[3-(2-Chloro-3,6-difluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2-chloro-3,6-difluorobenzoyl chloride (Compound No. 37).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)#[N:2].Br.Br.Br.[CH2:15]([C:17]1[C:18]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([C:34]4[NH:43][C:37]5[CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:36]=5[N:35]=4)=[N:30][NH:31]3)=[CH:27][CH:26]=2)=[CH:19][C:20]([F:24])=[C:21]([OH:23])[CH:22]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([OH:23])[C:20]([F:24])=[CH:19][C:18]=1[C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:34]3[NH:43][C:37]4[CH2:38][CH2:39][N:40]([C:9]([C:5]5[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=5)[C:1]#[N:2])=[O:11])[CH2:41][CH2:42][C:36]=4[N:35]=3)=[N:30][NH:31]2)=[CH:27][CH:26]=1)[CH3:16]
Reactant: N#Cc1ccnc(C(=O)O)c1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cc(C#N)ccn3)CC4)n[nH]c2c1
Yield: 15.6 %

Procedure:
The title compound was prepared from 4-cyano-pyridine-2-carboxylic acid (12.5 mg, 85 μmol) and 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) using the method of Example 8. The crude material was purified by HPLC Method B to afford 6.5 mg of the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][CH:28]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[I:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:32][CH:31]=1
Reactant: Ic1ccc(CCCCCCCCCCCCCCCCCCOCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Reaction time: 2 h

Procedure:
Finally, to a solution of 1-benzyloxy-18-(p-iodophenyl)octadecane (Compound V) (185 mg; 0.33 mmol) and anisole (0.15 ml; 1.32 mmol) in dichloromethane (3 ml) was added anhydrous aluminum chloride (135 mg; 1 mmol) at the room temperature. Stirring was continued for 2 h. The reaction was quenched by diluted hydrochloric acid and extracted by chloroform. Extract was dried (Na2SO4) and evaporated. The residue was chromatographed in hexane-ethyl acetate (gradient from 95:5 to 85:15) to give 18-(p-iodophenyl)octadecanol, Compound VI (123 mg; 77%).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(OCC)C.[OH-].[Na+].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>O>[OH:4][N:3]([CH3:2])[C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1)=[O:22]
Reactant: CNO
Reactant: CSc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CSc1ccc(NC(=O)N(C)O)cc1
Yield: 59.8 %

Procedure:
N-Methylhydroxylamine hydrochloride (1.1 g, 13 mmol) was dissolved in water (2 mL) then combined with diethyl ether (15 mL). The mixture was cooled in an ice bath then combined with a solution of sodium hydroxide (0.53 g, 13 mmol) in water (2 mL). The reaction mixture was allowed to stir for several minutes then 4-(methylthio)phenyl isocyanate (2.1 g, 13 mmol) was added dropwise via Pasteur pipette. A heavy white precipitate formed almost immediately. Diethyl ether (20 mL) was added and the reaction mixture was allowed to stir at ambient temperature overnight. The solid was isolated by filtration then recrystallized from 1,2-dichloroethane to afford 1.65 g of the desired product as a white crystalline solid, m.p. 146°-148° C. Analysis: Calculated for C9H12N2O2S: %C, 50.93; %H, 5.70; %N, 13.20; Found: %C, 50.82; %H, 5.63; %N, 13.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:3]=1[CH2:16][C:17]([OH:19])=O>O>[F:15][C:11]1[CH:12]=[CH:13][C:14]2[C:17](=[O:19])[CH2:16][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[S:8][C:9]=2[CH:10]=1
Reactant: O=C(O)Cc1c(Cl)cccc1Sc1cccc(F)c1
Solvent: O
Product: O=C1Cc2c(Cl)cccc2Sc2cc(F)ccc21
Reaction time: 3 h
Yield: 82.5 %

Procedure:
The mixture of 8.0g of 2-chloro-6-(m-fluoro-phenylthio)-phenylacetic acid and 80g at polyphosphoric acid was stirred at 120°-125° C for 3 hours. After cooling, to the mixture was added water and the mixture was extracted with chloroform. The extract was washed with 100ml of 1% sodium hydroxide solution, then water, dried over anhydrous sodium sulfate and freed of the solvent to afford 6.2g (83%) of 3-fluoro-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one having a melting point of 109°-111° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]([C:19]4[C:20]([CH3:29])=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][N:23]=5)=[O:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:29][C:20]1[C:19]([C:17]([NH:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:31][CH:30]=2)=[O:18])=[CH:28][C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
N-(4-(1,4-Dioxaspiro[4.5]decan-8-yl)benzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (35.9 mg, 0.086 mmol) was dissolved in THF (1 ml). Aqueous HCl (1 ml, 1M) was added and the reaction was stirred at room temp for 18 hours. Reaction was then diluted with NaHCO3 (10 ml, sat aq) and extracted with EtOAc (2*15 ml). Combined organics were dried over MgSO4 and evaporated to give 25 mg (88%) of title compound as a pale mass.
Reaction SMILES: C([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH:18]=[CH:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21]C(=O)C)=[CH:16][C:15](=O)[CH2:14][CH2:13]4)C.C[Mg]Br.Cl>O1CCCC1>[CH2:6]([C@:5]12[CH2:14][CH2:13][C@@H:12]3[C@@H:17]4[C:16]([CH2:15][CH:8]([CH3:19])[C@H:9]3[C@@H:10]1[CH2:11][CH2:3][C@@H:4]2[OH:21])=[CH:5][C:4](=[O:21])[CH2:3][CH2:18]4)[CH3:7]
Reactant: CC[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(C)=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@]12CC[C@H]3[C@@H](C(C)CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 0.33 h

Procedure:
Add dl-13-ethyl-17β-acetoxygona-4,6-dien-3-one (2.0 g) in tetrahydrofuran (30 cc) to tetrahydrofuran (20 cc) containing 3 moles methyl magnesium bromide (16 cc) and cuprous chloride (299 mg) at 0°. Stir for 20 minutes and pour into ice-cold brine saturated with hydrogen chloride. Extract with ether and chromatograph on Grade 2.5 neutral alumina. To obtain the title compound, recrystallize from ethyl acetate-hexane (0.56 g), m.p. 152°-154°; λ max. KBr 2.98, 6.02 μ; λ max. EtOH 242 mμ (ε16,730).
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:23]([N:25](CC)CC)[CH3:24]>[Pt]>[N:25]1[C:3]2[C:2](=[CH:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:24][CH:23]=1
Reactant: Cc1cccc(O)c1
Reactant: CCN(CC)CC
Agent: [Pt]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: c1ccc2ncccc2c1

Procedure:
A 5-inch platinum wire was coated with a thin film of the polymer of Example 1, by dipping the wire into a 5% solution of the polymer in a m-cresol/P2O5 mixture. The film-coated wire was neutralized by dipping into a 10% triethylamine-90% ethanol solution and dried in a vacuum oven at 60° C.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[C:22]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 4-carbamoylphenethyl bromide (0.25 g--see Preparation 13), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. On cooling to room temperature, water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.13 g.
Reaction SMILES: O.[CH2:2]([N:9]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>CO>[CH2:2]([N:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A 12-l stainless steel autoclave was charged on air with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid monohydrate (180.0 g, 0.54 mol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP)] (413.2 mg, 0.54 mmol, S/C 1,000) and methanol (7.1 l). The asymmetric hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen (99.3% conversion). After the pressure was released, a sample of the white suspension was evaporated to dryness affording crude (S,S)-Ia with 99.0% purity and >99.9% ee. The reaction suspension was concentrated to a volume of 1.8 l and stirred for 1 h at 0-5° C. After filtration, the filter cake was washed with cold methanol and dried on vacuum to yield 176.0 g (>99%) of (S,S)-Ia as a white solid with 99.0% purity and >99.9% ee.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])=O>>[CH2:44]([N:43]([CH2:46][CH3:47])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:37][CH:38]=1)[CH3:45]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 76.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-diethylacetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (23 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=2)[N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=3)[N:13]=1)[CH2:6]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CN1C2CCCC1CNC2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Temperature: 25 °C

Procedure:
A mixture of 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 3.56 mmol), 2-chloro-6-nitroquinoline (0.74 g, 3.56 mmol), N,N-diisopropylethylamine (0.92 g, 7.13 mmol) and dioxane (25 ml) was stirred at reflux for 40 h. The mixture was allowed to cool to room temperature. The precipitated product was filtered and was washed with diethylether. The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). The pure product was isolated. Yield 300 mg (27%). Mp 166.2° C. LC-ESI-HRMS of [M+H]+ shows 313.1674 Da. Calc. 313.166451 Da, dev. 3 ppm.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[C:12]([O:24][CH3:25])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[F:36][C:37]1[CH:38]=[C:39]([CH:57]=[CH:58][CH:59]=1)[CH2:40][N:41]1[C:45]([CH3:46])=[C:44](B2OC(C)(C)C(C)(C)O2)[C:43]([CH3:56])=[N:42]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:36][C:37]1[CH:38]=[C:39]([CH:57]=[CH:58][CH:59]=1)[CH2:40][N:41]1[C:45]([CH3:46])=[C:44]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[C:12]([O:24][CH3:25])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[C:43]([CH3:56])=[N:42]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1NS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1NS(C)(=O)=O
Yield: 32.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, N-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dimethoxyphenyl) methane sulfonamide (intermediate 34) (55 mg, 0.485 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate-16) (57.8 mg, 0.175 mmol) in sodium carbonate (28 mg, 0.263 mmol), Pd(PPh3)2Cl2 (3.0 mg, 0.0043 mmol), Toluene/ethanol/water (10/5/2 ml) to give 40 mg (64.5% yield) of titled compound. MS: m/z=704.2 (M+1).
Reaction SMILES: [CH:1]1([CH:9]=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH:1]1([CH2:9][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=CC1CCCCCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCC2CCCCCCC2)cc1

Procedure:
Cyclooctane carboxaldehyde (14.72 g, 0.105 mole) was added dropwise to a stirred and refluxing mixture of 13.7 g (0.1 mole) p-aminobenzoic acid, 25 g zinc dust, 25 ml glacial acetic acid and 125 ml of benzene. Water which evolved was collected in a Dean-Stark trap as the reaction mass was refluxed overnight. Following the reflux period, the resulting product mass was filtered while still hot. Upon cooling the filtrate, crystals formed therein. The benzene was evaporated and the residue recrystallized from acetonitrile. The crude product weighed 18.77 g. It was decolorized and recrystallized from benzene. The resulting purified 4-[(cyclooctylmethyl)amino]benzoic acid product weighed 12.93 g. It had a melting point of 160°-162° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O.CCOCC>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([O:20][C:17]2[CH:18]=[N:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)cc1I
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Br)c(F)cc1Oc1ccc(Cl)nc1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A flask was charged with 5-bromo-4-fluoro-2-iodobenzoic acid (4.00 g, 11.60 mmol), 6-chloropyridin-3-ol (1.803 g, 13.92 mmol), and cesium carbonate (7.56 g, 23.19 mmol). The flask was evacuated and flushed with nitrogen twice before copper (I) trifluoromethanesulfonate toluene complex (0.156 g, 0.302 mmol) was added. Toluene (58.0 mL) (degassed 10 minutes by bubbling nitrogen through the solution prior to use) and ethyl acetate (0.084 mL, 0.858 mmol) were added and the mixture was heated at 115° C. After 2 hours, the reaction was allowed to cool to RT and the mixture was diluted with water (50 mL) and stirred vigorously for 15 minutes. After diluting with ether (200 mL), the layers were separated and the organic layer was extracted with 10% sodium carbonate. The pH of the combined aqueous layers was adjusted to pH ˜2 and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to afford 5-bromo-2-(6-chloropyridin-3-yloxy)-4-fluorobenzoic acid as a solid. MS m/z=347.9 [M+H].
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[N:21]2[CH:16]([CH:17]([CH3:24])[CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH2:15]1.CI>CCCCCC.C1COCC1.CCOC(C)=O.CN(C)P(N(C)C)(N(C)C)=O>[O:13]=[C:14]1[N:21]2[CH:16]([CH:17]([CH3:24])[CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH:15]1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: CC1COC(C)(C)N2C(=O)CC12
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1COC(C)(C)N2C(=O)C(C)C12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
THF, (20 ml) is placed under N2 treated with 1.54 ml diisopropylamine and cooled to -78° C. A solution of n-butyl lithium 1.97 M in hexane 5.6 ml is added dropwise over 5 min. The reaction mixture is stirred at -78° C. for 10 min and then treated with 8-oxo-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane (1.55 g) in 15 ml THF added dropwise over 5 min. After another 10 min hexamethylphosphoramide 1.97 ml is added. The mixture is stirred another 10 min, then treated with 2 ml of methyl iodide. The reaction mixture is stirred at -78° for 154 min and allowed to warm to 25° C. and stirred for 15 min. The reaction mixture is diluted with EtOAc, washed once with pH 7 phosphate buffer and dried and evaporated. The residue is chromatographed on silica gel using 25% EtOAc/C 6 H6 as eluant to give 8-oxo-2,2,5,7-tetramethyl-3-oxa-1-azabicyclo[4.2.0]octane.