Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-4-n-octoxybenzophenone (652 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. for 6 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (85 mg, yield 33%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28]3)=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 7-hydroxy-2-phenyl-chromen-4-one via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH2:11][CH2:12][C:13]4[C:14](=[N:17][NH:18][CH:19]=4)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:8]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4([NH2:30])[CH2:29][CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[N:9][C:10]3[CH2:11][CH2:12][C:13]4[C:14](=[N:17][NH:18][CH:19]=4)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 63.7 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (6 mg, 0.012 mmol) was dissolved in TFA (0.8 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (3 mg, 50% yield). 1H NMR (500 MHz, CH3OD) 8.16 (s, 1H), 7.58 (s, 1H), 7.49 (d, 2H), 7.43 (d, 2H), 7.30 (m, 3H), 3.24 (t, 2H), 3.02 (t, 2H), 2.78 (m, 2H), 2.59 (m, 2H), 2.23 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: C([N:8]([CH2:26][CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:9][CH2:10][CH:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>C(Cl)Cl.[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:26][CH2:27][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(C(CCN(CCc2ncccn2)Cc2ccccc2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(C(CCNCCc2ncccn2)c2ccc(F)cc2)cc1
Temperature: 50 °C

Procedure:
To a mixture of N-benzyl-3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine (1.23 g, 2.77 mmol), ammonium formate (0.985 g, 15.6 mmol), and palladium (10% wt on carbon) (0.382 g, 3.59 mmol) was added MeOH (10 mL). The reaction mixture was heated to 50° C. for 1 h, diluted with DCM, filtered and partially concentrated, diluted with EtOAc, washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 10% MeOH (2 M NH3) in DCM) gave 3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:29][C:30]1[CH:37]=[CH:36][C:33](/[CH:34]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:28][CH:27]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
50.2 g (97.9 mmol) of 4-bromobenzyltriphenylphosphonium bromide and 21.7 g (118 mmol) of 4-bromobenzaldehyde were put into a 500 mL three-necked flask. Then, the atmosphere in the flask was substituted with nitrogen. Thereafter, 200 mL of tetrahydrofuran (abbreviation: THF) was added to the mixture. A suspension obtained by mixing 13.2 g (118 mmol) of potassium-tert-butoxide into 100 mL of THF was dropped to this mixture. Thereafter, the mixture was stirred at room temperature for 24 hours to be reacted. After the reaction, the reaction solution was washed with water, and then a precipitate was collected by suction filtration. Then, 14.0 g of objective (E)-4,4′-dibromostilbene was obtained as a white powdered solid in a yield of 42%. Further, the filtrate from which the precipitate was collected was extracted with ethylacetate and the extracted solution was dried over magnesium sulfate. After the drying, the mixture was subjected to suction filtration and the filtrate was condensed. The obtained residue was purified by silica gel column chromatography (developing solution: toluene). The obtained solution was condensed; then 14.8 g of (Z)-4,4′-dibromostilbene was obtained as a light yellow solid in a yield of 45%. Synthetic scheme of 4,4′-dibromostilbene is illustrated below (synthetic scheme a-2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Methyl 3-({3-[(tert-butoxycarbonyl)amino]propyl}amino)-4-nitrobenzoate (10.2 g) in solution in a mixture of ethyl acetate/methanol 3:1 (300 ml), and 10% palladium on carbon (1.02 g) are introduced into an autoclave. After stirring for 4 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (7.75 g; 83% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N[OH:15]>C(O)CCC>[OH:15][N:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: Nc1nc2ccccc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: CCCCO
Product: O=c1[nH]c2ccccc2[nH]c1=NO
Temperature: 25 °C
Yield: 4.6 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 3-aminoquinoxalin-2(1H)-one (1) (100 mg, 0.620 mmol) and hydroxylamine hydrochloride (94 mg, 1.3 mmol; Aldrich Co.) in 5 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 5 mg (42%) of 3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one as a pale yellow solid mp dec.>330° C. 1H NMR (300 MHz, DMSO-d6) δ 11.156 (br s, 1H, NOH), 10.776 (br s, 1H, NH), 9.878 (br s, 1H, NH), 7.258-6.813 (m, H, H-5+H-6+H-7+H-8). LRMS: 177 (M+, 78%), 161 (100%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>O1CCCC1>[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[NH:12][CH:11]=2)=[C:2]([F:1])[N:7]=1)=[O:27]
Reactant: COc1ncc(F)cc1C(=O)Cl
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ncc(F)cc1C(=O)Nc1ccc(Cc2c[nH]c3ncc(C)cc23)c(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a reaction flask, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 100 mg, 0.3902 mmol) was combined with 5-fluoro-2-methoxy-nicotinoyl chloride (151, 81.37 mg, 0.4292 mmol), 3.00 mL of tetrahydrofuran, and pyridine (0.06312 mL, 0.7804 mmol). The reaction was stirred at room temperature overnight, then poured into aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 1-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-2168, 100 mg). MS (ESI) [M+H+]+=409.9.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Br:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:36]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=4[Cl:28])(=[O:38])=[O:37])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: NCC1CCN(C[C@H]2COc3ccc(Br)cc3O2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Br)cc3O2)CC1)c1cccc(Cl)c1Cl
Reaction time: 24 h
Yield: 99.2 %

Procedure:
Triethylamine (0.63 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-bromo-1,4-benzodioxan-2-ylmethyl)piperidine (0.5 g) and 2,3-dichlorobenzenesulphonyl chloride (0.74 g) in dichloromethane (15 ml) and stirred under nitrogen for 24 hours. The reaction was diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 9:1 mixture of dichloromethane and methanol gave (S)-(-)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamide as a cream solid (0.8 g) m.p. 93-95° C., [α]D22 -37.1°(c=0.93, MeOH).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:23])[NH:13][C:14]2[S:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[N:18]=2)=[CH:8][CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:13][C:14]2[S:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[N:18]=2)=[O:23])=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)(=O)=O)cs2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1csc(NC(=O)c2ccc(O)cc2)n1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
2 M hydrochloric acid (3.0 mL) was added to a suspension of 83 (0.12 g, 0.35 mmol) in tetrahydrofuran (3.0 mL), and the resulting suspension was warmed to reflux. The reaction became homogeneous upon heating. After refluxing for 1.5 h, the reaction was allowed to cool to room temperature, and then partitioned between diethyl ether and water. The ether layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The ether layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue triturated with ethyl acetate, the solvent was removed under a stream of nitrogen, and the resulting solid was dried in vacuo at 55° C. to give 84 (0.086 g, 82%) as a light yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6](N)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.N([O-])=O.[Na+].[I-:19].[K+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[I:19][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([O:3][CH3:2])[CH:5]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: C1CCOC1
Product: COc1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of conc. HCl in H20 (1:1 v/v, 1.1 ml) was added to a solution of 3-methoxy-5-(trifluoromethyl)benzenamine (250 mg, 1308 μmol) in THF (2 ml). The mixture was stirred at RT for 1 hr and then cooled to 0 C. A chilled solution of sodium nitrite (208 mg, 3008 μmol) in H20 (2 ml) was added slowly. Additional H20 (0.8 ml) was added. A solution of potassium iodide (369 mg, 2223 μmol) in H20 (0.415 ml) was added dropwise. Additional H20 (0.62 ml) and THF (3.9 ml) was added and the reaction mixture was then gradually warmed to room temperature and stirred overnight. Analysis by LCMS indicated the reaction was complete. Saturated aqueous Na2CO3 was added, the volatiles were removed by rotovap, and the mixture was partitioned with DCM. The aqueous layer was extracted with DCM (2×), the organic layers were combined and washed with brine and dried over Na2SO4. Purification by Biotage was performed using 100% Hexanes to give a clear oil (208 mg, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[S:22])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=C1CC(=S)Nc2ccc(Cl)cc2N1c1ccccc1
Reaction time: 0.67 h

Procedure:
A solution of 28.6 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione and 23.3 g of phosphorus pentasulfide in 250 ml of pyridine is refluxed, with stirring, for 40 minutes under argon. The solvent is evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25][N:26]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=2)=[CH:5][CH:4]=1.O.NN.CCOCC.C1(=O)C2C(=CC=CC=2)C(=O)NN1>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=[C:11]([CH2:25][NH2:26])[CH:10]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(COc2cnc(CN3C(=O)c4ccccc4C3=O)cc2OCc2ccc(OC)cc2)cc1
Agent: NN
Agent: O=c1[nH][nH]c(=O)c2ccccc12
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(COc2cnc(CN)cc2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4,5-bis(4-methoxybenzyloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (Intermediate 64, 1.1 g, 2.15 mmol) in chloroform (20 mL) and methanol (10 mL) at room temperature was added hydrazine hydrate (0.328 mL, 4.31 mmol). The reaction was stirred overnight at room temperature. Another 1 eq of hydrazine hydrate was added. After 4 hours the reaction mixture was filtered to remove the solids. The filtrate was concentrated to afford an orange oil. The oil was dissolved in methanol and ether was added to crash out more solids. This was repeated until no 2,3-dihydrophthalazine-1,4-dione by product remained. The title compound was obtained as an orange foam (0.82 g, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.ClCCl>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:36])=[O:35]
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)ccc12)c1ccsc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride in 69 mL of pyridine is admixed at 0° C. with a solution of 1.14 g of 2,3-dichlorobenzenesulfonyl chloride in 23 mL of dichloromethane. The reaction mixture is stirred for 3 hours at a temperature in the region of 20° C. and then concentrated under reduced pressure. The dry residue is diluted in ethyl acetate, washed with water and then washed with saturated sodium chloride solution and concentrated under reduced pressure. The foam obtained is purified by flash chromatography, eluting with a dichloromethane/methanol/acetonitrile (96/2/2 by volume) mixture, to give 0.69 g of 3-thiophenecarboxylic acid {6-[4-(2,3-dichlorobenzenesulfonylamino)phenyl]-1H-indazol-3-yl}amide, whose characteristics are as follows:
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6].[C:25]1(=[O:35])[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>C1(C)C=CC=CC=1>[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]([C:5]([NH:4][CH2:3][C:2]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[C:28]([OH:30])=[O:29])=[O:35])[CH2:21][CH2:20]2)=[O:1])=[O:6])=[CH:12][CH:11]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(=O)O)CC1)c1ccc(-c2ccccc2)cc1
Yield: 48.9 %

Procedure:
Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (150 mg, 0.46 mmol) and phthalic anhydride (69 mg, 0.46 mmol) in toluene (20 mL) were heated to reflux for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by Preparative TLC (using silicagel 60F254 coated glass plate (20×20 cm, 1 mm (thickness) as the stationary phase with the mobile phase being 10% MeOH in Chloroform) to afford 106 mg (48.5% yield) of 2-(4-{2-[(biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-benzoic acid, LC-MS purity: 86.97%, 1H NMR: (DMSO) δ 8.6 (t, 1H), 7.9 (d, 2H), 7.85-7.7 (m, 4H), 7.5 (t, 2H), 7.4 (t, 1H), 7.3-7.2 (bs, 2H), 7.0 (bs, 1H), 4.25-4.05 (m, 2H), 3.75-3.4 (m, 6H), 3.1-3.0 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 6-bromo-3-hydroxypicolinate (26B) (464 mg, 2 mmol) in MeOH (0.5 mL) was added to a solution of LiOH (200 mg in 2 mL water). The reaction mixture was stirred at rt for 2 h. The product precipitated out of solution and was filtered, washed with water, and dried under reduced pressure to provide the desired product 6-bromo-3-hydroxypicolinic acid (55A). 1H NMR (300 MHz, CDCl3): 7.6 (1H, d), 7.32 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOCC.O.CO>[Si:14]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: OCc1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (6-chloropyridin-3-yl)methanol (643 mg, 4.48 mmol) in DMF (15 mL) was added tert-butylchlorodimethylsilane (675 mg, 4.48 mmol) and imidazole (610 mg, 8.96 mmol). The reaction mixture was stirred at room temperature for 5 h, then diluted with 200 mL of ether, washed with saturated NaHCO3 solution, 10% LiCl solution, and brine. The solution was dried with anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation 47A (869 mg, 75%). HPLC: RT=3.623 min (H2O/MeOH with TFA, CHROMOLITH® ODS, 4.6×50 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=258 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.1, 2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.75 (s, 2H), 0.93-0.86 (m, 9H), 0.12-0.06 (m, 6H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].ClC[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#CCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCC#N)ccc(C(C)=O)c1O

Procedure:
A solution of 44.4 g. of 2,4-dihydroxy-3-propylacetophenone, 42.2 g. of 6-chlorocapronitrile, 33.2 g. of potassium carbonate and 4.0 g. of potassium iodide in one liter of methyl ethyl ketone was allowed to reflux for three days. The reaction mixture was filtered and the filtrate was evaporated in vacuo. Chromatography of the residue over silica gel (0-30% ethyl acetate gradient in hexane) gave 53.6 g. of the title product as an oil.