Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:41][NH:42][C:43]([NH2:45])=[O:44]>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([NH:45][C:43]([NH:42][CH3:41])=[O:44])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(N)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 110 °C
Yield: 101.3 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.193 mmol), Pd2 dba3 (3.6 mg, 0.004 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg, 0.012 mmol), cesium carbonate (75 mg, 0.231 mmol) and methylurea (74 mg, 1.0 mmol) in dioxane (2.3 mL) and DMF (0.8 mL) was degassed, placed under an argon atmosphere and heated at 110° C. for 5 hours. On cooling, the reaction was partitioned between aqueous sodium hydrogen carbonate solution and DCM and the organic phase washed with brine, dried and concentrated in vacuo to give the crude title compound (100 mg) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:52]([O:56][C:57](=[O:63])[NH:58][CH2:59][CH2:60][CH2:61][NH2:62])([CH3:55])([CH3:54])[CH3:53].[Na]>ClCCCl.C(Cl)Cl>[C:52]([O:56][C:57]([NH:58][CH2:59][CH2:60][CH2:61][NH:62][CH2:29][C:27]1[CH:26]=[N:25][N:24]([CH2:23][C@@H:19]2[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:31]\[O:32][C:33]3([C:36]([O:38][CH:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:34][CH2:35]3)/[C:12]3[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:10][CH:11]=3)[C:21](=[O:22])[NH:20]2)[N:28]=1)=[O:63])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [Na]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCNCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (370 mg, 0.52 mmol) in DCE (4 mL) at 0° C. was added tert-butyl(3-aminopropyl)carbamate (180 mg, 1.04 mmol) and sodium triacetoxyhydroborate (165 mg, 0.78 mmol) sequentially. After stirring at rt for 16 h, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 (aq), brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (assumed quantitative). The crude residue was used as such in the following step. LCMS: Rt=0.99 min, m/z=873.2 (M+1). Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3F)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[CH2:21]([N:24]([CH3:29])[CH2:25][C@H:26]([OH:28])[CH3:27])[CH:22]=[CH2:23]>CC(N(C)C)=O.[H-].[Na+]>[CH2:21]([N:24]([CH3:29])[CH2:25][C@@H:26]([CH3:27])[O:28][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:20])=[C:2]([Cl:1])[CH:7]=1)=[N:10][CH:11]=[N:12]2)[CH:22]=[CH2:23]
Reactant: C=CCN(C)C[C@@H](C)O
Reactant: Oc1ccc(Nc2ncnc3cccc(F)c23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Temperature: 110 °C
Yield: 68.3 %

Procedure:
2-chloro-4-[(5-fluoroquinazolin-4-yl)amino]phenol (2 g) was added to a stirred solution of (2R)-1-[allyl(methyl)amino]propan-2-ol (2.24 g, prepared as described in Example 2-3) in DMA (100 ml) and sodium hydride (60% dispersion in oil, 692 mg), and the mixture heated to 110° C. for 16 hours. The mixture was concentrated in vacuo then a saturated solution of sodium bicarbonate (200 ml) was added and extracted with DCM (300 ml). The extract washed with brine, dried and concentrated in vacuo and the residue purified by chromatography using DCM—10% methanol/2N ammonia as eluent to give 4-[(5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}quinazolin-4-yl)amino]-2-chlorophenol as a yellow solid (1.88 g, 68%); NMR spectrum (DMSO-d6) 1.43 (d, 3H), 2.17 (s, 3H), 2.54 (dd, 1H), 2.97 (m, 3H), 4.94 (m, 1H), 5.00 (dd, 1H), 5.10 (dd, 1H), 5.63 (m, 1H), 6.98 (d, 1H), 7.18 (d, 1H), 7.29 (d, 1H), 7.42 (dd, 1H), 7.69 (t, 1H), 7.84 (d, 1H), 8.44 (s, 1H), 10.01 (bs, 1H), 10.26 (s, 1H); Mass spectrum MH+ 399.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[O-2].[Zn+2:7].[Zn]>N>[C:1]([O-:4])(=[O:3])[CH3:2].[Zn+2:7].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: N
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CC(=O)[O-]
Temperature: 10 °C

Procedure:
A stock solution of zinc acetate in aqueous ammonia was prepared by mixing 33.6 parts of glacial acetic acid with 48 parts of water followed by slow addition to the cooled mixture of 18.4 parts of commercial anhydrous liquid ammonia, while maintaining the temperature between 25° and 50° C. After cooling the solution to 10° C., 21.8 parts of zinc oxide were slowly added with stirring while maintaining the temperature below 25° C. The zinc oxide dissolved rapidly to afford a stock solution containing 17.5% weight percent zinc which had a pH of 11.4 and a specific gravity of 1.27.
Reaction SMILES: [C:1]([CH2:4][CH:5](OC)OC)(=O)[CH3:2].Cl.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].Cl.[OH-].[Na+]>C(O)C.O.N1C=CC=CC=1>[CH3:5][C:4]1[CH:1]=[CH:2][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)[N:21]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: COC(CC(C)=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: Cc1ccn(-c2ccc(C(=O)O)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
264 g of 1-acetyl-2,2-dimethoxyethane are added dropwise at room temperature to use a suspension of 465 g of 4-carboxyphenylhydrazine hydrochloride (81%) in 3400 ml of ethanol which contains 253 g of pyridine. The reaction mixture is then kept at reflux temperature for 1 hour. A solution of 73 g of hydrochloric acid in 240 ml of ethanol is then added dropwise. The mixture is stirred for a further 18 hours at 80° C., then a solution of 240 g of sodium hydroxide in 1500 ml of water is added, and the ethanol is distilled off. The precipitated sodium salt of 3-methyl-1-(4-carboxyphenyl)pyrazole is dissolved hot in 1000 ml of water and precipitated with dilute hydrochloric acid. The precipitate is filtered with suction, washed with water and dried. Recrystallisation from methanol affords 361 g (89% of theory) of 3-methyl-1-(4-carboxyphenyl)pyrazole with a melting point of 249°-250° C. A suspension of 101 g of this acid in 500 ml of hexane and 1 ml of dimethyl formamide is heated to 60° C. Then 71 g of thionyl chloride are run into the suspension in the course of 30 minutes. The reaction mixture is stirred for 18 hours at reflux temperature, then 100 ml of toluene are added, and the mixture is again heated to the boil. The clear solution obtained is filtered and, after cooling to 10° C., the precipitated 3-methyl-1-(4-chloroformylphenyl)pyrazole is filtered with suction and dried. Yield: 90 g (82% of theory) in the form of pale crystals which melt at 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[O:14])=[CH:8][CH:7]=[CH:6]2.[H-].[Na+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([C:20]([F:22])([F:21])[F:23])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([C:16]([O:17][CH3:18])=[O:19])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)NC(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Yield: 70.8 %

Procedure:
N-[[6-Methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, methyl ester (2.2 g, 6.72 mmol) was added to a suspension of sodium hydride (60% in oil, 0.29 g, 7.25 mmol) in tetrahydrofuran (anhydrous, 150 mL) and the mixture stirred for 1.5 hours at 20° C. tert-Butyl bromoacetate (1.20 mL, 7.40 mmol) was added and the resultant solution was stirred for 20 hours at 20° C. The solvent was evaporated and the residual solid triturated with hexanes (3×20 mL), to yield the pure product (2.1 g, 71.2%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=5)[CH2:7][CH:6]5[CH2:23][O:24][CH2:25][CH2:26][N:5]5[C:4]=4[N:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 50 mg, 0.127 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (61.6 mg, 0.253 mmol) and PdCl2(dppf) (4.63 mg, 6.33 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.22 (m, 4H), 3.48-3.55 (m, 1H), 3.57-3.68 (m, 1H), 3.93-4.05 (m, 2H), 4.07-4.17 (m, 1H), 4.68-4.79 (m, 3H), 7.00-7.09 (m, 1H), 7.21-7.30 (m, 1H), 7.44-7.50 (m, 1H), 7.52-7.58 (m, 1H), 7.60-7.71 (m, 4H), 7.90-7.98 (m, 2H), 11.44-11.51 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H23N5O3S, 476.17. found 476.4.
Reaction SMILES: Cl.C[O:3][C:4]1[C:9]([NH2:10])=[C:8]([NH2:11])[CH:7]=[CH:6][N:5]=1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=O.N>O>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]1[N:10]=[C:9]2[C:4](=[O:3])[NH:5][CH2:6][CH:7]=[C:8]2[N:11]=1
Reactant: COc1nccc(N)c1N
Reactant: COc1cc(SC)ccc1C(=O)Cl
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
0.88 g of 2-methoxy-3,4-diamino-pyridine hydrochloride and 1.08 g of 2-methoxy-4-methylmercapto-benzoyl chloride were intimately mixed, and the mixture was stirred into warm polyphosphoric acid at 120° C. The mixture was kept at this temperature for an hour and was then poured into water, the aqueous mixture was made alkaline with ammonia, and the precipitate thus obtained was purified on a silica gel column (eluant: methylene chloride/methanol=100:10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([Cl:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[C:6]([Cl:11])[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Br)c2)c(Cl)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 4-amino-3-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=2)[C:15]([C:30]([OH:32])=[O:31])=[CH:14]3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C[O-].[Na+:35]>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=2)[C:15]([C:30]([O-:32])=[O:31])=[CH:14]3)=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Na+:35]
Reactant: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc3ccccc3c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)[O-])n3-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-(4-Isopropoxyphenyl)-1-(2-naphthyl)indole-2-carboxylic acid (40 mg, 0.095 mmol; see Example 18) was dissolved in dry THF (1 mL) and NaOMe (3.37 M, 28 μL) was added via syringe. After stirring for 30 min at room temperature, the solvents were removed under reduced pressure and the residue dried in vacuo to yield the title compound (42 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Cc1ccc(Br)nc1
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Product: Cc1ccc(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)nc1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 2-bromo-5-methyl-pyridine were reacted according to the same procedure as Example 113 to give the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8].Cl>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
A 2N aqueous solution of sodium hydroxide (11 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (2.1 g.) in methanol (30 ml.) and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and methanol was removed. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystals of 2-methoxyimino-2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C1C2C(=C(NC(=O)C)C=CC=2)CC1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])N(C3C4CCCCC=4C(C#N)=CC=3)[C:51]2=[O:53])[CH2:47][CH2:46]1>>[OH:44][C@H:45]1[C@@H:52]2[N:48]([C:49](=[O:66])[N:1]([C:4]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[C:51]2=[O:53])[CH2:47][CH2:46]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ccc([N+](=O)[O-])c2cccnc12
Agent: CC(=O)Nc1cccc2c1CCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2cccnc12

Procedure:
The title compound was synthesized from compound 12C by procedures analogous to those described in Experiment 3A and Experiment 2 (2E to 2F). 99.8% at 2.05 min (retention time) (Conditions: YMC S5 ODS (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH:13]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:14](OCC)=[O:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH:13]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:14]=[O:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1nnn(Cc2ccccc2)n1)C1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=CC(c1nnn(Cc2ccccc2)n1)C1CCCC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
To a stirred mixture of 2-benzyl-α-cyclopentyl-2H-tetrazole-5-acetic acid, ethyl ester (2.92 g, 9.72 mmol, step 2 of Example 14) in CH2Cl2 (50 mL) at −78° C. was added diisobutylaluminium hydride (1.0 M in toluene, 22.5 mL, 22.5 mmol). The resulting mixture was stirred at −78° C. for 5 h. To the mixture were added 2 M aqueous HCl (50 mL) and saturated aqueous NH4Cl (10 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with Hexane/ethyl acetate (10:1) to give 862 mg (35%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Ic1ccc2nccn2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1cnc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture comprising 6-iodo-imidazo[1,2-a]pyridine (1 eq, 95 mmol, 23.3 g) in acetic acid (220 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 95 mmol, 4.8 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered. The resulting solid is suspended in DCM (1% MeOH) (500 ml) and washed with 4N sodium hydroxide (100 ml). When the solid dissolves, the organic layer is separated, dried (MgSO4) and evaporated to give a beige solid; [M+H]+323 (325).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH2:7])([O-:3])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:15]([CH3:14])(=[O:17])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 24 h

Procedure:
A mixture of 3,4-dinitroaniline (5.27 g, 28.8 mmol), methanesulfonyl chloride (3.36 mL, 43.1 mmol) and pyridine (5.82 mL, 71.9 mmol) in CH2Cl2 (100 mL) was stirred for 24 h. Mixture was concentrated under vacuum to provide a crude semi-solid title compound that was used without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]Br>C(OCC)(=O)C>[Br:11][C:4]1[C:3]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][N:5]=1
Reactant: BrBr
Reactant: Cc1cccc(S)c1C#N
Solvent: CCOC(C)=O
Product: Cc1cccc2snc(Br)c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 179.3 %

Procedure:
To a solution of 2-mercapto-6-methylbenzonitrile (1.00 g, 6.71 mmol) in ethyl acetate (10 mL), bromine (1.05 g, 6.60 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 3 h. The reaction mixture was then allowed to warm to room temperature, followed by heating at reflux for 3 h. The reaction mixture was concentrated under reduced pressure. Crystallization of the crude mixture with hexanes gave 3-bromo-4-methylbenzo[d]isothiazole (2.7 g), which was carried forward without further purification. MW=228 confirmed by LC-MS, tr=6.82 min (Method E) MH+=229.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[C:25]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:20]=[CH:21][C:22]=1[O:28][CH3:29]
Reactant: COc1ccc(Br)cc1OC
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (10 g, 41.1 mmol), and 4-bromoveratrole (8.93 g, 41.1 mmol) in THF (140 mL) were added Palladium catalyst Pd(PPh3)4 (1.43 g, 1.23 mmol) and the freshly prepared sodium hydroxide solution (5.08 g in 58 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 80° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 7.47 g (72%) of 4-(3,4-dimethoxy-phenyl)1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN1CCCC1=O.Cl[Cu]>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][NH:23][C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:8][O:9]4)=[CH:4][CH:3]=3)=[CH:29][CH:30]=2)=[O:32])=[CH:33][CH:34]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: COC(=O)C1CCOc2cc(O)ccc21
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)ccc21
Yield: 36.8 %

Procedure:
Methyl 7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate (0.075 g, 0.360 mmol), N-(4-chlorophenethyl)-4-iodobenzamide (0.126 g, 0.327 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.00603 g, 0.0327 mmol), CuCl (0.0162 g, 0.164 mmol) and Cs2CO3 (0.213 g, 0.655 mmol) were stirred together in N-methylpyrrolidone (2 mL) at 120° C. for 3 hours. The reaction was cooled and loaded onto a silica gel samplet. The product was a eluted over using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to provide the title compound (0.056 g, 37.8% yield).