Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-:30])([N+]([O-])=O)=[O:26].C(O)(=O)C>ClCCl>[N+:25]([C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:24][C:11]=2[C:12]=1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)([O-:30])=[O:26]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc(-c2coc3ccc(-c4ccccc4)cc23)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2c([N+](=O)[O-])oc3ccc(-c4ccccc4)cc23)cc1

Procedure:
A mixture of 3.2 g. of the product of step D, 2 g. of dinitrogen tetraoxide, 1 ml. of acetic acid and 200 ml. of dichloromethane is stirred at 20° C. for 16 hours, washed with water and evaporated. The residue is treated with cold 5 percent sodium hydroxide solution, then acidified with 6N hydrochloric acid. The solid residue is separated and recrystallized from N,N-dimethylformamide to provide 4-(2-nitro-5-phenylbenzofuran-3-yl)benzoic acid, m.p. 235°-249° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1.[BH4-].[Na+].[Na+].[Cl-]>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:30][CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: NCCc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CNCCc3ccc(Cl)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.62 g, 10.0 mmol, intermediate to which may be obtained according to methods disclosed in EP03103780.7) and 2-(4-chlorophenyl)ethylamine (Aldrich, 1.56 g, 10 mmol) was heated at reflux in toluene (50 mL) for 12 hrs with azeotropic removal of water. The mixture was evaporated under vacuum and the residue was taken up in MeOH (60 mL) and chilled at 0° C. NaBH4(567 mg, 15.0 mmol) was added portionwise and the reaction mixture was stirred for 30 min at 0° C. and 3 hrs at rt. The reaction mixture was poured into a saturated solution of NaCl and extracted with Et2O. The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give the crude product. Purification by chromatography on silicagel (EtOAc/c-hex 30/70) gave 2.96 g (54%) of the title compound as a white solid. HPLC, Rt: 5.0 min (purity: 99.9%).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.CSC.[CH2:12]([O:19][C:20]1[C:25]([CH2:26]O)=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]1[C:25]([CH2:26][Cl:8])=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CO)c(OCc2ccccc2)n1
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CCl)c(OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of NCS (70.2 mg, 0.515 mmol) in DCM (2 mL) was added DMS (34.9 mg, 0.562 mmol). The reaction mixture was cooled to −40° C., then a solution of [2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridin-3-yl]methanol (Cpd J, 175 mg, 0.468 mmol) in DCM (1 mL) was added drop-wise keeping the internal temperature below −30° C. Upon complete addition the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with brine, dried with MgSO4, filtered, then concentrated under vacuum. The residue was purified by column chromatography (0-30% EtOAc/heptane) to give the title compound (Cpd K, 120 mg, 65%) as an oil. 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J=7.3 Hz, 2H), 7.44-7.29 (m, 3H), 6.94 (s, 1H), 5.46 (s, 2H), 4.83 (s, 2H), 4.70 (s, 2H), 2.47 (s, 3H), 0.97 (s, 9H), 0.14 (s, 6H); MS 392 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CN1CCCC1=O.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH:6]([C:2]1[N:1]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: O=Cc1ncc[nH]1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cn1ccnc1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 1H-imidazole-2-carboaldehyde (2.0 g), N-methylpyrrolidone (25 mL) was added, followed by dissolution with heating. To the resultant solution, ethyl chloroacetate (11.1 mL) and potassium carbonate (2.9 g) were added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, water (30 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane) to obtain the title compound having the following physical properties (1.3 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(NS(C)(=O)=O)ccc32)cc1
Reaction time: 6 h
Yield: 88 %

Procedure:
To a stirred solution of 2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.40 mL, 5.25 mmol) and pyridine (0.42 mL, 5.25 mmol) at room temperature. After stirring for 6 h, the mixture was poured into 10% aqueous citric acid (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was made basic with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL) and dried (MgSO4), and concentrated to afford 1.28 g (88%) of the title compound as brown amorphous: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.66 (1H, d, J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t, J=7.0 Hz), 3.09 (2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36 (2H, q, J=7.7 Hz), 1.42 (3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5 Hz).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2([NH:18][C:19]([C:21]3[N:25]4[C@:26]([CH3:50])([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=5)[C:27](=[O:37])[N:28]([C:29]5[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=5)[C:24]4=[N:23][CH:22]=3)=[O:20])[CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)C.[NH2:52][NH2:53]>C(O)C>[Cl:35][C:33]1[CH:34]=[C:29]([N:28]2[C:27](=[O:37])[C@@:26]([CH3:50])([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:48])([F:47])[F:49])=[CH:41][CH:40]=3)[N:25]3[C:21]([C:19]([NH:18][C:15]4([C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([C:6]6[NH:53][N:52]=[C:4]([OH:3])[CH:5]=6)[CH2:9]5)=[O:14])[CH2:16][CH2:17]4)=[O:20])=[CH:22][N:23]=[C:24]23)[CH:30]=[C:31]([Cl:36])[CH:32]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(OC(F)(F)F)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)C1
Solvent: CCO
Product: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N4CC[C@@H](c5cc(O)n[nH]5)C4)CC3)n21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of 3-[(R)-1-(1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-pyrrolidin-3-yl]-3-oxo-propionic acid ethyl ester (35 mg, 0.05 mmol) in ethanol (2 mL) was added hydrazine (7.0 μL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo, and the residue was purified via reverse phase HPLC to afford the title compound (20 mg, 60%) as a white solid, m/z 718.1 [M+1]+.
Reaction SMILES: C[O:2][P:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19](Cl)=[O:20]>CCOCC>[CH3:16][C:17]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:18]=1[C:19]([P:3](=[O:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:20]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
648 parts of methoxydiphenylphosphine are added slowly to 547.5 parts of 2,4,6-trimethylbenzoyl chloride at 50°-95° C. in a stirred apparatus equipped with a reflux condenser and dropping funnel. The mixture is then stirred for 4-5 hours at 50° C., the contents of the flask are dissolved in ether at 30° C., and petroleum ether is added until the mixture starts to turn cloudy. On cooling, 910 parts (87% of theory) of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide crystallize. Pale yellow crystals, melting point 89°-92° C.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH:10]=2)[CH:4]=1.[CH:18](O)=O>C=O>[ClH:1].[ClH:1].[CH3:18][N:13]1[CH2:14][CH:15]2[CH2:17][CH:11]([CH2:10][C:9]([C:5]3[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=3)=[CH:16]2)[CH2:12]1
Reactant: C1=C(c2cccnc2)CC2CNCC1C2
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN1CC2C=C(c3cccnc3)CC(C2)C1

Procedure:
7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride (90 mg, 0.33 mmol) was dissolved in 37% aqueous formaldehyde (3 ml), and 98% formic acid (10 ml) was added. This mixture was refluxed for 1 h. The reaction was then cooled, concentrated by rotary evaporation, and treated with saturated sodium bicarbonate solution (15 ml). It was then extracted with chloroform (3×15 ml), and the extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. Concentrated HCl (5 drops) was added to a solution of the free base in ethanol (10 ml). The excess HCl and residual water were removed by repeated azeotropic rotary evaporation with ethanol. 3-Methyl-7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride was isolated as a white, hygroscopic solid (116 mg, >100% due to moisture content).
Reaction SMILES: Br[C:2]1[C:3]([O:21][C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=2)=[N:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(=O)(O)[O-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[O:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]=2)[N:6]=[CH:7][C:2]=1[C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CCc1csc(Nc2cc(Oc3c(F)cccc3F)c(-c3cccnc3)cn2)n1
Temperature: 80 °C

Procedure:
Ethyl 3-(2-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (0.1932 mmol), pyridin-3-ylboronic acid (0.02850 g, 0.2319 mmol), Pd(PPh3)4 (0.02233 g, 0.01932 mmol), in DME (10 mL), and 2M sodium bicarbonate (2 mL) are combined and heated to 80° C. overnight. The reaction mixture is cooled and partitioned between CH2Cl2 and water. The combined organic layers are dried, filtered, and concentrated. The residue is purified by silica gel, eluting with 30-40% EtOAc in hexane, to afford ethyl 3-(2-(4-(2,6-difluorophenoxy)-3,3′-bipyridin-6-ylamino)thiazol-4-yl)propanoate.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:14][CH2:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(C)cnc1C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cnc1CCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.9 %

Procedure:
As shown in step 11-ii of Scheme 11, Compound 2035 (354 mg, 1.98 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (689 mg, 2.96 mmol) were combined in DCM (1.8 mL). After stirring 18 hours at room temperature, the mixture was diluted with 20 mLs each of saturated sodium carbonate and dichloromethane. The organics were separated, washed with saturated sodium carbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(chloromethyl)-5-methylnicotinate (Compound 2036, 465 mg) as a pale yellow oil: ESMS (M+1) 213.86.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:27]\[OH:28])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CN(C)c1ccc(C(CC(=O)c2ccncc2)c2ccccn2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)c1ccc(C(C/C(=N\O)c2ccncc2)c2ccccn2)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-pyridin-2-yl-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a yellow foam, MS (ESI+): m/z=347.2 ([M+H]+).
Reaction SMILES: Cl.[C:2]1([CH2:12][CH2:13][NH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1>O.C(Cl)(Cl)Cl>[C:2]1([CH2:12][CH2:13][NH:14][C:25]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1cccc2ccccc12
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(NCCc1cccc2ccccc12)C1CCC1

Procedure:
0.01 mol of N-[2-(1-naphthyl)ethyl]amine hydrochloride is dissolved in a water/chloroform (40: 60; vol/vol ) mixture, and 0.02 mol of potassium carbonate is then added with magnetic stirring. The reaction mixture is cooled in an ice bath, and 0.01 mol of cyclobutanecarbonyl chloride is then added dropwise with magnetic stirring.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([OH:19])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:22]>CO.O>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1-c1ccccc1C2CCC(=O)O
Solvent: O
Solvent: CO
Product: Cc1cccc2c1-c1ccccc1C2CCC(=O)Cl
Reaction time: 2 h

Procedure:
3-(4-Methylfluoren-9-yl)propionic acid (3.5 g, 13 9 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C([Li])CCC.CCCCCC.CN(C)[CH:36]=[O:37]>C1COCC1>[F:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([CH:36]=[O:37])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of tert-butyl 4-(3-bromo-5-fluorophenoxy)piperidine-1-carboxylate (0.666 g, 1.78 mmol) in THF (9.0 mL) at −78° C. was added 2.5M n-butyllithium in hexane (0.78 mL, 2.0 mmol). The solution was stirred at same temperature for 30 minutes, then N,N-dimethylformamide (1.4 mL, 18 mmol) was added to reaction flask. The reaction solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, and aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was diluted with methanol and purified with prep-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product as an oil (75 mg, 13%). LCMS (M+H-100)+: 224.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CO[CH:14]([CH3:22])[C:15](OC)(OC)OC>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:22]=[CH:14][CH:15]=[N:9]2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(NN)ccc1Br
Reactant: COC(C)C(OC)(OC)OC
Solvent: CCO
Product: COc1cc(-n2cccn2)ccc1Br
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
To a solution of (4-bromo-3-methoxyphenyl)hydrazine (62 g, 245 mmol) in ethanol (310 mL) was added tetramethoxypropane (40.2 g, 245 mmol) over a few minutes, and the mixture was heated to an internal temperature of 70° C. The mixture was stirred at 70° C. for 1.5 h then slowly cooled to RT. Ethanol was removed in vacuo and the residue was slurried in EtOAc. The residue was neutralized with 1M aqueous sodium hydroxide (˜700 mL) to cause precipitation. The biphasic mixture was filtered and the filtrate was extracted with EtOAc, dried over sodium sulfate and concentrated to provide 30 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazole as a black solid (30 g, MS: 254 [M+H+].).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7]I.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)(=[O:20])=[O:19])([O-:11])=[O:10]>CN(C=O)C>[CH3:7][N:21]([S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N+:9]([O-:11])=[O:10])(=[O:20])=[O:19])[C:22]1[CH:23]=[C:24]([S:28]([OH:31])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(S(=O)(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1cccc(S(=O)(=O)O)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (177 mg, 1.28 mmol), DMF (2 ml) and MeI (60 ml) were added to the compound (230 mg, 0.65 mmol) obtained in Step 1. The mixture was stirred at 40° C. for 6 hours. Potassium carbonate (44.3 mg) and MeI (40 μL) were supplemented and stirred overnight. After the solvent was removed by distillation, the purification step A was applied to give the crude product of 3-{methyl[(2-nitrophenyl)sulfonyl]amino}benzenesulfonic acid (160 mg). This crude product (144 mg, 0.39 m ml) was dissolved in DMF (3 ml), and cesium carbonate (126 mg, 0.39 mmol) and thiophenol (40 μl, 0.39 mmol) were added to the solution. The mixture was stirred at 50° C. overnight. After the solvent was removed by distillation, the purification step A was applied to give the crude product of 3-(methylamino)benzenesulfonic acid (84.1 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][S:12][C:13]1[S:17][C:16]([CH:18]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=O)s1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 189.9 mg of the 5-methylmercaptothiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 246.6 mg (90%) of the title compound as a orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>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>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C#C[Si](C)(C)C)ccc1Cl
Temperature: 95 °C

Procedure:
Commercially available 5-bromo-2-chloroanisole (1.0 g, 4.52 mmol), trimethylsilylacetylene (1.07 mL, 7.5 mmol) and triethylamine (15 mL) were added to anhydrous toluene (15 mL) and degassed by purging with nitrogen. Bis(acetato)bis(triphenylphosphine)palladium II (340 mg, 0.45 mmol) was added and the reaction mixture was heated to ˜95° C. for 30 min. The reaction mixture was cooled to room temperature, filtered to remove the catalyst, and diluted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL) and brine (50 mL) separated, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography over silica gel eluted with hexane/ethyl acetate 20:1 to yield A60.1 (807 mg, 75%). 1H NMR (400 MHz): δ 7.40-7.25 (m, 2H), 7.10-7.00 (m, 1H), 3.90, (s, 3H), 0.24 (s, 9H).