Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[H-].[Na+]>CS(C)=O>[CH2:4]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[S:26][CH:25]=[CH:24][N:19]2[C:20](=[O:23])[CH:21]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)C
Yield: 64.9 %

Procedure:
This compound was prepared using Step 2 intermediate from Intermediate 2 (1.00 g, 2.160 mmol), (2-isobutoxy-3-methoxy)benzaldehyde (494 mg, 2.376 mmol) and NaH (95 mg, 3.958 mmol) in dry DMSO (10 ml) according to the procedure outlined in Intermediate 2, Step 3 to yield a crude residue which was purified by column chromatography using 2% ethyl acetate in DCM to afford the 500 mg of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) 1.05 (d, J=6.9 Hz, 6H), 2.01-2.06 (m, 1H), 3.69 (d, J=6.3 Hz, 2H), 3.80 (s, 3H), 6.28 (s, 1H), 6.94-7.18 (m, 3H), 7.34 (d, J=6.3 Hz, 1H), 7.47 (d, J=5.1 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H), 8.09 (d, J=16.2 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][N:6]1[CH2:7][C@H:2]([CH3:1])[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@@H:5]1[CH3:8]
Reactant: C[C@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)[C@@H](C)CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (2S,5S)-2,5-dimethyl-1-(phenylmethyl)piperazine (J. Med. Chem. 2006, 49, 716-726) (770 mg, 3.77 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (0.396 mL, 37% water solution, 5.28 mmol) followed by sodium triacetoxyborohydride (959 mg, 4.52 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were washed with brine, dried (MgSO4) and evaporated to yield (2S,5S)-1,2,5-trimethyl-4-(phenylmethyl)piperazine (782 mg, 95%). LCMS: (M+H)+: 219.1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46](O)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[S:74](Cl)(=[O:76])=[O:75])([O-:67])=[O:66]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([S:74]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=3[N+:65]([O-:67])=[O:66])(=[O:75])=[O:76])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(S(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (0° C.) of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (787mg) in dry methylene chloride (15 ml) is added diisopropylethyl amine (492.4 mg) followed by o-nitrobenzenesulfonyl chloride (281 mg) and a catalytic amount of N,N-dimethylaminopyridine. The yellow solution is stirred at room temperature under a nitrogen atmosphere for 3 hr., and then quenched with sat'd aqueous sodium bicarbonate. Organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compounds.
Reaction SMILES: Cl.COC[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]3)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1>CO>[OH:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]3)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1
Reactant: COCOC1CCN(CCN(CCCCOc2ccc3[nH]c(=O)ccc3c2)Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: O=c1ccc2cc(OCCCCN(CCN3CCC(O)CC3)Cc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
10 ml of 10% hydrochloric acid was added to a solution of 1.07 g of 6-[4-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-benzylamino}butoxy]carbostyril in 10 ml of methanol. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with chloroform and then made alkaline with a 10% aqueous potassium hydroxide solution, followed by extraction with chloroform. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 5% methanol/chloroform), followed by recrystallization from ethyl acetate-diethyl ether, to obtain 330 mg of 6-[4-{N-[2-(4-hydroxy-1-piperidinyl)ethyl]-N-benzylamino}butoxy]carbostyril.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.C1C(=O)N([I:18])C(=O)C1>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1[S:3][C:4]([I:18])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1nc(N)sc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
To a solution of methyl 2-aminothiazole-4-carboxylate (5.6 g, 35.4 mmol) in DCM (60 mL) was added NIS (9.56 g, 42.5 mmol). The mixture was stirred at rt for 24 hours and then diluted with EtOAc (200 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to provide 9.5 g (94%) of the desired product methyl 2-amino-5-iodothiazole-4-carboxylate (8A): LC/MS(APCI): m/z 284.9 (M+H).
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]1=[O:15])(=O)C>Cl.C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5](=[O:15])[NH:4][C:8]=2[CH:9]=1
Reactant: COc1ccc2sc(=O)n(C(C)=O)c2c1
Agent: Cl
Solvent: CCO
Product: COc1ccc2sc(=O)[nH]c2c1
Reaction time: 2 h

Procedure:
7.0 gm (0.0314 mol) of 3-acetyl-5-methoxy-2(3H)-benzothiazolone were suspended in a mixture of 210 ml of 5 N hydrochloric acid and 70 ml of ethanol, and the suspension was refluxed for one hour. The still hot mixture was filtered, diluted with 200 ml of water and brought to a temperature of 5° C. by external cooling with ice. After standing for 2 hours, the precipitate was filtered off, and the dried product was purified chromatographically on silica gel, using 1,2-dichloroethane-acetone (volume ratio 9:1) for elution, and finally recrystallized from methanol and from 1,2-dichloro-ethane, each time in the presence of activated charcoal. The slightly yellow crystals obtained with a yield of 3.25 gm (57% of theory) melted at 168°-170° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(F)cc1Br
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 5 °C
Yield: 91.6 %

Procedure:
Nitric acid (16.00 mL, 322 mmol) was cooled to −15° C. and treated portion-wise with 2-bromo-4-fluorophenylacetic acid (10.00 g, 42.9 mmol) maintaining an internal temperature of −10° C. to −5° C. Once the addition was complete the mixture was warmed to 5° C. over −15 minutes, poured onto ice (200 mL), stirred vigorously until all of the ice melted, and then filtered and rinsed with water. The resulting solid was dissolved in EtOAc, washed with brine, dried (MgSO4) and concentrated to dryness to afford 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (10.93 g, 92% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, 1H), 8.04 (d, 1H), 3.85 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:20][CH3:19])[CH:4]=1
Reactant: CSSC
Reactant: COc1ccnc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccnc(-c2sccc2SC)c1
Temperature: 25 °C

Procedure:
The product of step (b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyl lithium in hexane (2.2M, 13 ml) dropwise during 0.5 hour. The mixture was warmed to -10° for 10 minutes, then cooled to -30°. Dimethyl disulphide (3.5 ml) was then added dropwise. The mixture was maintained at -30° for 0.5 hour then warmed up to room temperature during several hours. Aqueous work-up and ethyl acetate extraction gave the sub-title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][OH:33])([CH3:29])[C:27]#[CH:28]>>[CH2:34]([N:30]([C:26]([CH3:25])([CH3:29])[C:27]#[C:28][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH2:31][CH2:32][OH:33])[CH3:35]
Reactant: C#CC(C)(C)N(CC)CCO
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 17.3, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester and 2-[(1,1-Dimethyl-prop -2-ynyl)-ethyl-amino]-ethanol were converted to Yield 2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-amino)-ethanol as orange viscous oil, MS: 365 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([O:28][C:29]([NH:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C1CCC(O)C(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O)C(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a stirred mixture of Racemate-ethyl 3-amino-4-hydroxycyclohexanecarboxylate (4.7 g, 25 mmol) in 120 mL of dichloromethane was added triethylamine (3.03 g, 30 mmol), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (6.55 g, 26.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then diluted with 200 mL of dichloromethane. The solution was washed with 5% citric acid solution (2×150 mL), 5% potassium carbonate solution (2×150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel chromatography (ethyl acetate:petroleum ether=1:4˜2:5), to thereby give the title compound (7.0 g, 87%) as a yellow oil. MS (ES+) C17H23NO5 requires: 321, found: 322 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[NH3:10]>>[CH3:9][C:3]1[C:2]([NH2:10])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: N
Product: Cc1cnc(C)c(N)n1
Temperature: 150 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A 100 mL autoclave vessel was charged with 3-chloro-2,5-dimethylpyrazine (25.0 g, 176 mmol), NH3 (aq. 25˜28% w/w, 80 mL) and Cu powder (1.69 g, 26.4 mmol) and the autoclave vessel was sealed. The resulting mixture was heated to 150° C. and stirred vigorously for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with brine (100 mL) and extracted with EtOAc (4×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with PE to render the title compound as a light yellow solid (17.6 g, yield 81%). ESI MS: m/z 124 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])=[O:19]
Reactant: CCOC(=N)c1c(F)cccc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1c(F)cccc1Cl

Procedure:
starting from ethyl 2-chloro-6-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-chloro-6-fluorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 80°-84° C.;
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:11]1[O:10][N:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Reactant: CNC
Product: CN(C)c1nc(Cc2ccccc2)no1

Procedure:
3-(Phenylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole is reacted with dimethylamine to yield 5-(dimethylamino)-3-(phenylmethyl)-1,2,4-oxadiazole.
Reaction SMILES: CC([O:5][C:6](=[O:18])[CH2:7][S:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][CH:10]=1)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:15]([NH:14][C:12]1[S:13][C:9]([S:8][CH2:7][C:6]([OH:18])=[O:5])=[CH:10][N:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ncc(SCC(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ncc(SCC(=O)O)s1
Yield: 97 %

Procedure:
A solution of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid 1,1-dimethylethyl ester (4.32 g, 15 mmol) in methylene chloride (30 mL) and trifluoroacetic acid (20 mL) was stirred at rt overnight and concentrated in vacuo. To the residue was added ethyl ether (50 mL). The precipitated solid was collected, washed with ethyl ether and dried to afford the desired product (3.38 g, 97%) as a solid, mp 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:6]2.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[CH:8]([CH2:14][C:15](=[O:17])[N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:19]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: NNc1ccccn1
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CC(=O)N(c3ccccn3)N=C21
Yield: 81.9 %

Procedure:
A mixture of 20 g of 6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid, 10.9 g of 2-hydrazinopyridine and 150 ml of ethanol is heated under reflux for 2 hours. The resulting crystals are collected, whereto 50 ml of acetic acid is added. The mixture is heated under reflux for 30 minutes. Acetic acid is distilled off under reduced pressure, and water is added to the residue. The resultant crystals are collected and recrystallized from chloroform - ethanol to give 21.5 g of 8-methoxy-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as white crystals, m.p. 194°-196° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl([O-])=[O:15].[Na+].Cl([O-])=O.P([O-])([O-])([O-])=O>O.CC(O)C>[Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]([OH:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cn1c(Br)c(C=O)c2ccccc21
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(Br)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a vigorously stirred solution of 2.38 g (10 mmol) of 2-bromo-1-methylindole-3-carboxaldehyde [XXVI: R1 =H, R3-dioxane at 25° C. was added dropwise over ca. 15 minutes a solution of 5 (55 mmol) of sodium chlorite and 5 g (36 mmol) of NaH2PO4.H2O in 25 mL of water. The solution was maintained at 25° C. After 3.5 hours, the mixture was treated with an additional 2.5 g each of the chlorite and phosphate. After a total reaction time of 24 hours, the mixture was extracted 3 times with dichloromethane, then the aqueous phase was acidified to pH 2 with aqueous HCl, and extracted once more. The combined organic extracts were washed with water, dried, and evaporated to leave a solid residue that was boiled in 2-propanol. After cooling, the solids were collected by filtration, washed with a little 2-propanol, and dried to leave 2.21 g (87%) of 2-bromo-1-methyl indole-3-carboxylic acid [XXVII: R1 =H, R3 =CH3, X=Br] as a beige solid; mp ca. 198° C. (dec), in 2 crops.
Reaction SMILES: [CH2:1]([C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:43][S:44]([OH:47])(=O)=[O:45]>ClCCl>[CH2:1]([C:7]1[C:8]([C:37]2[CH:42]=[CH:41][C:40]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:39][CH:38]=2)=[C:9]([C:31]2[CH:32]=[CH:33][C:34]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:35][CH:36]=2)[C:10]([C:25]2[CH:26]=[CH:27][C:28]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:29][CH:30]=2)=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:21][CH:20]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCc1c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Solvent: ClCCl
Product: CCCCCCc1c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 250 mL round bottom flask was charged with 2.0 g (0.004 mol) of 1-hexyl-2,3,4,5,6-pentaphenylbenzene and 50 mL of dichloromethane. Chlorosulfonic acid (15 mL) was added to the stirred reaction mixture at room temperature via an addition funnel. The reaction mixture turned immediately purple, and then clear orange after 1 h. The reaction mixture was stirred at room temperature for 1 d, and then poured onto crushed ice. The layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to deposit a light-gray solid. The product was recrystallized from ethyl acetate to provide 1.39 g (57%) of a white powder. 1H NMR (CDCl3) δ 7.96 (d, J=10, 4 H), 7.66 (m, 6), 7.41 (d, J=10, 4H), 7.08 (m, 6H). MS (FD) m/e 1034 (M+).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CC(N(C)C)=O.[OH-].[Na+]>O>[C:18]([CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)CSc1ccc(C(=O)c2ccccc2)cc1
Temperature: 107.5 °C
Yield: 80 %

Procedure:
55 g 4-chloro benzophenone and 24 g mercaptoacetic acid are added into a 500 ml three-neck flask, and are dissolved with 350 ml DME (dimethyl acetamide) to obtain a solution, and then 23 g solid sodium hydroxide is added into the solution. Heating the solution to reflux (105-110° C.), and starting to cool the solution when the content of 4-chloro benzophenone detected by HPLC is less than 1%. The reaction solution is added into 500 ml water, and then water insoluble substances are extracted with 100 ml methylbenzene. Concentrated hydrochloric acid is used to regulate the pH value of the aqueous phase to 3-4, then some solid substances precipitate, filtering to obtain crude products, and the weight after drying is 60 g; the dried crude products are recrystallized in dichloroethane to obtain 55.3 g white crystal, and the yield was 80%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:26])[CH2:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[C:10](=[CH:11][N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:13]=2)[CH:9]=1.[O:27]=[C:28]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41]([C:44](OC3C=CC([N+]([O-])=O)=CC=3)=[O:45])[CH2:40][CH2:39]2)[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]1.[H-].[Na+].C(Cl)Cl>O1CCCC1>[O:27]=[C:28]1[N:37]([CH:38]2[CH2:39][CH2:40][N:41]([C:44]([O:26][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH2:7][C:8]3[CH:16]=[C:15]([CH3:17])[C:14]4[C:10](=[CH:11][N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:13]=4)[CH:9]=3)=[O:45])[CH2:42][CH2:43]2)[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: Cc1cc(CC(O)c2ccco2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ccco2)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 8 h

Procedure:
To a solution of 1-(furan-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol (0.11 mmol) and 4-nitrophenyl 4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxylate (0.13 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (95%, 0.33 mmol) at room temperature under nitrogen. The reaction was stirred overnight. Methylene chloride (15 mL) was added and the mixture washed with water (4×5 mL). The organic layer was dried, filtered and concentrated to give the crude product, which was used without further purification.
Reaction SMILES: C([O:8][C:9]([C:11]1([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:32])[CH:25]=3)=[CH:19][C:18]=2[F:42])=[O:15])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:42][C:18]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]([CH3:41])[CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:32])[CH:25]=2)[CH:21]=[CH:22][C:17]=1[NH:16][C:14]([C:11]1([C:9]([OH:10])=[O:8])[CH2:13][CH2:12]1)=[O:15]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)OCc5ccccc5)CC4)c(F)c3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-N-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)cyclopropanecarboxamide (510 mg) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 20% palladium hydroxide on carbon (377 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr. The catalyst was removed by filtration, and washed with tetrahydrofuran-methanol (1:1). The filtrate was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white crystals (358.7 mg, 83%).