Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14])=[N+]=[N-].[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of 1-[4-[2-(2-azidomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (535 mg) in a mixture of methanol (35 ml) and dioxane (4 ml) containing catalytic palladium on carbon (60 mg) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 3 hours, the reaction mixture was filtered through a bed of celite, and then concentrated to give 1-{4-[2-(2-aminomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (395 mg) which was purified by recrystallization from a mixture of ethyl acetate and diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[SH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Sc1ccccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol)and diisopropylethylamine (2.6 mL, 15 mmol)in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C. The mixture was stirred for 1 minute under ice cooling, and cooled to −78° C. To the reaction mixture was added 2-mercaptopyridine (1.67 g, 15 mmol), and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, ethyl acetate-hexane 1:5) to give the titled compound as pale yellow oily substance (937 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.[CH:18]1([CH2:26][CH2:27]Br)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[CH:18]1([CH2:26][CH2:27][N:15]2[CH2:14][CH2:13][N:12]([C:4]3[C:3]([O:2][CH3:1])=[CH:11][C:7]4[CH2:8][CH2:9][O:10][C:6]=4[CH:5]=3)[CH2:17][CH2:16]2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19]1
Reactant: BrCCC1Cc2ccccc21
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Yield: 70.3 %

Procedure:
2.21 g (8.2 mmol) of 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine (Preparation 1), 1.72 g (8.2 mmol) of 2-(benzocyclobutan-1-yl)-1-bromoethane and 3.48 g (32.8 mmol) of sodium carbonate in 33 ml of methyl isobutyl ketone are heated at reflux for 14 h. The whole is evaporated to dryness, taken up in 200 ml of ethyl acetate and 100 ml of N sodium hydroxide solution and decanted, and the organic phase is washed with 100 ml of a saturated sodium chloride solution. After drying over MgSO4 and evaporation, the residue obtained is chromatographed on silica (eluant: CH2Cl2 /CH3OH: 98/2) to yield 2.1 g of the expected product. By the addition of a 2% fumaric acid solution in ethanol, 1.7 g of the fumarate of the title compound is obtained. M.p. 193°-194° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH2:33]([N:32]([CH2:31][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([OH:30])[C:10]([F:9])([F:36])[F:37])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:34][CH3:35]
Reactant: O=C(O)c1cccs1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][C:12]=1[NH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(N)cc2)cn1
Product: COc1ccc(-c2ccc(N)c(Br)c2)cn1

Procedure:
The title compound was prepared from 4-(6-methoxy-pyridin-3-yl)-phenylamine (as prepared in the previous step, 73 mg, 0.36 mmol) and NBS (65 mg, 0.36 mmol) according to the procedure in Example 16, step (b) (20 mg, 20%). Mass spectrum (ESI, m/z): Calcd. for Cl2H11BrN2O, 279.0 (M+H), found 279.2.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[H][H]>CO.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Yield: 100.2 %

Procedure:
Dimethyl-{3-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-propyl}-amine (1.4047 g, 4.62 mmol) and 5% Pd/C (114 mg) were stirred in methanol (50 mL) under 1 atm of hydrogen for 75 minutes. The suspension was filtered through celite and dried in vacuo to afford 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine as an orange oil (1.27 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:9][CH:8]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)(C)CCNCc1ccc(B(O)O)s1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCC(C)(C)C)s4)cc23)CC1
Yield: 5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3,3-dimethylbutyl)amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 4.5 mg of the title compound (5%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 87.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), K2CO3 (5.2 g, 0.04 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent was concentrated to yield initially an oil, which solidified upon standing. The solid was triturated with hexane and collected to afford 7.7 g of the product as a waxy solid. The compound was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with dichloromethane/methanol (5%). Concentration of the appropriate fractions yielded 5.1 g of off-white solid 1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone, which when recrystallized from ethyl alcohol yielded 3.2 g (36%) of feathery-white needles, m.p.=88°-90° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCCC1>[CH2:47]([N:46]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COc1ccc(C=O)cc1

Procedure:
To a 100 mL solution of freshly distilled tetrahydrofuran (THF) was added p-formylphenoxyacetic acid (K & K Labs) (MW 180, 0.540 g, 3.0 mmol), triethyl amine (MW 101.19, 0.333 g, 3.3 mmol) and trimethylacetyl chloride (MW 120.57, 0.398 g, 3.3 mmol). After 20 minutes of heating at reflux, dioctadecylamine (Fluke) (MW 522.01, 1.723 g, 3.3 mmol) was added. The reaction was refluxed overnight.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(O)(=O)[CH:12]([CH2:14][C:15](O)=O)[OH:13].S(=O)(=O)(O)O>[2H]C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]2[C:6]([CH:15]=[CH:14][C:12](=[O:13])[O:9]2)=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [2H]C(Cl)(Cl)Cl
Product: CN(C)c1ccc2ccc(=O)oc2c1
Temperature: 0 °C

Procedure:
m-Dimethylaminophenol 6.0g, malic acid 6.0g and 85% sulfuric acid 12.0ml were heated in an oil bath at 120° for an hour. The mixture was cooled, diluted with crushed ice 50g, filtered, made alkaline with sodium carbonate and extracted with chloroform, which was separated, washed and dried over sodium sulfate. Evaporation of the chloroform produced a deep red gum which could not be induced to crystallize. The material was separated down an alumina column using dichloromethane, and the strong blue fluorescent ring was cut out, eluted with methanol and evaporated to dryness. Crystallization from i-propanol gave light brown needles, which on resrystallization became light yellow and lustrous, 0.65g (8%), m.p. 161°-161.5found C 69.95, 69.80; H 5.74, 5.79; N 7.36, 7.37; C11H11NO2 requires C 69.8; H 5.82; N 7.41%. The nuclear magnetic resonance spectrum (A-60) in deuterochloroform showed the methyl singlet 3.02 and the aromatic protons as follows: H4 and H3 centered at 6.00 and 7.54 respectively split by 9 cycles to give an AB quartet, H8 singlet at 6.47, H6 and H5 centered at 6.51 and 7.27 respectively split by 9 cycles to give another AB quartet and the H6 was further split by interaction with H8. Integrated intensities were in accord with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:25]=[N:24][N:23]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)[CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1F
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1cnn(C3CCOCC3)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine in tetrahydrofuran (3 mL) were added tetrahydro-2H-pyran-4-ol (0.160 ml), triphenylphosphine (527 mg) and di-tert-butyl (E)-diazene-1,2-dicarboxylate (2.505 ml) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (140 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(Cl)cc2n1)CCC3=CCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC=C1CCc2c(Cl)cc3nn(C)cc3c21
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
2-(5-Chloro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (105 mg, 0.424 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine (88.6 μL, 0.636 mmol) and acetic anhydride (48.1 μL, 0.509 mmol) were added under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (96.7 mg, yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20]O)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20][Cl:46])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)c(COCC[Si](C)(C)C)c21
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)c(COCC[Si](C)(C)C)c21
Reaction time: 18 h

Procedure:
To a cold (0° C.), stirred solution of 426 mg of N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 0.46 mL of 2,4,6-collidine in 4 mL of dry DMF is added 0.17 mL of methanesulfonyl chloride. The ice bath is removed and the mixture is allowed to stir for 18 h, then is diluted slowly with water to a volume of 25 mL. The resulting solid is filtered, washed well with water, and dried in vacuo to furnish 429 mg of the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=1[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(O)ccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-3-methyl-benzaldehyde (3.31 g, 21.8 mmol), benzylbromide (4.09 g, 23.9 mmol), NaHCO3 (5.49 g, 65.4 mmol), 1,4-dioxane (30 mL) and water (12 mL) was stirred at 60° C. for overnight. Then the reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (2×200 mL). The extract was dried over Na2SO4, evaporated. The residue was purified on SiO2 (25 g) column, hexane-EtOAc (0 to 5%). Yield 1.57 g (6.48 mmol, 29%) as off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: COc1ccc(-c2ccccc2-c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 84.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 5.0 g (16 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Step 2) was reacted with 4.1 g (24 mmol) of 3-fluoro-4-methoxyphenylboronic acid (Step 3). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (35:65) and subsequent recrystallization from ethyl acetate/hexane gave 4.82 g (88%) of 2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 136.2-136.6° C.; NMR (CDCl3) δ 3.06 (s, 3H), 3.87 (s, 3H), 6.72-6.89 (m, 3H), 7.31-7.51 (m, 6H), 7.81 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 356 (100), 262 (28), 246 (22); HRMS Calc'd for C20H17FO3S: 356.0882. Found: 356.0881. Anal. Calc'd for C20H17FO3S: C, 67.40; H, 4.81; F, 5.33. Found: C, 67.24; H, 4.83; F, 5.25.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH:5]12[CH2:14]C3C[CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.ON1C(=O)C2=CC=CC=C2C1=O.O=O>>[C:1]12([OH:4])[CH2:2][CH:11]3[CH2:13][CH:7]([CH2:6][CH:5]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: CC(=O)O
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 37 %

Procedure:
To 25 mmol of acetic acid were added 10 mmol of adamantane, 1 mmol of N-hydroxyphthalimide (NHPI) and a binary co-catalyst [0.03 mmol of acetylacetonatovanadium V(AA)3 and 0.02 mmol of actylacetonatomangan Mn(AA)3], and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 6 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, the adamantane was converted into 1-adamantanol (yield: 37%). 1,3-adamantanediol (yield: 35%). 1,3,5-adamantanetriol (yield: 5%), 1,3,5,7-adamantane-tetranol (yield: 4%) with the adamantane conversion of 100%. The spectrum data of the 1,3,5,7-adamantanetetranol was as follows:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl.CC(O)C>C(OCC)(=O)C>[NH:13]1[CH2:12][CH2:11][CH:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCOCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C1CC(OCCN2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Tert-butyl 4-(2-morpholinoethoxy)piperidine-1-carboxylate (78) (7.0 g, 22.26 mmol) was added to 6.0 HCl in propan-2-ol (30 mL, 180.00 mmol) and the reaction was stirred at 25° C. for 2 hours. The reaction mixture was evaporated to dryness and redissolved in methanol (75 mL) and water (7 mL), this was basified by stirring with solid sodium hydroxide for 1 hour. The reaction was filtered and evaporated to afford a gummy solid. This was stirred with ethyl acetate (75 mL) for 20 minutes, filtered and evaporated to afford a clear liquid. The crude product was purified by distillation at 1.2 mBar, collecting fractions that distilled at 120° C. to afford the desired material as a colourless oil (3.10 g, 65.0%); 1H NMR (400.132 MHz, CDCl3) δ 1.47-1.38 (2H, m), 1.93-1.89 (2H, m), 2.53-2.51 (4H, m), 2.63-2.56 (4H, m), 3.08 (2H, dt), 3.38-3.31 (1H, m), 3.61 (2H, t), 3.71 (4H, dd).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[CH:7]2.[CH3:14][C:15](O)([C:17]#[CH:18])[CH3:16].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:14][C:15]1([CH3:16])[O:13][C:3]2=[C:2]([CH3:1])[C:11]3[O:10][C:9](=[O:12])[CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]2[CH:18]=[CH:17]1
Reactant: Cc1c(O)ccc2ccc(=O)oc12
Reactant: C#CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c2c(cc3ccc(=O)oc13)C=CC(C)(C)O2
Reaction time: 4 h
Yield: 33 %

Procedure:
A solution prepared from 5.0 mmol of 8-methyl-7-hydroxycoumarin and 6.0 mmol of 2-methyl-3-butyn-2-ol in 40 ml of xylene containing 0.095 g (0.50 mmol) of p-toluenesulfonic acid was refluxed with magnetic stirring for 4 hours. The solvent was distilled off in vacuo and the oily contents of the flask chilled in an ice-salt water bath to induce crystallization. The white microneedles, 33% yield, were recrystallized from methanol to analytical purity, m.p. 105°-107° C. (lit. m.p. 106°-107° C.). The 1H-NMR spectrum was also identical to that reported, see P. Rodighiero et al., reference cited above.