Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:12]#[N:13].Cl.O>CN(C=O)C>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:13]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10% sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6](=O)[CH2:5]2.C([BH3-])#N.[Na+].Cl.[CH3:17][NH:18][CH3:19].Cl>CO>[CH3:17][N:18]([CH3:19])[CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1
Reactant: O=C1Cc2ccc(Cl)cc2C1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C1Cc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g. of 5-chloro-2-indanone (0.0025 mole) was partially dissolved in methanol (10 ml.) and 0.4 g. of sodium cyanoborohydride (0.0065 mole) and 0.6 g. of dimethylamine hydrochloride (0.0075 mole) were added. The pH of the mixture was adjusted to 4.5 with 10% hydrochloric acid and 3 A molecular sieves were added. The mixture was stirred for 16 hours at 25° C., acidified, evaporated to dryness, dissolved in 10% hydrochloric acid, extracted with ether, basified and extracted with ether to yield N,N-dimethyl-5-chloro-2-aminoindane.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)=[O:7])#[N:2].[CH2:16]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:35])[CH2:31][C:32](=[O:34])[CH3:33])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31]([C:32](=[O:34])[CH3:33])=[CH:11][C:10]2[CH:9]=[C:8]([CH:15]=[CH:14][CH:13]=2)[C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:7])=[O:35])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CCCOC(=O)c1cccc(C=O)c1
Reactant: CC(=O)CC(=O)N1CCCN(Cc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(C(=O)OCCC#N)c1)C(=O)N1CCCN(Cc2ccccc2)CC1

Procedure:
1.12 g (5.00 mmol) of 3-(2-cyanoethoxycarbonyl)benzaldehyde, 1.38 g (5.03 mmol) of 1-(4-benzyl[1,4]-diazepane-1-yl)butane-1,3-dion and 0.05 ml (0.51 mmol) of piperidine were stirred in 50 ml of benzene at 105° C. overnight. Ethyl acetate was added to the reaction mixture. After drying over anhydrous sodium sulfate, the product was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>O1CCCC1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:23](=[O:24])[CH2:22][Cl:21])([CH3:13])[CH3:12]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reaction time: 10 h

Procedure:
Part A. A solution of 2,6-diisopropylaniline (10.0 mL, 53.0 mmol) and triethylamine (10.0 mL, 71.7 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., and treated dropwise with a solution of chloroacetyl chloride (5.00 mL, 62.8 mmol) in tetrahydrofuran (20 mL). After being stirred for 10 hours, the solution was poured into water (200 mL) and extracted with methylene chloride (2×200 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the product, N-(2,6-diisopropylphenyl)-2-chloroacetamide, as a solid. The solid was purified by trituration in boiling ether, filtration and drying; mp 157°-158° C. (10.7 g, 42.0 mmol, 79%). 1HNMR (CDCl3): δ 7.81 (1H, br s); 7.32 (1H, t, J=8.1 Hz); 7.19 (2H, d, J=8 Hz); 4.26 (2H, s); 3.02 (2H, heptet, J=6.6 Hz); 1.21 (12H, d, J=6.6 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 271 (100%); 256 (11%); 255 (6%); 254 (30%); 219 (1%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[C:28]([F:27])([F:37])[F:38])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3C(F)(F)F)C2=O)CC1
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-(trifluoromethyl)benzyl bromide, to give the desired product as a light yellow foam (93%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:7]1[N:8]=[C:9]([CH3:13])[O:10][C:11]=1[CH3:12])[C:4]([OH:6])=[O:5].Cl.[CH3:15]O>>[ClH:1].[NH2:2][CH:3]([C:7]1[N:8]=[C:9]([CH3:13])[O:10][C:11]=1[CH3:12])[C:4]([O:6][CH3:15])=[O:5]
Reactant: CO
Reactant: Cc1nc(C(N)C(=O)O)c(C)o1
Agent: Cl
Product: COC(=O)C(N)c1nc(C)oc1C
Yield: 84 %

Procedure:
Prepared using General Procedure 22: To a stirred solution of 2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride (150 mg, 0.726 mmol) in MeOH (5 mL) was added HCl (1.2 mL of a 37% aqueous solution, 14.5 mmol) and the mixture heated under reflux for 4 h. The mixture was allowed to cool and solvents evaporated. The residue was treated with MeOH (12 mL) and filtered. The filtrate was evaporated to afford 135 mg (84%) of methyl 2-amino-2-(2,5-dimethyloxazol-4-yl)acetate hydrochloride INT-43. LCMS-ESI (m/z) calculated for C8H12N2O3: 184.1. found 185.1 [M+H]+, tR=0.23 min (Method 11). 1H NMR (400 MHz, DMSO) δ 8.94 (br s, 3H), 5.35 (s, 1H), 3.73 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:10]Cl>>[Cl:10][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: ClCl
Reactant: Cc1ccc(F)c(F)c1
Product: Cc1cc(F)c(F)cc1Cl
Temperature: 15 °C

Procedure:
To 925 g of 3,4-difluorotoluene prepared in Example 15 were added 17 g of shaving steel and 2.5 g of ferric chloride, and then chlorine gas was injected at the rate of 10.0 l/hr for 19 hours, maintaining the temperature between 15° C. The reaction mixture was washed with 10%/ aqueous sodium sulfite and water. After drying with 32 g of calcium chloride, the resultant was purified by fractional distillation to give 980 g of the desired product as a colorless liquid, collecting at temperature of 156° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:24][CH2:25][CH3:26].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH2:22][CH3:23])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(/C(CC)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-pent-2-en-1-ol (Compound A-137, 885 mg, 2.08 mmol), tetrapropylammonium perruthenate (20 mg, 0.057 mmol) and 4-methylmorpholine N-oxide (487 mg, 4.16 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: C([CH2:3][C:4]([NH2:6])=O)=C.[CH2:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH:4]([NH2:6])=[CH2:3].[CH2:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CCC(N)=O
Solvent: C=Cc1ccccc1
Product: C=CN

Procedure:
The preparation of Example I is repeated five times. In the first repeat, the mole ratio of vinylacetamide to styrene is changed from 1:1 to 1:2. Upon hydrolysis, a 0.33:0.67. vinylamine/styrene copolymer results.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCOC(C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 36.4 %

Procedure:
Dissolve 3-nitro-5-(trifluoromethyl)aniline (300 mg, 1.45 mmol) in DCM (5 mL), add triethylamine (294 mg, 2.9 mmol) and then methylsulfonyl chloride (182 mg, 1.6 mmol). Stir the reaction at room temperature for 17 hrs. TLC (EtOAc:PE=1:3) shows the reaction is complete. Concentrate under reduced pressure to afford the crude product. Purification by chromatography (silica gel, EtOAc:PE=3:7) affords the title compound (150 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[NH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([OH:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+].CO>CN(C=O)C.O.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]>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[NH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=1)=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of Intermediate 16 (35 g, 0.086 mol, 1.0 eq) and 3-carboxyphenylboronic acid (14.27 g, 0.086, 1.0 eq) in DMF (350 ml) and H2O (87.5 ml) was added Na2CO3 (18.2 g, 0.172 mol, 2.0 eq). Then Pd(dppf)Cl2 (3.15 g, 0.0043 mol, 0.05 eq) was added to the solution under N2. The resulting solution was stirred at 100° C. for 16 hrs. Solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel using DCM: MeOH=10:1 to give the title compound (27 g, 70% yield) as brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32]O)=[CH:25][CH:24]=1.N1C=CN=C1>C(Cl)Cl>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][Br:20])=[CH:25][CH:24]=1
Reactant: OCCCCc1ccc(O)cc1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCCBr)cc1
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
A solution of triphenylphosphine (144.1 mmole, 37.80 g) in methylene chloride (556 ml) was treated with bromine (144.1 mmole, 23.03 g) until a pale yellow color persisted. After stirring approximately 15 minutes, a solution of 4-(4-hydroxyphenyl)butanol (96.1 mmole, 15.97 g) and imidazole (192.2 mmole, 13.08 g) in methylene chloride (355 ml) was added over a 15 minute period. Approximately 4 hours later, the reaction suspension was filtered and the filtrate was reduced in volume. To the reduced filtrate was added silica gel and the suspension was reduced to dryness. This material was filtered and the first six fractions were eluted with 10% ethyl acetate:hexane. Fractions 7 through 12 were eluted with 20% ethyl acetate:hexane. Fractions 7 through 10 were combined, reduced in volume, dried over sodium sulfate, filtered and concentrated in vacuo to afford 19.32 g (88%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C)C=O>[CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=3[F:49])[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(F)cc2F)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(F)cc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Yield: 56.7 %

Procedure:
In a microwave vial was placed ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester (78.2 mg, 0.12 mmol), 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101.3 mg, 0.42 mmol, 3.5 eq.), cesium carbonate (196.4 mg, 0.60 mmol, 5.0 eq), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexed with dichloromethane (1:1) (29.5 mg, 0.036 mmol, 0.30 eq), and anhydrous N,N-dimethylformamide (3.5 mL). The reaction mixture was degassed with N2 for 10 minutes and then subjected to microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and then filtered through a pad of Celite. The filtrate was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 40 to 100% ethyl acetate/heptane to give 46.4 mg (56.5%) of desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.63 (s, 1H), 8.14-8.04 (m, 1H), 7.82 (s, 1H), 7.31 (s, 5H), 7.03-6.87 (m, 2H), 5.11-5.00 (s, 2H), 4.84-4.74 (m, 1H), 3.95-3.85 (m, 1H), 3.74 (s, 3H), 3.35-3.24 (m, 2H), 3.23-3.11 (m, 2H), 2.18-2.03 (m, 2H), 1.97-1.65 (m, 4H), 1.53 (s, 9H); MS (ESI) m/z: 682.6 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[CH:11]=1)[C:7]#[N:8])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>O1CCOCC1.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Oc2cncnc2)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(N)cc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Compound 21 (100 mg, 0.413 mmol, 1.00 eq) was dissolved in Dioxane (2.0 mL) and added to argon purged vial. Tin(II) chloride (390 mg, 2.06 mmol, 5.00 eq) was dissolved in concentrated HCl (0.66 mL) and added to the reaction vial dropwise. The solution stirred at rt for 1 h. The reaction was neutralized with 6N NaOH (2.0 mL) and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 58 mg (67%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.68 (s, 2H), 6.71 (t, J=1.5 Hz, 1H), 6.68 (t, J=2.2 Hz, 1H), 6.51 (t, J=2.2 Hz, 1H), 5.86 (s, 2H); ES-MS [M+1]+: 213.1.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH:13]([F:25])[CH2:14][CH:15](N)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[PH2](O)=O.[OH-].[Na+]>Cl.O>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH:13]([F:25])[CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CC(F)N1CCN(c2ccccc2)CC1)C(=O)c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: O=C(CCC(F)N1CCN(c2ccccc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a cooled solution of 3.4 g of γ-(4-phenylpiperazino)-2-amino-4-fluorobutyrophenone in 100 ml of lN hydrochloric acid was added dropwise 0.7 g of sodium nitrite dissolved in 10 ml of water under stirring at a temperature below 0°C. The resulting diazonium salt solution was added to a cooled solution of 20 ml of 50 % hypophosphorous acid with vigorous stirring. The stirring was continued for 90 minutes below 0°C and the reaction mixture was stored in a refrigerator overnight. The cold reaction mixture was made alkaline with 10 % sodium hydroxide and extracted with ether. The etheral layer was washed with water, dried over anhydrous sodium sulfate and concentrated to an oily residue, which was crystallized on standing. Recrystallization from isopropanol gave γ-(4-phenylpiperazino)-4-fluorobutyrophenone, melting point 104.0°-106.0°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:13]([O:20][C:21]1[CH:48]=[C:47](I)[CH:46]=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:48]=[C:47]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:46]=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(I)cc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Piperidine (0.049 mL), cesium carbonate (0.22 g), tris(dibenzylideneacetone)dipalladium(0) (3.0 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (7.9 mg), and palladium(II) acetate (1.5 mg) were added to a toluene (2.0 mL) suspension of tert-butyl 2-(2-(benzyloxy)-4-iodobenzamido)-4-phenylbenzoate (0.20 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then piperidine (0.033 mL), cesium carbonate (0.11 g), tris(dibenzylideneacetone)dipalladium(0) (3.0 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (7.9 mg), and palladium(II) acetate (1.5 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 4 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-85% hexane/ethyl acetate] to obtain 0.13 g of tert-butyl 2-(2-(benzyloxy)-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:32][CH2:31][N:30](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:29][CH2:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:23][CH2:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:20][CH2:19][CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.S(=O)(=O)(O)O.O>C(OCC)C>[NH:10]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: C1CNCCNCCCNCCNCCNCCNCCNC1
Temperature: 90 °C
Yield: 53.9 %

Procedure:
63.3 g (0.045 mol) of the 1,5,8,12,15,18,21-Heptakis(p-tolylsulfonyl)-1,5,8,12,15,18,21-heptaazacyclotricosane was mixed with 300 ml of 98% sulfuric acid and 8 ml of water, and then the mixed solution was heated at a temperature of 90° C. for 3 days and then cooled. The mixed solution was added to 2000 ml of diethylether and then diethylether was subjected to decanting, and the residual was dissolved in 200 ml of water. A pH of the resultant solution was controlled to be pH 13 by using a NaOH aqueous solution, and the solution was filtered and extracted with ethanol. The ethanol used was evaporated from the extraction product and impurities were removed therefrom under vacuum conditions according to a kugelrohr distillation method to produce 8 g of 1,5,8,12,15,18,21-heptaazacyclotricosane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N+:10]([O-])=[C:9]([CH3:14])[CH:8]=1.C([OH:17])C>C(OC(=O)C)(=O)C>[OH:17][CH2:14][C:9]1[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:11][N:10]=1
Reactant: CCO
Reactant: COCCCOc1cc[n+]([O-])c(C)c1
Solvent: CC(=O)OC(C)=O
Product: COCCCOc1ccnc(CO)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4.05 g (0.02 mol) of 4-methoxypropoxy-2-methylpyridine 1-oxide was dissolved in 50 ml of acetic anhydride to obtain a solution. This solution was stirred at 90° C. for 0.5 hour and cooled, followed by the addition of ethanol. The obtained mixture was concentrated under a reduced pressure, followed by the addition of 150 ml of 1N hydrochloric acid. The obtained mixture was stirred at 100° C. for one hour, cooled, neutralized with sodium hydrogencarbonate and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. Thus, 3.64 g of the title compound was obtained as a crude product.