Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]4[CH2:22][CH2:21][CH:19]([CH:20]=3)[N:18](C3C=CC(OC)=CC=3)[CH2:17]4)=[CH:12][CH:13]=2)[N:8]([CH3:31])[C:7]1=[O:32].CC#N.OS(O)(=O)=O.I(O)(=O)(=O)=O>O>[CH:19]12[CH2:21][CH2:22][CH:16]([C:15]([C:11]3[N:10]=[C:9]4[N:8]([CH3:31])[C:7](=[O:32])[N:6]([CH2:5][CH:3]5[CH2:4][C:2]5([F:1])[F:33])[C:14]4=[CH:13][CH:12]=3)=[CH:20]1)[CH2:17][NH:18]2
Reactant: COc1ccc(N2CC3CCC2C=C3c2ccc3c(n2)n(C)c(=O)n3CC2CC2(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CCC3CN4)nc21
Temperature: 50 °C

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-[2-(4-methoxyphenyl)-2-azabicyclo-[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (6-2, 52 mg, 0.12 mmol, 1.0 equiv) was added to CH3CN (1 mL) and water (1 mL). To this suspension was added aqueous H2SO4 (115 μL, 0.12 mmol, 1.0 equiv, 1.0 M) followed by periodic acid in one portion (26 mg, 0.12 mmol, 1.0 equiv). The reaction contents were heated to 50° C. for 18 h. Following this duration, LCMS showed consumption of starting material. The mixture was subsequently filtered through Celite, rinsed with CH3CN and purified by reverse-phase HPLC (10-90% CH3CN:H2O) to give 6-3 as an off-white solid. MS m/z (M+H): calculated=346.4; observed=347.1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S-:6])[N:3]=[N:2]1.[Na+].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16]CO>CCOC(C)=O>[CH2:8]([S:6][C:4]1[N:3]=[N:2][N:1]([CH3:16])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: [S-]c1c[nH]nn1
Reactant: CCO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1cc(SCc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of sodium 1H-1,2,3-triazole-4-thiolate (30, 1.0 g, 8.13 in EtOH (10 mL) was added benzyl bromide (1.4 g, 8.13 mmol) drop-wise. The mixture stirred at room temperature for 20 minutes then diluted with EtOAc and washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(benzylthio)-1-methyl-1H-1,2,3-triazole as a white solid (55, 1.5 g, 93%); 1H NMR (300 MHz, CDCl3): δ 13.37 (bs, 1H), 7.48 (s, 1H), 7.21 (m, 5H), 4.09 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>>[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2ccc(C)cc21
Reactant: BrCCCCCBr
Product: CCC1(CCCCCBr)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[S:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1>C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[S:27])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1cccc(NC(=S)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 73 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-aminobenzanilide (0.213 g, 1.0 mmol) and 3,5-dichlorophenyl isothiocyanate (0.208 g, 1.0 mmol). Trituration in ethyl acetate gave the product (0.304 g); m.p. 174-177° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OCCCC)(=O)C>C(#N)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:11][C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Solvent: CCCCOC(C)=O
Product: O=C(O)Cc1cccc(CBr)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
m-Tolylacetic acid (4.0 g, 26.64 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) were dissolved in acetonitrile (11.9 g) and the solution was raised to 80° C. To this solution was dropped a solution of N-bromosuccinimide (4.98 g, 27.97 mmol) and AIBN (α,α′-azobisisobutyronitrile) (0.044 g, 0.266 mmol) in acetonitrile (32 g) for 1.5 hours. After stirring for 30 minutes the mixture was cooled to 50° C. and thereto was added butyl acetate (38.7 g). The mixture was concentrated to remove only acetonitrile. The resulting succinimide (crystal) was removed and the residue was washed three times with water. After concentrating to a desired concentration, thereto was added at 45° C. n-heptane (45.6 g) to produce a crystal. After cooling to 5° C., the crystal was filtered to give the sub-subject compound (3.76 g) as a white crystal. Yield: 62%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:8]([O:20][CH3:21])[CH:7]=1.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:3]([O-:22])(=[O:2])[CH3:4].[CH3:21][O:20][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:22])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:29](=[O:30])[C:28]1[CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COC(=O)C=Cc1ccc(OCCCCCCO)c(OC)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)[O-]
Product: COC(=O)C=Cc1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Yield: 176.7 %

Procedure:
2.50 g (8.11 mmol) of 4-(6-hydroxyhexyloxy)-3-methoxycinnamic acid methyl ester, 1.96 g (8.51 mmol) of 3,5-dinitrobenzoyl chloride and 10 mg (0.08 mmol) of dimethylaminopyridine were dissolved in 25 ml of methylene chloride. 3.3 ml (40.5 mmol) of pyridine were added dropwise, in the course of 20 minutes at 0° C., to the resulting clear solution. After 2 hours at 0° C. the reaction mixture was partitioned between methylene chloride and water; the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over magnesium sulphate, filtered and concentrated by evaporation. Chromatography of the residue on 150 g of silica gel using toluenelethyl acetate 9:1 yielded 3.6 g of 3,5-dinitrobenzoic acid 6-[2-methoxy-4-(2-methoxycarbonylvinyl)phenoxy]hexyl ester.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17](Br)=[C:18]([Br:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:3]=1[Br:50].Cl.C(O)(=O)C.C(O)C>[Zn].C1(C)C=CC=CC=1>[Br:50][C:3]1[C:4]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][CH:17]=[C:18]([Br:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)[S:6][CH:2]=1
Reactant: CCCCCCCCCCCCCCc1c(-c2nc3sc(-c4sc(Br)c(Br)c4CCCCCCCCCCCCCC)nc3s2)sc(Br)c1Br
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1c(Br)csc1-c1nc2sc(-c3scc(Br)c3CCCCCCCCCCCCCC)nc2s1
Temperature: 100 °C

Procedure:
To a 50 mL round bottom flask were added to 0.800 g of 2,5-bis(5,4 dibromo-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole, 0.500 g Zn dust, 3 mL 3 M HCl, 2 mL acetic acid, 15 mL ethanol, and 15 mL toluene. The flask was heated to 100° C. for 3 hours. The reaction mixture was then filtered and the solvents were removed by rotary evaporation. The residue was purified by column chromatography using a mixture of hexane and dichloromethane to give the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[C:15]([OH:18])(=[O:17])[CH3:16].[CH2:19]([CH2:22]OC)OC>>[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]=1[CH2:16][C:15]([O:18][CH2:19][CH3:22])=[O:17]
Reactant: COCCOC
Reactant: CC(=O)O
Reactant: CC1C(=O)CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1=C(C)c2ccccc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 24 g (0.5 mole) of sodium hydride (50% in oil dispersion) in 750 ml of dimethoxyethane, cooled to 0° C., was added dropwise over a one hour period a solution of 112.1 g (0.5 mole) of triethyl phosphonoacetate [(C2H5)2OP(O)CH2CO2C2H5 ] in 140 ml of dimethoxyethane. The reaction mixture was maintained at about 15° C. during the addition and then stirred at room temperature for two hours. It was then cooled to 5° C. and treated dropwise with a solution of 68.7 g (0.386 mole) of 1-methyl-2-tetralone in 70 ml of dimethoxyethane over a period of one hour. The reaction mixture was stirred overnight, then cooled in an ice bath and acidified with 27 ml of glacial acetic acid. The mixture was poured into ice-water and the layers separated. The aqueous layer was extracted with cyclohexane, and the combined organic layers washed with water and saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate and concentrated to give 95.8 g of ethyl 3,4-dihydro-1-methyl-2-naphthaleneacetate as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)cc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.C[N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1.[C:14](O)(=O)C>>[Br:1][C:2]1[CH:5]=[C:11]2[C:10]([CH3:14])=[N:9][NH:8][C:12]2=[N:13][CH:3]=1
Reactant: Cn1nccc1N
Reactant: CC(=O)O
Reactant: O=CC(Br)C=O
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
A solution of 2-bromomalonaldehyde (4.0 g, 30 mmol) and methyl-1H-pyrazol-5-amine (2.57 g, 26.5 mmol) in acetic acid (40 mL) was heated to 116° C. for 2.5 hours. The reaction was then stirred at room temperature for 2 days. The solution was concentrated and the residue was taken up in methanol, filtered through diatomaceous earth and concentrated. Purify by silica gel chromatography (2-5% CH2Cl2/methanol) to afford 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (515 mg, 9%).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:14](=O)[CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([CH2:14][CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2cc(C(=O)CCl)sc2C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)N1CCCc2cc(CCCl)sc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of 2.1 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at room temperature for 12 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The exract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 1.8 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22](/[C:25](/[Sn](CCCC)(CCCC)CCCC)=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:50]I>C1COCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22](/[C:25](/[I:50])=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/CCCC(=O)OC(C)(C)C)c1ccc(-c2nc(C(=O)NCCCCC3CCCCC3)co2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC/C=C(/I)c1ccc(-c2nc(C(=O)NCCCCC3CCCCC3)co2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 2-necked 50 mL round bottom flask was charged under nitrogen atmosphere with a stir bar, the above alkyne (148.6 mg, 0.302 mmol), and tetrakis(triphenylphosphine)palladium(0) (17.4 mg, 0.0015 mmol). Anhydrous toluene (5 mL) was added via syringe, and the mixture was stirred until the two solids dissolved. A 2 mL solution of tributyltin hydride (0.392 mmol) in anhydrous toluene was added, and the reaction stirred at room temperature for 30 minutes. The solution was then transferred to a dry 50 mL round bottom flask and the toluene was removed in vacuo to afford tert-butyl (E)-6-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-6-(tributylstannyl)hex-5-enoate as a residue which was used directly. The stannane was dissolved in 10 mL anhydrous THF and the flask was cooled to 0° C. in an ice bath. A 10 mL solution of iodine (84.2 mg, 0.3318 mmol) in anhydrous THF was added dropwise via pressure equalizing addition funnel over 30 minutes. The ice bath was removed and the reaction stirred at room temperature for 2 hours. Saturated sodium bisulfite solution (50 mL) was added, and the organics were extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. Filtration and solvent removal gave a yellow oil which was purified by radial chromatography (2 mm plate, 10% ethyl acetate in hexanes) to give 193.6 mg of a pale yellow oil: 1H NMR (CDCl3) δ8.24 (s, 1H), 8.00 (d, 2H), 7.41 (d, 2H), 7.05 (broad t, 1H), 6.52 (t, 1H), 3.45 (q, 2H), 2.15 (q, 2H), 2.04 (q, 2H), 1.70 (m, 7H), 1.40 (m, 9H), 1.23 (m, 6H), 0.93 (m, 4H); IR (cm-1) 2926, 2853, 1721, 1664, 1599. High Resolution MS Accurate mass calculated for C30H42IN2O4 : 621.2189. Found: 621. 2183.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:63]=[CH:62][CH:61]=[CH:60][C:54]=1[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][CH:62]=[CH:63][C:53]=2[O:52][CH3:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccccc1OCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4ccccc4OC)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 54.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-methoxyphenoxy)-1-propanol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 51%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:27]O>>[CH3:27][N:1]1[CH2:6][CH2:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])=[CH:3][CH2:2]1
Reactant: CO
Reactant: O=C1Nc2cccnc2N(C(=O)c2ccncc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: CN1CC=C(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Temperature: 0 °C

Procedure:
A quantity of 2.3 gm (0.005 mol) of 5,11-dihydro-11-[(4-pyridinyl)-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one methoiodide was suspended in 200 ml of methanol, and at 0° C. 0.25 gm (0.006 mol) of sodium borohydride were added thereto in portions. The resulting mixture was stirred for a further hour in an ice bath. Then, the mixture was stirred into 1 liter of ice-cold water and extracted exhaustively with methylene chloride. The combined extracts were washed with water, dried over sodium sulphate, and concentrated by evaporation in vacuo. After being recrystallized from diisopropyl ether/methanol, the colorless crystals melted at 226°-227° C.
Reaction SMILES: O1C=C(CN)N=C1.[F:8][C:9]([F:18])([F:17])[C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH2:16])[N:14]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=3)[C:33](O)=[O:34])[C:26]2=[O:39])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=3)[C:33]([NH:16][CH2:15][C:13]3[N:14]=[C:10]([C:9]([F:8])([F:17])[F:18])[S:11][CH:12]=3)=[O:34])[C:26]2=[O:39])=[CH:40][CH:41]=1
Reactant: NCc1csc(C(F)(F)F)n1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: O=C(NCc1csc(C(F)(F)F)n1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 30 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (2-(trifluoromethyl)thiazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((2-(trifluoromethyl)thiazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 30% yield: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=5.1 Hz, 1H), 7.28-7.20 (m, 2H), 7.17-6.99 (m, 3H), 4.78 (d, J=6.0 Hz, 2H), 4.43 (s, 2H), 4.03 (t, J=8.0 Hz, 2H), 3.37 (t, J=8.0 Hz, 2H); MS (ES+) m/z 479.8 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][CH:7]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1COC(c2cccs2)c2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1COC(c2cccs2)c2cc(-c3cccc(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chlorobenzeneboronic acid generally according to the procedure described in example 1. 1H-NMR (CDCl3) δ 8.26 (br s, 1H), 7.51 (dd, J=8.3, 2.1 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.42 (dd, J=5.1, 0.9 Hz, 1H), 7.36 (m, 3H), 7.24 (d, J=2.0 Hz, 1H), 7.05 (m, 2H), 6.93 (d, J=3.5 Hz, 1H), 6.24 (s, 1H), 4.56 (d, J=17.0 Hz, 1H), 4.47 (d, J=17.0 Hz, 1H); MS (ES) m/z 356 (M+H)+; Anal. Calc. For C19H14ClNO2S: C, 64.13, H, 3.97; N, 3.94. Found: C, 64.1, H, 3.83; N, 3.99.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH:5]1[CH:14]=[N:15][OH:16].[Cl:17]N1C(=O)CCC1=O>CN(C=O)C>[OH:16][N:15]=[C:14]([Cl:17])[C@H:5]1[C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6]1
Reactant: COCC1OC2(CCCCC2)OC1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Temperature: 25 °C
Yield: 93.1 %

Procedure:
3-(Methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (33.2 g, 145 mmol) was dissolved in DMF (600 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (19.3 g, 145 mmol) was added and the reaction allowed to slowly warm to ambient temperature overnight. Most of the DMF was removed under reduced pressure and the remaining material was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford (2R,3S)—N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135 mmol, 93.2% yield) which was taken forward without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].CN(C)C=O.[NH2:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>O>[NH2:10][C:11]1[CH:16]=[C:15]([S:4][CH3:3])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2 g. sodium hydroxide, 2.4 g. methylmercaptan and 20 ml. dimethylformamide is stirred at room temperature for two hours. 3.0 g. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for 1 1/2 hours. Water is added and the crude product filtered off. Recrystallization from methanol yields pure 2-amino-4-methylthio-1-nitrobenzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])(C)C.[C:13]([OH:17])(=O)[CH2:14][SH:15].[C:18]1(C)C=CC=CC=1>>[SH:15][CH2:14][C:13]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][CH2:8][CH:11]=[CH2:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)CS
Reactant: Cc1ccccc1
Product: C=CCOC(=O)NCCCNC(=O)CS
Temperature: 115 °C
Yield: 42 %

Procedure:
To a solution of tert-butyl 3-aminopropylcarbamate (85b, 2 g, 11.48 mmoles) in toluene (8 mL), in a pressure tube, was added 900 μL of thioglycolic acid (12.95 mmoles). Argon was bubbled through the solution for 15 min, and the mixture was capped and heated to 115° C. (bath temperature) for 24 h. The solution was then concentrated to dryness in vacuo and the residue was subjected to SiO2 chromatography on a Biotage™ flash chromatography system using 25-0% hexanes in EtOAc as the eluent to furnish 91 (1.19 g, 4.77 mmoles, 42% yield) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 1.65 (quintet, J=6.3 Hz, 2H), 1.94 (t, J=9.0 Hz, 1H), 3.17 (t, J=6.2, 2H), 3.24 (d, J=8.9 Hz, 2H), 3.33 (q, J=6.3 Hz, 2H), 4.11 (q, J=7.1 Hz, 1H), 4.87 (broad s, 1H), 7.12 (broad s, 1H).