Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15]C)[CH2:7][CH2:6]1>ClCCl>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([CH:5]2[CH2:7][CH2:6]2)=[C:9]([OH:15])[CH:10]=1
Reactant: COc1cc(N)ccc1C1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(C2CC2)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of BBr3 in dichloromethane (4.47 mL of 1 M, 4.47 mmol) was added to a solution of 4-cyclopropyl-3-methoxyaniline (243 mg, 1.49 mmol) in dichloromethane (15 mL) at 0° C. under N2 atmosphere. The reaction was stirred for 30 min at 0° C. then diluted with dichloromethane (10 mL). The reaction mixture was washed with aqueous NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by HPLC (10-99% CH3CN 0.05% TFA) to provide 5-amino-2-cyclopropylphenol (115 mg, 52% yield). LC/MS m/z 150.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:4][F:5])#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(C#N)(CF)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)(CF)NC(=O)OCc1ccccc1
Yield: 98.3 %

Procedure:
Under argon, 1.2 g (5.08 mmol) of rac-benzyl (2-cyano-1-fluoropropan-2-yl)carbamate from Example 54A in 14.9 ml of 7 N ammonia in methanol were admixed with 1.55 g of Raney nickel (aqueous slurry) and hydrogenated at hydrogen pressure about 25 bar and RT for 24 hours. The reaction mixture was filtered through kieselguhr, washed with methanol and concentrated. 1.2 g of the target compound were obtained (98% of theory).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:44])[NH2:43])[CH:38]=2)[CH:33]=1)(=O)=O>N1C=CC=CC=1>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:43])[NH2:44])[CH:38]=2)[CH:33]=1)=[O:4]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C(=O)Oc1ccc2cc(C(=N)N)ccc2c1)c1ccccc1
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To 50 ml of dried pyridine, were added 3.0 g of α-methylphenylacetic acid and 4.9 g of DCC. The mixture was stirred for 30 minutes under cooling in ice. After adding 5.6 g of 6-amidino-2-naphthol methanesulfonate, while being cooled in ice, the mixture was stirred for one hour, then overnight. The reaction mixture was filtered to collect the precipitate. The precipitate was washed with pyridine and ethyl ether, added to DMF and heated. The insolubles were filtered off and ethyl ether was added to the filtrate to collect the precipitate by filtration. The precipitate was recrystallized from a mixed solvent comprising ethanol and ethyl ether to obtain 1.8 g of a white powder of 6-amidino-2-naphthyl α-methylphenylacetate methanesulfonate.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:24])[CH:6]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29]>C1(C)C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[C:9]([O:11][CH3:29])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from step (i) was taken up in toluene (3 ml) and methanol (1 ml) and TMS-diazomethane (0.6 ml, 2M in diethylether) added, the mixture stirred at RT for 3 h then evaporated under reduced pressure. The residue was taken up in THF (2 ml) and methanol (1 ml) then 3M NaOH (2 ml) added and the mixture stirred at RT for 2 h. The mixture was then acidified to pH 2 and extracted with ethyl acetate. The organics were dried (MgSO4), evaporated under reduced pressure and then passed onto a Varian NH2 resin (eluting with ethyl acetate, acetonitrile, methanol, DCM then 20% acetic acid in DCM). The acidic fraction was evaporated under reduced pressure and then purified by RPHPLC to give a white solid.
Reaction SMILES: Cl[C:2]1[CH2:7][CH:6]2[CH:4]([CH2:5]2)[C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11].[N-:15]=[N+]=[N-].[Na+]>>[CH2:13]([O:12][C:10]([C:9]1[NH:15][C:2]2[CH2:7][C@@H:6]3[CH2:5][C@@H:4]3[C:3]=2[CH:8]=1)=[O:11])[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C/C1=C(Cl)CC2CC12
Agent: [Na+]
Product: CCOC(=O)c1cc2c([nH]1)C[C@@H]1C[C@H]21

Procedure:
(E)-Ethyl 3-(3-chlorobicyclo[3.1.0]hex-2-en-2-yl)acrylate (142 mg, 0.67 mmol) was reacted with sodium azide (65 mg, 1.00 mmol) according to General Procedure 1.1.C. The product was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 10% EtOAc to afford the title compound. 38 mg. 1H NMR (CHLOROFORM-d) δ: 8.67 (br. s., 1H), 6.71 (d, J=1.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 2.95 (dd, J=16.6, 6.6 Hz, 1H), 2.73 (d, J=16.6 Hz, 1H), 1.87-2.07 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.02 (td, J=7.6, 4.7 Hz, 1H), 0.17 (q, J=4.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]([O-])(=O)=O.[Na+].CCOC(C)=O.S(=O)(O)[O-].[Na+]>O>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reaction time: 144 h

Procedure:
To a solution of 2-Fluoro-1-methyl-4-nitro-benzene (1 g, 6.45 mmol) and sodium bromate (2.92 g, 19.33 mmol) in an EtOAc:water (12 mL:9 mL) mixture, is added dropwise via addition funnel a 3.85M solution of sodium bisulfite 5.20 mL, 19.33 mmol). The mixture is vigorously stirred for six days and then sodium bisulfite (10 mL) is added and organic layer separated and washed with aqueous saturated solution of sodium bicarbonate. The organic phase is dried with magnesium sulfate, filtered and evaporated at reduced pressure to afford a mixture of title compound and starting 2-fluoro-1-methyl-4-nitro-benzene in a 5:1 ratio (1H-NMR) which is used in the next step without further purification. ES+(m/z) 235 [M+H]).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48]([C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and nicotinoyl chloride as starting materials in 37% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH3:28]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][C:21]([O:23][CH2:27][CH3:28])=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1
Reactant: Oc1ccc2c(c1)CN(c1cc(Cl)c3ccccc3n1)CCC2
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CN(c1cc(Cl)c3ccccc3n1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol (36 mg, 0.11 mmol) in 5 mL of dry N,N-dimethylformamide was added sodium hydride (8 mg, 0.17 mmol), then bromoethane (18.5 mg, 0.17 mmol) was added dropwise under nitrogen. After the addition, the reaction was stirred at room temperature for further 1 hour. The resulting mixture was diluted with dichloromethane (10 mL), washed with brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 28 mg of product. MS obsd. (ESI+) [(M+H)+] 353.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 4 h

Procedure:
1-Acetyl-4-(4-nitrophenyl)piperazine [Ger. Pat. No. 1,239,940; Chem. Abs., 67, 101031z (1967)] (76.64 g) in ethanol (1000 ml) was hydrogenated over Raney nickel at 40° and 60 p.s.i. for 4 hours. The catalyst was then filtered off and the filtrate evaporated to give a residual solid which was crystallised from ethyl acetate, yield of the title compound 47.88 g, m.p. 129°-130°.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH2:19][CH:20]1[CH2:22][O:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>C(O)(=O)C>[CH2:1]([O:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:22][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCOCCC1CO1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOCCC(O)CO
Reaction time: 0.5 h

Procedure:
A solution of 40 g of [2-(hexadecyloxy)ethyl] oxirane in 270 ml of glacial acetic acid containing 0.265 g of p-toluenesulfonic acid was stirred at reflux for 4.5 hours. The acetic acid was removed, the residue dissolved in toluene the toluene removed and this residue dissolved in 300 ml of methanol. A solution of 17.9 g of sodium hydroxide in 18.5 ml of water was added, the mixture was stirred 1/2 hour and the solvent removed. The solid was dissolved in a mixture of ether and water. The ether layer was washed twice with saline, dried and filtered. The filtrate was warmed to dissolve the solid which formed, then concentrated to about 400 ml and allowed to stand at room temperature. Petroleum ether was added and the resulting solid collected, giving 32 g of the desired compound, mp 60°-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:14][C:15]=1[CH3:16]
Reactant: CCOC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of ethyl {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetate (10.00 g), 2N aqueous sodium hydroxide solution (40 mL), tetrahydrofuran (100 mL) and ethanol (20 mL) was stirred overnight at room temperature. The reaction mixture was acidified by adding hydrochloric acid and concentrated. The residue was extracted with an ethyl acetate/tetrahydrofuran (1:1, v/v) mixed solvent. The organic layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from methanol-diethyl ether to give {3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetic acid as a white solid (7.92 g, yield 85%). melting point: 176-177° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:24]=1[Cl:25]>>[Br:19][C:20]1[CH:21]=[C:22]([S:26]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:28])=[O:27])[S:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cc(Br)c(Cl)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 4-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.42-7.34 (m, 2H), 7.25 (br m, 3H), 7.13 (dd, J=9.0 & 17.1 Hz, 1H), 6.02 (dt, J=2.4, 6.6 & 17.4 Hz, 1H), 5.52 (br s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][NH:16][C:15](=[S:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]1.FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O.O>CN(C)C=O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]([CH2:33][C:34]([F:37])([F:36])[F:35])[C:15](=[S:18])[C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=S
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 39 mg, 0.975 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (202 mg, 0.567 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (141 μL, 1.131 mmol) in N,N-dimethylformamide at −25° C. After 15 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% hexanes→30% ethyl acetate/hexanes) gave the title compound (105 mg). MS 439.1 (M+1).
Reaction SMILES: [C:1]([NH:18][C:19]1[S:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].B.Cl>O1CCCC1>[CH2:1]([NH:18][C:19]1[S:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)s1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)s1

Procedure:
To 1.1 g. of ethyl 5-hexadecanamido-2-thiophenecarboxylate is added 5 ml. 1 M borane in tetrahydrofuran. The reaction mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into 50 ml. of 1 N hydrochloric acid. The solid is collected and then recrystallized from both carbon tetrachloride and ethanol to yield the product.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12.[CH3:23]I>CN(C)C=O>[CH3:23][O:3][CH2:4][C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12
Reactant: CN1Cc2c(C#CCO)ncn2-c2ccccc2C1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
5.05 g (90 mmol) of freshly powdered potassium hydroxide was suspended in 50 ml of N,N-dimethylformamide and cooled to 3°. 6.0 g (22.5 mmol) of 4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 6.39 g (45 mmol) of methyl iodide was added thereto in succession, the ice-bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was poured into 200 ml of water, acidified to pH 7 with 4N hydrochloric acid and extracted five times with methylene chloride. The combined organic extracts were dried over magnesium sulphate, evaporated and after crystallization of the residue from ethyl acetate there was obtained 4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 114°-115°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:21])[CH3:20])=[CH:7][N:6]2[CH:8]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(C(=O)c3ccccc3)cn2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc(C(=O)c3ccccc3)cn2c1

Procedure:
The (6-aminoimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone is dissolved in 7 mL of acetic acid and treated with 0.8 mL of acetic anhydride. The reaction medium is refluxed for 2 hours, cooled, filtered and concentrated to dryness. The residue is taken up in ethyl acetate and saturated sodium hydrogen carbonate solution. The organic phase is washed and concentrated, and the product obtained is chromatographed on a column of silica, eluting with a 95/5 mixture of dichloromethane and methanol. The fractions containing the expected product are combined and concentrated to give 150 mg of N-(2-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide as a mixture with N-(3-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide. The two isomers are separated by preparative LC/MS preparative to give 54 mg of purified N-(2-benzoylimidazo[1,2-a]pyridin-6-yl)acetamide in the form of a beige-colored solid.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
Concentrated H2SO4 (20 mL) was cooled to 0° C. and treated with 4-phenyl-cyclohexanone (4.22 g, 24.2 mmol), and fuming nitric acid (1.6 mL) was added very carefully dropwise, keeping the temperature of the mixture below 20° C. After the addition of nitric acid was complete, the mixture was warmed to RT and allowed to stir for 5 h. The mixture was poured over ice (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography with 10% EtOAc-hexane on a 70-g Isolute SPE column (FlashMaster system) afforded the title compound (0.512 g, 10%) as a pale yellow solid. 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.42 (d, 2H, J=8.8 Hz), 3.16 (tt, 1H, J=12.0, 4.0 Hz), 2.58-2.51 (m, 4H), 2.31-2.21 (m, 2H), 2.05-1.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]([F:15])[F:14])=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 85 °C
Yield: 55 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.20 g, 6.90 mmol), sodium 2-chloro-2,2-difluoroacetate (1.577 g, 10.35 mmol), and potassium carbonate (1.239 g, 8.97 mmol) in 10 mL of anhydrous DMF was heated at 85° C. for 1.5 days. The reaction mixture was diluted with 50 mL of EtOAc, washed with 50 mL of H2O, followed by washing with 50 mL of NaOH (1N) solution, the EtOAc layer was dried (Na2SO4) and concentrated to give a light brown oil that was purified by Shoko silica gel chromatography instrument eluting with 0-10% EtOAc in hexanes (0-10% over 25 min; GRACE column: 80 g pre-packed). Desired fraction were combined and concentrated to give the titled compound as a colorless oil: 0.85 g, 55% yield. MS m/z=223.9, 225.9 [M+H]+. Calculated for C6H4BrF2NO: 222.9, 224.9.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5](=[O:8])[CH2:6][SH:7].C1(C)C=CC=CC=1.[Cl:16][CH2:17][CH2:18][N:19]([CH2:43][CH2:44][Cl:45])[P:20]([N:36]([CH2:40][CH2:41][Cl:42])[CH2:37][CH2:38][Cl:39])(=[O:35])[O:21][CH2:22][CH2:23]OS(C1C=CC(Br)=CC=1)(=O)=O>CO>[CH3:3][NH:4][C:5](=[O:8])[CH2:6][S:7][CH2:23][CH2:22][O:21][P:20]([N:36]([CH2:40][CH2:41][Cl:42])[CH2:37][CH2:38][Cl:39])([N:19]([CH2:18][CH2:17][Cl:16])[CH2:43][CH2:44][Cl:45])=[O:35]
Reactant: CNC(=O)CS
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CNC(=O)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Reaction time: 0.5 h

Procedure:
To a solution of crushed sodium hydroxide pellets, 2.28 g (57 mmol), in 20 mL anhydrous methanol cooled in an ice bath was added N-methyl-2-mercaptoacetamide, 3 g (28.5 mmol), slowly, followed by the addition of 20 mL anhydrous toluene and 2-(4-bromobenzenesulfonyloxy)ethyl tetrakis(2-chloroethyl)-phosphorodiamidate, 34.4 mL of 0.83 M solution in toluene (28.5 mmol), while maintaining the temperature at 5° C. or less. After stirring for about 30 min, the reaction mixture became a white slurry. It was stirred at 5° C. to room temperature overnight. LC-MS analysis indicated all the starting material, N-methyl-2-mercaptoacetamide, was consumed and the desired product was formed as a major product. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between diisopropyl acetate and brine. The aqueous phase was further extracted with diisopropyl acetate three times, and the combined organic phases were dried (MgSO4) and evaporated to give the crude product, which was purified by column chromatography on a silica column using hexane/acetate and acetate/methanol as eluting solvents to afford N-methyl-2-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]acetamide as a light yellow oil, 12 g (88% yield). 1H NMR (DMSO): δ 7.90 (bs, 1H) 4.05 (m, 2H), 3.71 (m, 8H), 3.33 (m, 8H), 3.12 (s, 2H), 2.87 (m, 2H), 2.59 (d, 3H, J=4.7 Hz), 2.76 (m, 1H). Mass spectrum (LC-MS): m/z 496 [C13H26Cl4N3O3PS+H]+.