Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[CH:2].[CH2:12]([C@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([C@H:17]1[CH2:18][CH2:19][C@H:20]([O:10][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[CH:2])[CH2:4][CH2:5]2)=[O:11])[CH2:21][CH2:22]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC[C@H]1CC[C@H](O)CC1
Reactant: C#C[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#C[C@H]1CC[C@H](C(=O)O[C@H]2CC[C@H](CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 122 mg of trans-4-ethynylcyclohexanecarboxylic acid, 145 mg of trans-4-pentylcyclohexanol, 206 mg of dicyclohexylcarbodiimide and 12.2 mg of 4-(dimethylamino)pyridine in 10 ml of methylene chloride was stirred at room temperature for 21 hours. The separated white precipitate was filtered off, the filtrate was poured into 50 ml of water and extracted three times with 50 ml of methylene chloride each time. The organic phases were washed once with 50 ml of water, twice with 30 ml of 5% aqueous acetic acid each time and twice with 30 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue on silica gel with 5% ethyl acetate/petroleum ether gave 159 mg (65%) of trans-4-ethynylcyclohexanecarboxylic acid trans-4-pentylcyclohexyl ester as a colourless crystallizing oil. Additional crystallization from isopropanol at -20° C. yielded and analytically pure ester; m.p. (C-I) 54.2° C., cl.p. (N-I) 40.5° C.
Reaction SMILES: C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:25][CH:24]=1.CO>O1CCCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([OH:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:28]=1
Reactant: COC(=O)CCCCCC(=O)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
To a solution of (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2]oxazaborole (1.1 g) in tetrahydrofuran (20 ml) was added at 0° C. 1M tetrahydrofuran solution of boranetetrahydrofuran complex (4 ml). To this solution were added dropwise a solution of methyl 7-(4-fluorophenyl)-7-oxoheptanoate (10.0 g, 39.6 mmol) in tetrahydrofuran (20 ml) and 1M tetrahydrofuran solution of boranetetrahydrofuran complex (20 ml), simultaneously, taking 25 minutes. The mixture was stirred for 30 minutes at the same temperature range, to which was added methanol (20 ml), followed by stirring for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (9.91 g). Physico-chemical properties and spectral data of this product are shown in [Table 7]. Likewise, Compound 1-2 was prepared.
Reaction SMILES: Cl[C:2]1[CH:7]=C(NC2N=CN=C(NC(C3CC3)=O)C=2)C(=O)[N:4]2C(C3C=CC=C(F)C=3)(C)NC(=O)[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Cl.[Br:41][C:42]1[C:47](=[O:48])[N:46]2[C:49]3([NH:55][C:56](=[O:57])[C:45]2=[C:44]([Cl:58])[CH:43]=1)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3>C(#N)C>[Br:41][C:42]1[C:47](=[O:48])[N:46]2[C:49]3([NH:55][C:56](=[O:57])[C:45]2=[C:44]([Cl:58])[CH:43]=1)[CH2:54][CH2:53][N:52]([CH2:7][CH2:2][C:3]#[N:4])[CH2:51][CH2:50]3
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: O=C1NC2(CCNCC2)n2c1c(Cl)cc(Br)c2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC2(CC1)NC(=O)c1c(Cl)cc(Br)c(=O)n12
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A flask was charges with 6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione hydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was added. The reaction mass was cooled to 0° C. and potassium carbonate (281 mg, 2.03 mmol) was added followed by addition of 2-bromoacetonitrile (2, 218 mg, 1.63 mmol). The reaction mass was stirred at room temperature for 10 h. After completion, the solvent was removed under reduced pressure to get the crude. The crude was purified by Biotage snap using 1-3% methanol in dichloromethane. The desired fractions were concentrated to get 3-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-yl)propanenitrile (3) as brown solid. Yield: 0.42 g, 83%; MS (ESI) m/z 373.18 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.25 (s, 1H), 3.75 (s, 2H), 3.15-3.10 (m, 2H), 2.87-2.72 (m, 2H), 2.66-2.60 (m, 2H) 1.57-1.54 (m, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.Cl.[CH:25]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:31]2[CH2:32][CH2:33][N:28]([CH:25]3[CH2:27][CH2:26]3)[CH2:29][CH2:30]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: C1CN(C2CC2)CCN1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CC2)CC1
Temperature: 65 °C
Yield: 54.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 1-cyclopropylpiperazine dihydrochloride (0.081 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.44 g, 1.4 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give the desired product (61.1 mg, 55%). LCMS calculated for C18H21 ClN3O (M+H)+: m/z=330.1; Found: 330.1.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].CN(C1C=CC=CN=1)C.[C:23]([N:33]1[CH2:36][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH2:49])[O:45][C:44]3=[O:50])=[CH:39][C:38]=2[F:51])[CH2:34]1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[F:51][C:38]1[CH:39]=[C:40]([N:43]2[CH2:47][C@H:46]([CH2:48][NH:49][C:7](=[O:9])[CH3:8])[O:45][C:44]2=[O:50])[CH:41]=[CH:42][C:37]=1[CH:35]1[CH2:36][N:33]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:34]1
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4 dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][O:35][CH2:36][C:37](O)=[O:38]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and methoxyacetic acid (9.2 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([CH3:16])([CH2:14][OH:15])[CH2:12][OH:13]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]([CH3:16])([CH2:12][OH:13])[CH2:14][OH:15])=[C:2]([F:1])[CH:7]=1
Reactant: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: CC(CO)(CO)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrophenyl)-2-methylpropane-1,3-diol (100 mg, 0.34 mmol, 1.0 eq) in ethanol was added 10% Pd/C (30 mg) and the mixture was stirred under hydrogen gas balloon atmosphere for 3 h at RT. The reaction mixture was filtered through celite pad and filtrate concentrated under vacuum to get 2-(4-amino-2-fluorophenyl)-2-methylpropane-1,3-diol (65 mg, 76%; TLC system: EtOAc/PE (1:1), Rf: 0.4).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:25]([C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[O:16][CH3:15])(=[O:27])=[O:26])[C:8](=[O:13])[C:7]2=[O:14]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(=O)c3cc(Cl)ccc32)c(OC)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
0.5 g of 60% sodium hydride in oil is added to a mixture of 3.6 g of 5-chloro-1H-indole-2,3-dione in 20 ml of DMF, and the mixture is stirred for 30 minutes at 20° C. 4.8 g of 2,4-dimethoxybenzenesulphonyl chloride are then added and the mixture is stirred at 20° C. for 1 hour. The resulting mixture is concentrated under vacuum (1.3 Pa), the residue is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is triturated in iso ether and the precipitate formed is filtered off by suction. 2.9 g of the expected product are obtained after crystallization from hot EtOAc, m.p.=194.5° C.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5](Br)=[C:6]([CH3:9])[C:7]=1[CH3:8].[I-].[K+].[CH3:15][O:16][C:17]1[C:18](=[O:24])[CH:19]=[CH:20][C:21](=[O:23])[CH:22]=1.[Br-]>CN(C)C=O.O>[CH3:15][O:16][C:17]1[C:18](=[O:24])[C:19]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:8][C:7]1[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:9]=2
Reactant: Cc1c(C)c(Br)c(Br)c(Br)c1Br
Reactant: COC1=CC(=O)C=CC1=O
Agent: [Br-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=CC(=O)c2cc3ccccc3cc2C1=O

Procedure:
16 g of, α, α, α', α', -tetrabromo-o-xylene, 44 g of potassium iodide and 10 g crude 2-methoxy-1,4-benzoquinone were stirred in 160 ml of N,N-dimethylformamide at 70° C. overnight. After the reaction was complete, no bromide was left as determined by thin layer chromotography and the reaction mixture was poured into 1200 ml of H2O. 10%aq Na2S2O5 solution was added to decolorize the solution. The precipitate formed in the aqueous solution was collected and dried. Continuous extraction of the dark precipitate using benzene as a solvent yielded a dark colored solution. The solution was then washed with 2.5% NaOH, H2O, dried and concentrated. 7 g of crude product was obtained. Recrystallization from methanol yielded 5 g of pure yellow powder of MAQ.
Reaction SMILES: C[N:2]([CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[C:17]([F:25])[CH:18]=[C:19](F)[CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:3](=O)[C:4]1C=CC=CC=1.C(NC1CC2C3C(=C(F)C=CC=3)NC=2CC1)(=O)C>>[CH2:3]([NH:2][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[C:17]([F:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[CH3:4]
Reactant: CN(C(=O)c1ccccc1)C1CCc2[nH]c3c(F)cc(F)cc3c2C1
Agent: CC(=O)NC1CCc2[nH]c3c(F)cccc3c2C1
Product: CCNC1CCc2[nH]c3c(F)cccc3c2C1

Procedure:
Following a reductive procedure similar to that described in Example 260 but substituting for 3-(N-methyl-benzamido)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole an equivalent amount of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole there can be obtained 3-(ethylamino)-8-fluoro-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](N)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=[O:17]>CN(C=O)C.O>[CH2:1]([C:8]1[CH:9]=[C:10]([Br:15])[C:11](=[O:17])[NH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)ON=O
Reactant: Nc1ncc(Cc2ccccc2)cc1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(Cc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-benzyl-3-bromopyridin-2-amine 3 (0.2 g, 0.7 mmol) in DMF (4 mL) was added water (2 drops) followed by t-butyl nitrite (0.378 g, 3.6 mmol) and the reaction mixture stirred at RT for 30 min. DMF and the excess reagent were distilled off, and the residue purified by flash chromatography on silica gel (EtOAc:hexane, 1:1). Yield 7.3 g (86%), white solid, mp 151-152° C. 1H NMR (CDCl3, 500 MHz): δ 3.77 (s, 2H, CH2), 7.17-7.36 (m, 6H, Ar—H and CH), 7.76 (d, 1H, CH, J=1.5 Hz) 13.25 (bs, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 37.3, 115.4, 121.0, 126.9, 128.8, 128.8, 128.9, 128.9, 132.4, 138.5, 145.3, 161.0; HRMS (M+H)+ calcd for C12H11BrNO 264.0024, found 264.0014.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]([CH3:29])[N:8]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([CH3:28])[CH:21]=3)(=[O:19])=[O:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:8]2[CH:7]([CH3:29])[C:6]3[C:15](=[CH:16][C:3]([OH:2])=[CH:4][CH:5]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)(=[O:19])=[O:18])=[CH:21][C:22]=1[CH3:28]
Reactant: COc1ccc2c(c1)-c1ccccc1N(S(=O)(=O)c1ccc(OC)c(C)c1)C2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)N2c3ccccc3-c3cc(O)ccc3C2C)ccc1O
Yield: 39.7 %

Procedure:
The title compound was prepared from 9-methoxy-5-[(4-methoxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.27 g, 0.66 mmol), tetrabutylammonium iodide (0.61 g, 1.7 mmol), and 1 M boron trichloride in dichloromethane (3.3 mL, 3.3 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 1:1 gradient), followed by re-crystallization from a mixture of dichloromethane-hexane, to yield 5-[(4-hydroxy-3-methylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridin-9-ol as a homogeneous solid (0.10 g, 40%);
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.NO.NOS(O)(=O)=O.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: NO
Agent: NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1

Procedure:
A suspension of 4-nitrocinnamic acid (13.5 g, 70 mmol) in H2O (100 mL) was treated with hydroxylamine sulfate (18.5 g, 113 mmol) and hydroxylamine-o-sulfonic acid (43.5 g, 385 mmol) at 0° C. The pH was adjusted to 7.6 with 50% NaOH, and additional base was added as needed over the next 6 hours to maintain a pH of 7.6. The mixture was then filtered, and the filtrate was acidified to pH 2 with 2N H2SO4. The solids that formed were filtered, washed with H2O, and recrystallized from EtOH:H2O (30 mL:150 mL) to give the title compound. 1H NMR (CDCl3) δ 2.71 (t, 2 H), 3.03 (t, 2 H), 7.34 (d, 2 H), 8.13 (d, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][C:9](O)=O.[C:12]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>Cl>[C:12]([C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:9]([CH2:8][S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:27][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CSc1ccccn1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Agent: Cl
Agent: N
Product: O=C(c1ccccc1)c1ccc2nc(CSc3ccccn3)[nH]c2c1

Procedure:
8.45 g of 2-(2-pyridylthio)acetic acid (0.05 mole) and 10.6 g of 4-benzoyl-1,2-phenylenediamine (0.05 mole) in 100 ml of 4N hydrochloric acid are heated under reflux for 2 days. The mixture is allowed to cool and is neutralized with ammonia solution. It is extracted with ethyl acetate (3×100 ml), and the extract dried (Na2SO4), filtered and concentrated to a volume of 125 ml. From this solution, 11.7 g (68%) of 5-benzoyl-2-(2-pyridylthiomethyl)benzimidazole crystallize. The product thereby obtained is identical to that obtained by Method A, and the data for the identification appeat in Tables 1 and 2.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=3)[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([F:45])[N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:45][C:19]1[N:18]=[C:17]([NH2:7])[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Temperature: 50 °C
Yield: 62.6 %

Procedure:
To {6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrol [2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (136, 21 g, 32.4 mmol) in 500 mL of acetonitrile, triethylsilane (51.7 mL, 324 mmol) and trifluoroacetic acid (24.93 mL, 324 mmol) were added. The reaction was stirred at 50° C. for several hours, solvents removed under vacuum, and the residue taken up in 250 mL of dichloromethane and 250 mL of trifluoroacetic acid was added. The mixture was stirred at reflux for several hours, then concentrated under vacuum. The residue was taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum and purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (137, 5.2 g, 20.29 mmol, 62.7% yield).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10].C(N(C(C)C)CC)(C)C>[Cl-].[Cl-].[Zn+2].C(#N)C>[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([O:16][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C1C=C(Cl)CCC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c([N+](=O)[O-])c1
Temperature: 45 °C
Yield: 50.5 %

Procedure:
To a mixture of 157 mg (1.15 mmol) of 3-chlorocyclohex-2-en-1-one (prepared as described in Synthesis (1974), (1), 47-8), 16 mg (0.12 mmol) of ZnCl2, 297 mg (1.15 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 3 ml of anhydrous acetonitrile there are added dropwise, under a nitrogen atmosphere, over the course of 15 minutes, 166 mg (1.27 mmol) of diisopropylethylamine. A further 2 ml of acetonitrile are then added and the reaction mixture is maintained at a temperature of 45° C. for 18 hours in an oil bath, with stirring. The reaction mixture is then heated up again and maintained at reflux temperature for 40 hours. The reaction mixture is then brought to ambient temperature and the solvent is removed in vacuo. 25 ml of dichloromethane and 0.35 g of 36% hydrochloric acid in 5 ml of water are then added and the phases are separated. The organic phase is washed twice with 10 ml of water, dried using magnesium sulfate and concentrated in vacuo. 197 mg of 3-(2-nitro-4-methylsulfonyl-phenylcarbonyloxy)-cyclohex-2-en-1-one are obtained in the form of a brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.CO[C:28]1C=CC=C(OC)[C:33]=1[C:34]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:34]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]4[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]4)[CH:12]=[C:7]23)[CH2:33][CH2:28]1
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(Br)cccc4C3=C2)cn1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4CC4)C3=C2)cn1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 306.8 %

Procedure:
Example 96-1. 9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (7.73 g, 19.26 mmol) was dissolved in toluene (155 mL) and S-Phos (2.58 g, 6.16 mmol), cyclopropylboronic acid (3.45 g, 38.5 mmol) and K3PO4 (8.59 g, 40.5 mmol) were added. The suspension was degassed, Pd(OAc)2 (0.87 g, 3.85 mmol) was added under Argon and the mixture was heated at 100° C. for 1 h. The mixture was allowed to warm to RT and filtered through a pad of celite. The residue was diluted with DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 5 min, then from 1% MeOH in DCM to 5% MeOH in DCM in 60 min, 5% MeOH in DCM for 10 min) to yield a beige foam (6.85 g). The residue was crystallized from AcOEt to afford the title compound as white crystals (5.8 g). UPLC-MS: MS 363.3 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.50-0.72 (m, 2 H), 0.79-1.06 (m, 2 H), 1.77-2.08 (m, 1 H), 2.93-3.14 (m, 2 H), 3.24 (s, 3 H), 3.87 (br. s, 2 H), 4.13-4.39 (m, 4 H), 7.09-7.21 (m, 2 H), 7.24-7.35 (m, 1 H), 7.62 (s, 1 H), 7.84-7.94 (m, 1 H), 8.20 (s, 1 H).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])=[O:6])[CH2:3][CH3:4].[N:15]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[CH2:2]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:11][C:20]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[NH:21])[CH:12]=[CH:13][CH:14]=1)=[O:6])[CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1cccc(N)c1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: CCCC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.3 g, 0.0135 moles. in 35 ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.2 ml, 0.006 moles, and the reaction was heated to reflux for 8 hours. The reaction cooled to room temperature and the solvent was decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 80° C. for 24 hours giving N-(3-(((propyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide hydrochloride, 1.5 g, m.p. 207-208° C.