Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH:8]([CH3:28])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=1)=[O:10])([CH3:3])[CH3:2].O.Cl>C(#N)C.[OH-].[Na+]>[CH:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][CH:8]([CH3:28])[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1)=[O:10])([CH3:2])[CH3:3]
Reactant: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(NC(=O)C(C)Oc2cccc(C(C)C)c2)cc1
Yield: 37 %

Procedure:
A solution of 156 mg of ethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}-hex-4-ynoate in 7 ml of acetonitrile and 7 ml of 1 N NaOH (aq) was stirred at room temperature for 18 h. The reaction mixture was admixed with water and adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. This gave 109 mg of 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoic acid in 37% yield over the two stages.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][NH:15][CH3:16].O.ON1C2C=CC=CC=2N=N1.CN(C=O)C>>[CH3:11][O:12][CH:13]([O:17][CH3:18])[CH2:14][N:15]([CH3:16])[C:8]([C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CNCC(OC)OC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN(C)C(=O)[C@H]1CC[C@H](O)CC1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-hydroxycyclohexanecarboxylic acid (1.00 g, 6.94 mmol), 2,2-dimethoxy-N-methylethanamine (0.909 g, 7.63 mmol), and 1-Hydroxybenzotriazole hydrate (1.17 g, 7.63 mmol) in DMF (25 mL, 320 mmol) was added N-(3-Dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (1.46 g, 7.63 mmol) at ambient temperature, and the solution was stirred at ambient temperature overnight. Most of the DMF was evaporated in vacuo, and the residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (4×25 mL), saturated with NaCl, and extracted again with EtOAc (5×25 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as yellow oil that was used without further purification in the next step. 1H NMR (400 MHz, CDCl3): δ=4.48 (t, J=5.4 Hz, 1H, major rotamer), 4.39 (t, J=5.4 Hz, 1H, minor rotamer), 3.70-3.61 (m, 1H), 3.45-3.42 (m, 2H), 3.43 (s, 6H, minor rotamer), 3.40 (s, 6H, major rotamer), 3.11 (s, 3H, major rotamer), 2.97 (s, 3H, minor rotamer), 2.56 (tt, J=11.6, 3.8 Hz, 1H, minor rotamer), 2.46 (tt, J=11.8, 3.4 Hz, 1H, major rotamer), 2.11-2.00 (m, 2H), 1.86-1.74 (m, 2H), 1.71-1.55 (m, 3H), 1.36-1.23 (m, 2H). MS (ES+): m/z=268.11 (87) [MNa+], 246.15 (42) [MH+], 214.13 (100) [MH+−MeOH]. HPLC: tR=2.36 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][C:19]4([O:20][CH2:21][CH2:22][O:23]4)[CH2:24][CH2:25]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ccc(C2=CCC(CCC3CCC4(CC3)OCCO4)CC2)cc1
Agent: [Pd]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccc([C@H]2CC[C@H](CCC3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 0 °C

Procedure:
A solution of 35.0 g of 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)-1-cyclohexenyl]benzene in 1 l of toluene is treated with 2.6 g of palladium/carbon (10%) and hydrogenated at room temperature under normal pressure until the uptake of hydrogen comes to a standstill. Thereafter, the reaction mixture is filtered and the filtrate is concentrated, there being obtained crude 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)cyclohexyl]benzene. A suspension of 32.8 g of aluminium chloride in 215 ml of methylene chloride is treated at 18° C. while stirring and gassing with nitrogen within 10 minutes with a solution of the crude product obtained in 110 ml of methylene chloride and stirred at 0° C. for a further 30 minutes. Subsequently, the reaction mixture is poured on to 600 ml of ice/water, stirred for 10 minutes and then extracted three times with methylene chloride. The organic phases are washed in succession with water, with saturated sodium hydrogen carbonate solution and with water, then dried over sodium sulphate and filtered. Concentration of the filtrate gives 4-chloro-1-[trans-4-[2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl]cyclohexyl]benzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[N:7]=[C:6]([CH2:8][N:9]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]3=[O:19])[CH:5]=[C:4]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:3]=2)[CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
To a solution of 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-isoindole-1,3-dione (0.30 g, 0.72 mmol) in DME (4 mL) and H2O (1 mL) was added 3-pyridine boronic acid (0.09 g, 0.72), Pd(PPh3)4 (0.04 g, 0.04 mmol), and K3PO4 (0.21 g, 1.01 mmol) at rt. The resulting mixture was heated to 80° C. for 12 hours then allowed to cool to rt. At which time the mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated and purified by FCC to afford the title compound as a colorless solid (0.11 g, 33%). MS (ESI): mass calcd. for C25H15F3N4O2, 460.1; m/z found, 461.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[CH:40]12[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]1)[CH2:43][NH:42][CH2:41]2.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:42]2[CH2:41][CH:40]3[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (226 mg, 0.39 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.56 mmol), NaHCO3 (196 mg, 2.33 mmol) in NMP (4 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.38 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed m/z 758.3 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]([C:21](O)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:16]1[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1
Yield: 68.6 %

Procedure:
N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), biphenyl-2-carboxylic acid (0.0943 g; 0.466 mmol), HATU (0.193 g; 0.508 mmol) and N,N-diisopropylethylamine (0.179 mL; 1.06 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.109 g (68%) of N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>C1COCC1>[Cl:30][CH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])=[O:35]
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added 4-chlorobutyryl chloride (21.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (58.8 mg, 84%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](C)(C)[C:9]([O:11]CC)=O)=O)=[CH:4][CH:3]=1.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:18]1([N:24]2[C:9](=[O:11])[CH2:8][C:6]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=3)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Yield: 93.6 %

Procedure:
A mixture of 15 g (64 mmol) of ethyl α-(4-methylbenzoyl)isobutyrate, 10 g (93 mmol) of phenyl-hydrazine and 100 ml of toluene was dehydrated under reflux in the presence of p-toluenesulfonic acid monohydrate (catalytic amount) for 18 hours. The reaction solution was washed successively with 1N sodium hydroxide, 1N hydrochloric acid and saturated brine solution, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was recrystallized from methanol to give 15 g of the object compound as white crystals (yield 84%).
Reaction SMILES: [CH2:1]1[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]>C(O)C>[CH2:15]([NH:16][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCCCCCN
Reactant: CCCCCC1CO1
Solvent: CCO
Product: CCCCCC(O)CNCCCCCCNCC(O)CCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-heptene oxide (71.8 g.) and hexamethylenediamine (32 g.) and recrystallization of the resulting product from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxyheptylamine] (I: R = CH3 (CH2)4, R' = H, X = (CH2)6, Z = H) (16.5 g., m.p. 131.2°-134.2° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(#N)C.I.C(=O)(O)[O-].[Na+]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1ccc(N2CCc3c(Cl)ncnc3C2)nc1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(Nc2ncnc3c2CCN(c2ccc(C(F)(F)F)cn2)C3)c1
Temperature: 160 °C
Yield: 443.9 %

Procedure:
A mixture of 4-chloro-7-(5-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.035 g, 0.00011 mol), 3-methoxyaniline (0.018 mL, 0.00016 mol) in acetonitrile (0.5 mL, 0.01 mol) and 47% HI (0.05 mL, 0.0007 mol) was heated at 160° C. for 20 minutes in in a sealed tube via microwave. After cooling to r.t., the mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine and dried over magnesium sulfate. Concentrated to leave a brown solid. Residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.196 g of a white foam.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][C:15]=1[S:25]([NH2:28])(=[O:27])=[O:26]>Cl>[ClH:20].[CH3:1][NH:2][CH:3]([CH3:12])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2([NH:13][C:14]3[CH:19]=[C:18]([Cl:20])[C:17]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:16][C:15]=3[S:25](=[O:27])(=[O:26])[NH:28]2)[CH2:7][CH2:6]1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: CNC(C)CC1CCC(=O)CC1
Agent: Cl
Product: CNC(C)CC1CCC2(CC1)Nc1cc(Cl)c(S(N)(=O)=O)cc1S(=O)(=O)N2

Procedure:
A mixture of 4-(2-methylaminopropyl) cyclohexanone (4.0 g., 0.024 mole) and 4-amino-6-chloro-1,3-benzenedisulfonamide (4.4 g., 0.0154 mole) in 2 N ethanolic HCl (75 ml.) is refluxed for one hour and cooled to give 7.0 g. of 4'-(2-methylaminopropyl)-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H)-1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride which melts at 296° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a mixture of 2-amino-5-bromopyridine 1 (1.80 g, 10.4 mmol) in 104 ml toluene and 24 ml ethanol (EtOH) was added 4-fluorophenyl boronic acid (1.75 g, 12.5 mmol) followed by 10 ml of 2.0 M aqueous Na2CO3. The reaction was degassed with nitrogen and Pd(PPh3)4 (0.60 g, 0.52 mmol) was added in one portion and the reaction was heated to reflux for 26 hours. The reaction was then cooled to ambient temperature and diluted with 50 ml water. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc) (2×100 mL). The organic layers were combined, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to a brown oil. Automated purification on a silica gel ISCO column (120 g column, 2.5% MeOH—CH2Cl2) gave 1.20 g (60%) of 2-amino-5-(4-fluorophenyl)pyridine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([O:18][CH3:19])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[CH:3][C:4]=1[O:18][CH3:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)c2ccccc2)c(OC)cc1Br
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cc2ccccc2)c(OC)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of (4-bromo-2,5-dimethoxyphenyl)(phenyl)methanone (100 mg, 0.311 mmol) in 0.2 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (0.24 mL, 10 eq) and triethylsilane (0.2 mL, 4 eq). After 16 h of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL). The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted twice with DCM (2×10 mL) The combined organic phase was washed twice with a saturated NaHCO3 solution (2×20 mL), brine (2×20 mL), dried over MgSO4, filtered and concentrated in vacuo. The product was obtained pure enough for further reaction in 98% yield (93.4 mg). 1H NMR (300 MHz, CDCl3) δ 7.34-7.25 (m, 2H), 7.24-7.17 (m, 3H), 7.08 (s, 1H), 6.69 (s, 1H), 3.95 (s, 2H), 3.78 (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.9 (C), 150.1 (C), 140.4 (C), 129.9 (C), 128.9 (CH), 128.5 (CH), 126.1 (CH), 116.1 (CH), 115.0 (CH), 109.1 (C), 57.0 (OCH3), 56.3 (OCH3), 35.9 (CH2Bn); MS (ESI) m/z: 324.5, 326.1 [M+NH4, 79Br, 81Br]+; 630.3, 632.0, 634.2 [2M+NH4, 79Br, 81Br]+.
Reaction SMILES: C(C1C=CN=CC=1)#N.[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22](=[O:25])[CH2:23][Br:24])=[CH:20][CH:19]=1.C(Br)C(C1C=CC=CC=1)=O>>[Br-:24].[CH2:23]([N+:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]#[N:10])[CH:12]=1)[C:22]([C:21]1[CH:26]=[CH:27][CH:18]=[CH:19][CH:20]=1)=[O:25]
Reactant: N#Cc1cccnc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: N#Cc1ccncc1
Agent: O=C(CBr)c1ccccc1
Product: N#Cc1ccc[n+](CC(=O)c2ccccc2)c1
Product: [Br-]

Procedure:
Employing the procedure of Example II but replacing 4-cyanopyridine with a substantially equimolecular amount of 3-cyanopyridine and replacing 4-chlorophenacyl bromide with a substantially equimolecular amount of phenacyl bromide there is obtained N-(phenacyl) 3-cyanopyridinium bromide, a white solid soluble in water.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:7])[CH3:4].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.[Na+].[Cl-].[CH2:32]1COCC1>O.C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:32][C:22]2[CH:29]=[CH:28][C:25]([CH3:26])=[CH:24][CH:23]=2)[CH:10]=[C:11]([CH3:20])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(C)cc1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C)cc2)c(C)cn1Cc1ccc(C)cc1
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Sodium hydride (470 mg, 60% in mineral oil, 11.8 mmol) was added to a solution of 4-methyl-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.42 g, 5.84 mmol) in THF (10 mL) at 0° C. and under nitrogen as inert gas and the reaction mixture was stirred for 15 min. Then p-bromobenzyl bromide (2.16 g, 11.7 mmol) was added to the reaction mixture and the reaction mixture was stirred for 30 min at 0° C. and overnight at RT. After the addition of a few drops of water and aq. sat. NaCl solution (100 mL), extraction was performed with DCM (2×50 mL). After drying of the combined organic phases over sodium sulfate, filtration and removal of the solvent, purification was performed via column chromatography. 4-Methyl-1-(4-methylbenzyl)-3-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.03 g, 51% of theoretical) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1)#[N:6].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][C:31]([C:33]2[N:42]3[C:36]([CH2:37][NH:38][C:39]4[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=4[CH2:41]3)=[CH:35][CH:34]=2)=[O:32])[CH:24]=1.CN(C)C=O>O1CCOCC1>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][N:42]3[C:33]([C:31]([NH:30][CH2:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[O:32])=[CH:34][CH:35]=[C:36]3[CH2:37]2)=[O:22])=[CH:18][CH:19]=1)#[N:6]
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: N#CCc1ccccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
A mixture of 20 mL of thionyl chloride and 0.243 g (0.001 mol) of 2′-(cyanomethyl)-1,1′-biphenyl-4-carboxylic acid of Step A was heated under reflux for 1 hour. The excess thionyl chloride was removed in vacuo. To the residue was added 35 mL of dry 1,4-dioxane, 0.318 g (0.001 mol) of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide and 0.122 g (0.001 mol) of N,N-dimethylformamide. The reaction was heated under reflux for three hours, cooled and evaporated to dryness. The residue was collected, washed with water and triturated with ether to give 0.62 g. of a tan solid, m.p. 105-108° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15]N.O.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.Cl>C(O)C(F)(F)F>[N+:12]([C:9]1[C:8]2[C:20]3[CH2:19][NH:18][CH2:23][CH2:22][C:21]=3[NH:15][C:7]=2[C:6]([S:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: O=C1CCNCC1
Reactant: NNc1cc([N+](=O)[O-])ccc1SCCCCl
Agent: Cl
Solvent: O
Solvent: OCC(F)(F)F
Product: O=[N+]([O-])c1ccc(SCCCCl)c2[nH]c3c(c12)CNCC3
Temperature: 25 °C
Yield: 96.9 %

Procedure:
1-{2-[(3-Chloropropyl)sulfanyl]-5-nitrophenyl}hydrazine (100 mg, 0.38 mmol) and 4-piperidone mono hydrate (58 mg, 0.38 mmol) were dissolved in trifluoroethanol (1 mL) andheated at reflux for 1 hour. To this was added 12 N HCl (3 mL) and the reaction allowed to heat at reflux for 2 hours. The product percipatated out upon cooling to room temperature, it was filtered off and washed with cold 2-propanol to give 3-chloropropyl 9-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl sulfide (120 mg, 75.4%). 1H NMR (CD3OD, 300 MHz): δ8.00 (d, 1H, J=8.4 Hz), 7.30 (d, 1H, J=8.4 Hz), 4.68 (s, 2H), 3.69 (t, 2H, J=6.2 Hz), 3.60 (t, 2H, J=6 Hz), 3.23 (t, 2H, J=6.2 Hz), 2.08 (q, 2H, J=6.2 Hz) ppm.