Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1([O:41][C:42](N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C([N:52]([CH2:56][CH3:57])[CH:53]([CH3:55])C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:55][CH:42]([OH:41])[CH2:57][CH2:56]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(O)CC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4-difluoro piperidine(commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: O=[C:2]([CH2:11][CH2:12][CH3:13])[CH2:3][C:4]([O:6]CCC#N)=[O:5].[NH2:14]/[C:15](/[CH3:21])=[CH:16]\[C:17]([O:19][CH3:20])=[O:18].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)(C)C>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:2]([CH2:11][CH2:12][CH3:13])=[C:3]2[C:4]([OH:6])=[O:5])=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCCC(=O)CC(=O)OCCC#N
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCCC1=C(C(=O)O)C(c2ccc(OC)cc2)C(C(=O)OC)=C(C)N1
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyanoethyl 3-oxohexanoate (11.9 mmol), methyl 3-aminocrotonate (11.9 mmol), and 4-methoxybenzaldehyde in 25 mL of isopropanol is heated at reflux temperature for 16 h, cooled, and the solvent is removed under reduced pressure. The residue is dissolved in 15 mL of dioxane and 626 mg of NaOH in 15 mL of water is added to the reaction mixture. After 0.5 hrs, the solution is concentrated to a small volume under reduced pressure, partitioned between 50 mL of water and 50 mL of ethyl acetate, separated, and the aqueous solution is washed with 2×20 mL of ethyl acetate. The organic solutions are discarded. The aqueous extract is acidified with concentrated HCl (pH=2), and the precipitated oil is extracted with ethyl acetate (2×40 mL). The combined organic extracts are dried (MgSO4), and the solvent is removed in vacua to give a residue, which is characterized spectroscopically.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:40][O:39][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1)=[O:38]
Reactant: COC(=O)CCCCBr
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (300 mg) obtained in Example 219 is suspended in N,N-dimethylacetamide (5 ml), and thereto are added methyl 5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl), and potassium iodide (111 mg), and the mixture is stirred at 100° C. for 24 hours. Methyl 5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl) and potassium iodide (111 mg) are further added thereto, and the mixture is stirred at 100° C. for 12 hours. The reaction solution is diluted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate) to give trans-3-[4-(4-methoxycarbonylbutylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (101 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:7]=1[Cl:15])=[O:4].CC(O)C.Cl.[H][H]>[Pd].CO>[NH2:14][CH2:13][C:9]1[CH:8]=[C:7]([Cl:15])[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[C:11]([Cl:12])[CH:10]=1
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Yield: 100 %

Procedure:
A mixture of 10.5 parts of 2-chloro-N-(2,6-dichloro-4-cyanophenyl) acetamide, 22 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 10.7 parts (100%) of N-[4-(aminomethyl)-2,6-dichlorophenyl]-2-chloroacetamide as a residue (int. 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:45](I)[CH3:46]>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:34][CH2:35][C:36]([O:38][CH2:45][CH3:46])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
To a solution of 1{(2-carboxyethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid benzyl ester (147 grams) in N,N-dimethyl formamide (3 L) at room temperature was added potassium carbonate (150 grams, 1.08 mole) and ethyl iodide (32.4 mL, 0.405 mole). The mixture was stirred for 16 hours at room temperature. After filtration, most of the solvent was removed under vacuum. The residue was taken up in water and acidified using 6N aqueous hydrogen chloride solution. The resulting mixture was extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate, and concentrated to yield 1{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acid benzyl ester as a yellow semi-solid (149.1 grams, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[OH:13])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([CH2:12][CH2:11][CH2:10][CH2:9][C:8]3([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[OH:13])[O:30]2)=[CH:20][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(Cn2cncn2)CCCCC1=Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: OC1(Cn2cncn2)CCCCC12OC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
A mixture of 9 g of 2-(4-chlorobenzylidene)-1-(1,2,4-triazol-1-ylmethyl)cyclohexan-1-ol and 14.8 g of m-chloroperbenzoic acid in 50 ml of dichloromethane is stirred for 3 h at room temperature. 200 ml of water are then added and extracted with 3×100 ml of dichloromethane. The organic phase is washed with a potassium carbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallised from diisopropyl ether to produce 6 g of white solid (M.p.=150.5° C.)
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.2 %

Procedure:
Ethylsulfonyl chloride (113 uL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 uL, 3.1 mmol) in DCM (5 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 14 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 95%) in hexanes to afford the title compound (345 mg, 94%) as an amber oil that solidified upon standing. LCMS (M+H)+=371.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([O:8][C:9]([C:11]1[S:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:18][CH2:17]2)=[N:14][N:15]=1)=O)C>>[CH2:1]([NH:5][C:9]([C:11]1[S:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:20][CH2:21]2)=[N:14][N:15]=1)=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Product: CCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-butylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.042 g, yield 79%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.69 (m, 1H), 7.63-7.49 (m, 2H), 7.33-7.3 (m, 1H), 7.03 (m, 1H), 4.08-3.8 (m, 1H), 3.9-3.8 (m, 1H), 3.68-3.62 (m, 2H), 3.54-3.47 (m, 2H), 3.42-3.35 (m, 2H), 3.33-3.28 (m, 2H), 1.6-1.5 (m, 2H), 1.42-1.3 (m, 2H), 0.9 (t, J=7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 155.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 126.3, 125.4, 121.7, 49.5, 48.9, 45.9, 40.7, 39.4, 31.5, 19.9, 13.6. MS (ES+) m/z 442 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[NH2:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[C:17]#[N:18]>O>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH3:24])[C:20]([Br:1])=[C:21]([F:23])[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(N)c1C#N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)c(F)cc(N)c1C#N
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
N-Bromosuccinimide (16.6 g, 93.3 mmol) was gradually added to an N,N-dimethylformamide (250 ml) solution of 2-amino-4-fluoro-6-methylbenzonitrile (I-264) (14.0 g, 93.3 mmol). After stirring for 6 hours, the reaction liquid was poured into water with ice (750 ml), the precipitated solid was collected by filtration. The solid was washed with water, then dried to obtain the entitled compound (20.2 g, 95%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]1[C@H:24]2[NH:25][C@H:20]([CH2:21][CH:22](O)[CH2:23]2)[CH2:19]1>>[CH:24]12[NH:25][CH:20]([CH2:19][CH2:18]1)[CH2:21][CH:22]([N:14]1[C:4]3=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]([Cl:1])=[C:3]3[C:16]([CH3:17])=[N:15]1)[CH2:23]2
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Product: Cc1nn(C2CC3CCC(C2)N3)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIIa was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and nortropine following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:27])=[N:16][CH:17]=[C:18]([C:20]3=[CH:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26]3)[CH:19]=2)=[N:12][N:11]=[N:10]1.C(Cl)CCl.[F:32][C:33]([F:38])([F:37])[C:34](O)=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:27][C:15]1[N:16]=[CH:17][C:18]([C:20]2[CH2:26][CH2:25][CH2:24][N:23]([C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[CH2:22][CH:21]=2)=[CH:19][C:14]=1[C:13]1[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:10]=[N:11][N:12]=1
Reactant: Nc1ncc(C2=CCNCCC2)cc1-c1nnnn1-c1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(C2=CCN(C(=O)C(F)(F)F)CCC2)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
3-(1-(2,3-Difluorophenyl)-1H-tetrazol-5-yl)-5-((E)-2,5,6,7-tetrahydro-1H-azepin-4-yl)pyridin-2-amine (37 mg, 100 μmol, 1 eq.) was diluted in DCM (1.5 mL). EDC (34.4 mg, 150 μmol, 1.5 eq.), trifluoroacetic acid (17.1 mg, 150 μmol, 1 eq.), and DIEA (53 μL, 300 μmol, 3 eq.) were added. The reaction was stirred at room temperature overnight then concentrated. The product was purified by reversed-phase HPLC purification to give 1-((E)-5-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3,4-dihydro-2H-azepin-1(7H)-yl)-2,2,2-trifluoroethanone (13.6 mg, 30% yield); 1H NMR (300 MHz, DMSO-d6): 8.25 (m, 1H); 7.87 (m, 1H); 7.77 (m, 1H); 7.55 (m, 1H); 7.37 (m, 1H); 5.95-5.7 (m, 1H); 4.12 (m, 2H); 3.75-3.6 (m, 2H); 2.4 (m, 2H); 1.75 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][N:3]=1.[CH3:23][N:24](C=O)C>[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[N:3][CH:4]=3)[N:12]=2)=[CH:14][CH:15]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C#N)nc3)no2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of 2-chloro-5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine (5.0 g, 16.0 mmol), zinc cyamide (1.13 g, 9.58 mmol), tetrakis(triphenylphosphine) palladium (0) (0.74 g, 0.64 mmol) and DMF (16 mL) was stirred at 80° C. for 24 hours. The reaction mixture was cooled to room temperature, quenched with H2O (10 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and brine (2×100 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 2:8 EtOAc:hexanes) provided the title compound (2.87 g, 59% yield) as a solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[CH:6]=[C:5]([CH3:33])[N:4]=1.Cl>[OH-].[Na+]>[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[CH:6]=[C:5]([CH3:33])[N:4]=1
Reactant: CCOC(=O)c1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C(=O)O)c(C)n1
Yield: 32.4 %

Procedure:
A solution of ethyl 2,6-dimethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylate hydrochloride (240 mg) in 2M aqueous sodium hydroxide (5 ml) was heated under reflux for 2 hours. The solution was cooled and acidified to pH 3 with 6M hydrochloric acid. The precipitated solid was collected by filtration and triturated with hot methanol to give 2,6-dimethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine-3-carboxylic acid (67 mg), as a white powder, m.p. 237° C.; NMR (d6 -DMSO, d4 -acetic acid): 2.45(s,3H), 2.55(s,3H), 5.3(s,2H), 7.1(s,1H), 7.2(d,2H), 7.4(d,2H), 7.4-7.75 (complex m,4H); mass spectrum (DMSO/GLY): 400 (M-H)-, 166; microanalysis, found: C,64.5; H,4.5; N,17.0%; C22H19N5O3.0.5H2O requires: C,64.5; H,4.9; N,17.1%.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=O)=[O:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([Cl:3])(=[O:23])=[O:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
Thionyl chloride (200 mL, 326.2 grams, 2742 mmol) is added to the solid title A compound, 4-benzyloxybenzenesulfonic acid sodium salt, followed by 10 drops of DMF. The mixture is heated to reflux overnight and then concentrated under vacuum. Hot toluene (250 mL) is added, and the mixture is filtered. The filtrate is concentrated under vacuum. Toluene is again added to the residue followed by filtration and concentration under vacuum to give 4-benzyloxybenzenesulfonyl chloride as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]([OH:16])[CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1.C(#N)C>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(C)O)ccc3n2CC2CC2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(Cc2nc3cc(C(C)=O)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
To a mixture 1-[1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazol-5-yl]ethanol (1.35 g, 3.86 mmol), N-methylmorpholine-N-oxide (0.497 g, 4.24 mmol) and 4 Å molecular sieves (2.0 g) in CH2Cl2 (10 mL) was added tetrapropylammonium perruthenate (0.068 g, 0.193 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. N-methylmorpholine-N-oxide (0.124 g, 1.06 mmol) and acetonitrile (1 mL) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the crude product was purified by silica gel column chromatography (30% EtOAc/hexanes to 60% EtOAc/hexanes) to provide the title compound (0.880 g, 65%) as a white solid. 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.94 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.91 (dd, J=6.4 Hz, J=2.0 Hz, 2H), 4.29 (s, 2H), 3.98 (q, J=7.2 Hz, 2H) 3.41 (d, J=6.8 Hz, 2H), 2.67 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.07–1.00 (m, 1H), 0.55–0.51 (m, 2H), 0.29–0.26 (m, 2H). 13C NMR (CDCl3): δ 198.71, 159.01, 156.43, 143.29, 140.01, 132.68, 130.44, 128.67, 123.50, 121.95, 115.83, 110.73, 64.38, 49.23, 34.63, 27.63, 15.76, 11.99, 5.20. MS (ESI) (M+H)+=349. Anal. Calcd for C22H24N2O2+0.1H2O: C, 75.44, H, 6.96; N, 8.00. Found: C, 75.48; H, 7.13; N, 8.01.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([N:26]([CH:30]([CH:39]2[CH2:41][CH2:40]2)[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=2)[CH2:27][CH2:28][CH3:29])[S:23][C:24]=1[CH3:25].CO>N1C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([N:26]([CH:30]([CH:39]2[CH2:40][CH2:41]2)[C:31]2[CH:32]=[CH:33][C:34]([CH2:37][O:38][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:28][CH3:29])[S:23][C:24]=1[CH3:25]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(COC(=O)c2cccc(CCl)c2)cc1)C1CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
0.6 ml of 3-chloromethylbenzoyl chloride is added dropwise, at 0° C., to 1.6 g of the compound of Example 4 dissolved in 10 ml of anhydrous pyridine. After 2 hours at 0° C., methanol is added to hydrolyze the excess acid chloride and the organic phase is diluted with methylene chloride. This is then washed with 2N hydrochloric acid, with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. The organic solvent is evaporated off and the product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent, to give the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH2:6]2.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O1CCOCC1>C(Cl)CCl>[Cl-:13].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N+:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: ClCc1ccccc1Cl
Reactant: COc1ccc2c(c1)CCN=C2
Solvent: C1COCCO1
Solvent: ClCCCl
Product: COc1ccc2c(c1)CC[N+](Cc1ccccc1Cl)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6-methoxy-3,4-dihydro-isoquinoline and 2-chlorobenzyl chloride in ethylene chloride. Melting point: 156°-158° C. (Decomp., from dioxan).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:24])[C:10]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:11]1)[S:6]2.[Br:25]Br.CCCCCC>C(O)(=O)C>[Br:25][C:8]1[C:9](=[O:24])[C:10]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[CH:11][C:12]2[C:7]=1[S:6][C:5]1[C:14](=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)[N:13]=2
Reactant: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)cc-3sc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1ccc2nc3cc(N4CCN(C)CC4)c(=O)c(Br)c-3sc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of 7-methoxy-2-(4-methylpiperazin-1-yl)-3H-phenothiazin-3-one (500 mg) in acetic acid (10 ml) was added a solution of bromine in acetic acid (0.5M) (6 ml) and stirred for 5 minutes. Hexane (100 ml) was added and the resulting precipitate was filtered. The solid was suspended in a mixture of aqueous K2CO3 (50 ml), EtOAc (100 ml) and methanol (20 ml) and stirred for 15 minutes. After filtration and decantation, the organic layer was washed with brine, dried and evaporated to dryness to afford the title compound (190 mg) m.p. 209°-210° (dec.).