Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[C:38]([C:39]#[N:40])=[CH:37][N:36]=[CH:35][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:39]#[N:40])[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1cnccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4C#N)ccc3O2)CC1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-bromo-nicotinonitrile following a procedure analogous to that described in Example 1. LC (method 6): tR=1.31 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.[Cu]Br>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Ic1ccccc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 96 mg, 2.4 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (435 mg, 2.0 mmol) and copper (I) bromide (402 mg, 2.8 mmol) in pyridine (10 ml) at 0° C. After stirring for 0.5 hour at room temperature, iodobenzene (0.45 ml, 4.0 mmol) was added and the reaction mixture was heated to reflux for 24 hours. The reaction was allowed to cool, filtered and the filtrate then concentrated in vacuo. The crude residue was dissolved with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) to afford the title compound (E128); MS (ES+) m/e 294 [M+H]+.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21](O)=[CH:20][C:19]=2[CH3:26])=[CH:14][C:13]=1[CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH3:26])=[CH:20][C:21]([O:5][C@H:6]3[CH2:10][CH2:9][O:8][CH2:7]3)=[CH:22][C:23]=2[CH3:24])=[CH:14][C:13]=1[CH2:27][OH:28]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(F)c(CO)c1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(CO)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 105.4 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (83 mg, 0.50 mmol), 4′-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 18c (110 mg, 0.45 mmol) and cesium carbonate (293 mg, 0.90 mmol) were dissolved in 2 mL of N,N-dimethylformamide. The reaction mixture was heated to 90° C. and stirred for 12 hours. The resulting mixture was concentrated under reduced pressure, mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-(4-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 18d (150 mg) as a colorless slime, which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([OH:12])=O.S(Cl)(Cl)=O.C(#[N:19])C.C(Cl)Cl.N.O1CCOCC1>Cl>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([NH2:19])=[O:12]
Reactant: N#Cc1c(Br)sc(C(=O)O)c1Br
Reactant: CC#N
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1c(Br)sc(C(N)=O)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
3,5-Dibromo-4-cyanothiophene-2-carboxylic acid (5.90 g, 18.6 mmol) was added to a solution of thionyl chloride (27.1 mL, 371 mmol) in acetonitrile (40.0 mL, 766 mmol). The mixture was refluxed for 30 min then cooled to rt. The solvent was evaporated in vacuo to dryness to yield a lightly yellow solid. Methylene chloride (100 mL, 2000 mmol) was added to dissolve the solid, then the solution was cooled to 0° C. Under a nitrogen atmosphere, a solution of 0.500 M ammonia in 1,4-dioxane (111.5 mL, 55.7 mmol) was slowly added, and the mixture was brought to room temperature for 1 h. The mixture was evaporated in vacuo to give a solid residue. 100 mL of 1N HCl was added and the suspension was stirred for 1 h at room temperature. The solid product was collected by filtration and dried under high vacuum to give product (5.64 g, yield 98%). LCMS: (FA) ES−, 308, 310, 312.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:11][CH:12]=1)#[N:15]
Reactant: COC(=O)CN
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
Prepared using General Procedure 13. To a stirred solution of methyl 2-aminoacetate hydrochloride (5.07 g, 40.4 mmol) and 4-(bromomethyl)benzonitrile (7.20 g, 36.7 mmol) in DMF (40 mL) was added potassium carbonate (11.2 g, 81 mmol). After stirring at room temperature for 3 h the reaction mixture was diluted with water (300 mL) and the product extracted into EA (200 mL). The organics were washed with water (200 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (MeOH/DCM) to afford 1.6 g (21%) of methyl 2-((4-cyanobenzyl)amino)acetate INT-73 as a clear oil. LCMS-ESI (m/z) calculated for C11H12N2O2: 204; found 205 [M+H]+, tR=0.4 min (Method 10).
Reaction SMILES: CN(C=O)C.Br[C:7]1[C:27]([O:28][CH3:29])=[CH:26][C:10]2[N:11]([CH3:25])[C:12](=[O:24])[CH2:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[C:9]=2[CH:8]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:29][O:28][C:27]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]2[C:15]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])=[N:14][CH2:13][C:12](=[O:24])[N:11]([CH3:25])[C:10]=2[CH:26]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: OB(O)c1ccccc1
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: CN(C)C=O
Product: COc1cc2c(cc1-c1ccccc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Temperature: 120 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To 5 mL of degazed DMF were added 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 (200 mg, 0.52 mmol), benzene boronic acid (160 mg, 1.32 mmoles), tripotassium phosphate (300 mg, 1.42 mmol), Pd(PPh3)4 (30 mg, 0.03 mmoles). The mixture was stirred for 16 hours at 120° C. under nitrogen atmosphere. The working solution was diluted ten times with water and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was chromatographied: eluant: CH2Cl2/Et2O: 1/1. The obtained compound was crystallised from ether/pentane to afford the title compound (118 mg): white solid, (yield=60%).
Reaction SMILES: C([N:4]([C:8]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[N:12][CH:11]=[C:10](Br)[N:9]=1)[C:5](=[O:7])[CH3:6])(=O)C.[NH2:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH2:36])[N:28]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:36][C:29]1[N:28]=[C:27]([NH:26][CH2:25][CH2:24][NH:23][C:11]2[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:8]([NH:4][C:5](=[O:7])[CH3:6])=[N:9][CH:10]=2)[CH:32]=[CH:31][C:30]=1[N+:33]([O-:35])=[O:34]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CC(=O)N(C(C)=O)c1nc(Br)cnc1-c1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of N-acetyl-N-[3-(2,4-dichlorophenyl)-6-bromopyrazin-2-yl]acetamide (57 mg, 0.14 mmol) in DMF (2 ml) were added (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine (28 mg, 0.141 mmol), sodium tert-butoxide (20 mg, 0.21 mmol), BINAP (38 mg, 0.06 mmol) and palladium acetate (10 mg, 0.04 mmol). The reaction mixture was stirred overnight at 80° C. The solution was cooled to room temperature, taken in ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine, dried, concentrated and purified to afford the title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
20.0 g (0.107 mol) of 4,4′-dihydroxybiphenyl, 10.0 g (0.070 mol) of 3-bromo-1-propanol and 15.0 g (0.109 mol) of potassium carbonate are heated under reflux in 300 ml of acetone for 16 h. The batch is subsequently filtered, and the filtrate is evaporated. The residue is taken up in MTB ether, washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the crude product is chromatographed on silica gel with toluene/ethyl acetate (1:1). Crystallisation from toluene/ethyl acetate gives 4′-(3-hydroxypropoxy)biphenyl-4-ol as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH2:16][CH2:17][NH2:18])[CH3:2].[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH2:16][CH2:17][NH:18][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(CCNC(=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
61.7 g (0.223 mol) of the 2-aminoethyl-5-fluoro-indole-3-acetic acid ethyl ester produced in (d) are dissolved in 600 ml of methylene chloride and the solution is covered with a layer of 150 ml of 2 N sodium hydroxide solution. A solution of 43 g (0.245 mol) of benzoyl chloride is added, at 0°-5°, in the course of 21/2 hours, while stirring vigorously, and extraction by stirring is then carried out for a further hour. The methylene chloride phase is then separated off, washed with water, dried over MgSO4 and concentrated to dryness by evaporation. The residue crystallises on being taken up in ether, to form colourless crystals of 2-[(benzoyl-amino)-ethyl]-5-fluoro-indole-3-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:24]=[O:25]
Reactant: Brc1cccc(CCOC2CCCCO2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(CCOC2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(3-bromo-phenyl)-ethoxy]-tetrahydro-pyran (20 g) in anhydrous tetrahydrofuran (300 mL) at −78° C. was added n-butyl lithium (2.5M in hexanes, 33.6 ml) dropwise over 5 minutes. The dark solution was kept at −78° C. for 30 minutes then N,N-dimethylformamide (16.35 ml) was added. The mixture was stirred −78° C. for half hour then quenched with aqueous ammonium acetate, and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate, and the organics washed with brine, dried over sodium sulfate and concentrated in vacuo to give a yellow/orange oil (16.0 g). The material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.C(Cl)(=O)C(Cl)=O.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.[Al+3].[Cl-].[Cl-].[Cl-].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[CH2:7][C:28]1[CH:27]=[CH:26][C:25]2[O:20][CH2:21][CH2:22][O:23][C:24]=2[CH:29]=1
Reactant: c1ccc2c(c1)OCCO2
Reactant: COc1cc(Cl)c(C(=O)O)cc1Br
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a stirred suspension of 5-bromo-4-methoxy-2-chlorobenzoic acid (128, 4 g, 15.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (1.6 mL, 18.3 mmol) and DMF (2 drops) at 0° C. and stirred for 2 h. The mixture was concentrated, and the residual colorless solid was dissolved in dichloromethane (100 mL). To this solution were added 1,4-benzodioxane (2 mL, 16.7 mmol) and then AlCl3 (2.23 g, 16.7 mmol) portionwise. After being stirred at room temperature overnight, the mixture was poured into ice water and extracted with dichloromethane two times. The combined organic layers were washed with 1 M HCl, water, and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was diluted with dichloromethane/acetonitrile (35 mL/35 mL) and added triethylsilane (7.4 mL, 45.6 mmol) followed by boron trifluoride diethyl etherate (5.8 mL, 45.6 mmol) at −10° C. The solution was allowed to warm to room temperature over 5 h prior to quenching with saturated sodium bicarbonate solution. After removal of organic volatiles under a reduced pressure, the crude residue was purified by silica gel chromatography (3 to 10% tetrahydrofuran in hexane) to yield the title compound (130, 3.6 g, 9.74 mmol, 64%; 3 steps) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:20])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:17])=[CH:13][CH:12]=[C:11]([CH3:18])[C:10]=2[C:9](=O)[CH2:8]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:20])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:17])=[CH:13][CH:12]=[C:11]([CH3:18])[C:10]=2[C:9](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1cc[n+]([O-])c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cc[n+]([O-])c2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Temperature: 105 °C
Reaction time: 2 h
Yield: 175.8 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (426 mg) and aminoguanidine hydrochloride (159 mg) were added ethanol (8 ml) and concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 105° C. for 2 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (Compound 158) (480 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O
Product: O=C(Nc1cccc(O)c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 3-aminophenol (Aldrich) according to the method described in Example 2. Melting Point: 158-160° C. (water)
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]>ClCCl>[CH2:7]([O:9][C:10](=[O:26])[C:11]1[CH:23]=[C:22]([CH2:24][O:25][CH:3]([CH3:4])[CH3:2])[CH:21]=[C:13]([C:14]([N:16]([CH3:20])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:12]=1)[CH3:8]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(COC(C)C)cc(C(=O)OCC)c1
Reaction time: 0.08 h

Procedure:
Mix dichloromethane (1.8 mL), pyridine (56 μL, 0.7 mmol), and trifluomethanesulfonic anhydride (97 μL, 0.58 mmol) to a flask at −35 to −45° C. Add premixed 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (65 mg, 0.23 mmol) in dichloromethane (4 mL) dropwise at −40° C. Stir for 5 min and quench with isopropyl alcohol (2 mL). Dilute the reaction mixture with dichloromethane (10 mL), wash with water (2×10 mL), and concentrate to give the title compound and used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCS(=O)(=O)C2)cn1
Solvent: CC#N
Product: Nc1ncc(C2CCS(=O)(=O)C2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38 %

Procedure:
3-(6-aminopyridin-3-yl)tetrahydrothiophene 1,1-dioxide (96 mg, 0.452 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to 0° C., to it was added NBS (80 mg, 0.452 mmol) and the mixture was stirred at 0° C. for 40 min. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc/sat. NaHCO3 (30 mL/20 mL), the EtOAc layer was washed with sat. Na2CO3 (20 mL), brine (20 mL), dried (Na2SO4), filtered off and concentrated in vacuo yielding 3-(6-amino-5-bromopyridin-3-yl)tetrahydrothiophene 1,1-dioxide as light brown oil (50 mg, 38% yield). LCMS (m/z): 293.0/291.0 (MH+), 0.29 min.
Reaction SMILES: C(O[CH:5]=[CH2:6])(=O)C.OS(O)(=O)=O.CCOC(C)=O.[I:18][C:19]1[N:27]=[C:26]2[C:22]([N:23]=[CH:24][NH:25]2)=[C:21]([Cl:28])[N:20]=1>[Hg](OC(C)=O)OC(C)=O>[Cl:28][C:21]1[N:20]=[C:19]([I:18])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH:5]=[CH2:6]
Reactant: Clc1nc(I)nc2[nH]cnc12
Reactant: C=COC(C)=O
Agent: CC(=O)O[Hg]OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=Cn1cnc2c(Cl)nc(I)nc21
Temperature: 47.5 °C
Reaction time: 8 h

Procedure:
In a 250 mL pressure tube, Hg(OAc)2 (2.52 g, 7.88 mmol) was suspended in vinyl acetate (73 mL, 788 mmol). To this suspension was added H2SO4/EtOAc (1.5 mL/15 mL). A clear solution was formed. The 2-iodo-6-chloro-9H-purine (22.1 g, 78.8 mmol) was added. A suspension formed again. It was degassed and stirred at 45-50° C. overnight. A dark solution was formed. The mixture was passed through celite, washed with EtOAc. Organic layer was washed with Sat. NaHCO3> dried Na2SO4. The product was purified on silica gel chromatography column (1-5% MeOH/DCM).
Reaction SMILES: [I].[Na].C(=O)([O-])[O-].[K+].[K+].C(N[C:14]1([CH2:34][CH2:35][CH2:36][CH2:37]Cl)[CH2:19][N:18]2[N:20]=[C:21]([CH3:32])[C:22]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])=[C:17]2[N:16]=[C:15]1[CH3:33])CCC.O>CN1CCCCC1=O>[CH2:15]([N:16]1[CH2:37][CH2:36][CH2:35][CH2:34][C:14]2[C:15]([CH3:33])=[N:16][C:17]3[N:18]([N:20]=[C:21]([CH3:32])[C:22]=3[C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=3[CH3:31])[C:19]1=2)[CH2:14][CH2:34][CH3:35]
Reactant: CCCCNC1(CCCCCl)Cn2nc(C)c(-c3c(C)cc(C)cc3C)c2N=C1C
Agent: CN1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [I]
Solvent: O
Product: CCCCN1CCCCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Temperature: 150 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
Sodium iodine (catalytic amount) and potassium carbonate (65 mg, 0.47 mmol) were added to a solution of N-butyl-N-(6-(4-chlorobutyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)amine (65 mg, 0.15 mmol) in 1-methyl-2-piperidone (2 mL), followed by stirring at 150° C. for four hours. Then, the mixture was treated with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (15% ethyl acetate/hexane), to give the title compound (18 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([O:16]C)=[O:15])=[N:7]2.O1CCCC1.O.[OH-].[Li+]>O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([OH:16])=[O:15])=[N:7]2
Reactant: COC(=O)c1ccc2c(Br)ccc(OC)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c2ccc(C(=O)O)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.9 %

Procedure:
Methyl 5-bromo-8-methoxyquinoline-2-carboxylate (154 g), tetrahydrofuran (40 ml), water (40 ml) and lithium hydroxide monohydrate (0.436 g) were combined and stirred at room temperature for 1.5 h. The tetrahydrofuran was removed in vacuo and the resulting aqueous mixture was acidified with hydrochloric acid. The resulting white precipitate was collected by filtration and dried in vacuo to give the title compound (1.33 g) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:12]=[C:13]1[CH2:16][CH2:15][CH2:14]1>>[CH3:12][C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1ccccc1
Reactant: C=C1CCC1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture of benzene (5.0 ml, 56 mmol) and Sulfuric acid (1.17 ml, 21.9 mmol) was cooled to 0° C. and treated dropwise with a solution of Methylenecyclobutane (1.00 ml, 10.8 mmol) in Benzene (3.0 ml, 34 mmol) over-1 h. Upon completion of the addition, the reaction mixture was stirred an additional 1 h while being warmed to RT. The mixture extracted with 15 ml of hexane. The organic phase was washed with 10 ml H2O and 10 ml sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield a colorless liquid. The liquid was purified by kugelrohr distillation (5-10 torr) to yield the desired compound as a colourless liquid. First fraction was collected at 75-85° C. as a colorless liquid (330 mg) of product as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:13]=[O:14]>>[F:10][C:4]1[C:3]([CH3:11])=[C:2]([N:1]=[C:13]=[O:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1c(N)ccc(C#N)c1F
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: Cc1c(N=C=O)ccc(C#N)c1F

Procedure:
2-Fluoro-4-isocyanato-3-methylbenzonitrile was prepared from 4-amino-2-fluoro-3-methyl-benzonitrile (72D) following a procedure analogous to the procedure used in the preparation of compound 2E (Example 2).