Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:15]([O-:17])=O)[C:10](OCC)=[O:11].[NH2:18][C:19]([NH2:21])=[S:20].[OH-].[Na+].[CH3:24]I.Cl>C1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[C:15](=[O:17])[NH:21][C:19]([S:20][CH3:24])=[N:18][C:10]1=[O:11]
Reactant: CCOC(=O)C(C(=O)[O-])c1c(F)cccc1Cl
Reactant: NC(N)=S
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCCCC1
Product: CSC1=NC(=O)C(c2c(F)cccc2Cl)C(=O)N1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
60.0 g (208 mmol) of ethyl 2-(2-chloro-6-fluorophenyl)malonate and 19.0 g (249 mmol) of thiourea were heated for 2.5 hours at 150° C. in 77 g (416 mmol) of n-tributylamine. Most of the ethanol formed was distilled off. 180 ml of an aqueous solution of 24.9 g (623 mmol) of NaOH were added to the reaction mixture once it had cooled down. After the aqueous phase had been treated with 50 ml of cyclohexane and stirred for approximately 30 minutes, it was separated off, treated with 35.4 g (142 mmol) of methyl iodide and stirred for approximately 16 hours at approximately 20 to 25° C. After acidification with dilute HCl solution and stirring for approximately 30 minutes, the precipitate was filtered off washing with water and drying gave 16.7 g of the title compound as white crystals of m.p. 250° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2Cl)[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[NH3:22]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:22])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: N
Reactant: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Yield: 61 %

Procedure:
3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W) (8.2 g, 21 mmol), conc. ammonia (100 mL) and dioxan (100 mL) were heated in a Parr pressure vessel at 120° C. for 20 hrs. The solvents were evaporated and the residue partioned between EtOAc and water. The EtOAc layer was dried over Na2SO4, filtered and evaporated to leave 3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a solid (4.7 g, 61%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 8.21 (1H, s), 4.71 (1H, m), 3.90 (4H, m), 2.11(2H, m), 1.72-1.88 (6H, m ) HPLC: Tr=11.84 mins, 92.1%
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([Cl:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]1([CH2:23][CH2:24][OH:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[O:26]1CCC[CH2:27]1.O>ClCCl>[N:17]1([CH2:23][CH2:24][O:25][C:27](=[O:26])[NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])=[CH:9][C:10]=2[Cl:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(Cl)c1
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCCN2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) in dichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl) carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL) dropwise over 20 minutes. The reaction is stirred at room temperature for 30 minutes at which point a precipitate forms. To his mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is added to maintain homogeneity. After heating at reflux overnight the reaction is cooled and then poured into water, the organic layer separated and then washed with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a crude oil that is purified by chromatography over silica gel (5% methanol in dichloromethane is used as the eluant) to give the desired product as a white foam.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[S:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[S:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1csc(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CSc1cc(S(N)(=O)=O)sc1Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.4 %

Procedure:
To a solution of 4-methylsulfanylthiophene-2-sulfonamide (210 mg, 1.00 mmol) in CHCl3 (10 mL) and AcOH (10 mL) is added N-bromosuccinimide (231 mg, 1.30 mmol). The reaction mixture is stirred at room temperature for 7 hr. After 7 hr, the reaction mixture is neutralized with 1 M NaOH and the solution is extracted with EtOAc (200 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (3:1) to afford the title compound (200 mg, 70%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]1[CH2:17][CH2:16][N:15]([C:18]([CH2:20][C:21]#[N:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:19]=[C:18]([N:15]1[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1)[CH:20]=[C:21]1[NH:22][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4]1
Reactant: N#CCC(=O)N1CCCCC1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NC(=CC(=O)N2CCCCC2)Sc2ccccc21
Yield: 25 %

Procedure:
Methyl thiosalicylate (1.7 g, 10.1 mM) and 1-cyanoacetylpiperidine (2.0 g, 13.1 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml, 14.4 mM) was added to the solution. After heating for 30 hours under reflux, the reaction solution was concentrated to give crude crystals. The crude crystals were recrystallized from ethanol to give the title compound as needles (730 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[CH:3]=[C:4]([I:15])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ncc(Cl)cc1I

Procedure:
A 6.48 g sample of 5-chloro-2-pyridinol (Aldrich) and 10.8 g of Na2CO3 were dissolved in 250 mL of water. To this solution was added 12.73 g of I2, and the mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 7 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystallized from ethanol/water to afford 4 g of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 7.71 (d,1H), 8.18 (d, 1H); MS m/z: 256 (M+H)+, 273 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[C:31](Cl)(=[O:33])[CH3:32].[Cl-].C(N(CC)CC)C>O.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:33])[CH3:32])[CH2:29][CH:30]=3)=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncncc2C2=CCNCC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1

Procedure:
To a round bottom flask was added (1H-benzo[d]imidazol-2-yl)(4-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yloxy)phenyl)methanone (60.8 mg, 0.153 mmol) with DCM (1 mL) under nitrogen. With stirring, acetyl chloride (12 μL, 0.168 mmol) was added dropwise to a yield a suspension that quickly became a solution. After complete addition of the chloride, triethylamine (32.0 μL, 0.229 mmol) was added in one aliquot. The reaction was diluted with water after 10 minutes and extracted with dichloromethane before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a yellow oil. It was purified by column chromatography (2M NH3/MeOH/DCM). The resulting oil was resolubilized in dichloromethane and flushed through a plug of silica to yield 1-(4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a pale yellow oil. MS (ESI, pos. ion) m/z: 440.2 (M+1). IC50 (uM) ++++.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([CH3:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O>[CH2:15]([N:14]([CH3:22])[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N(C)Cc3ccccc3)nc(Cl)nc12
Solvent: CS(C)=O
Product: CSc1ncnc2c(N(C)Cc3ccccc3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-(N-benzyl-methylamino)-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[C:15]1([S:21]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)(Cl)[Cl:24]>C(O)(=O)C>[C:15]1([S:21][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: ClSc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)C(CCl)Sc2ccccc2)c1

Procedure:
In a mixture of 50 ml of glacial acetic acid and 100 ml of carbon tetrachloride at 56° was dissolved 30.9 g (0.145 mole) of m-nitrophenyl vinyl sulfone. Addition of 21.0 g (0.145 mole) of benzenesulfenyl chloride produced an exotherm to 58°. The clear solution was allowed to stand for seventy hours. Removal of the solvent by evaporation at reduced pressure and recrystallization of the residue from toluene gave yellow needles, m.p. 125.5°-126.5°.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[O:3]1
Reactant: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: Cc1cc(O)cc2c1C(CC(=O)OCc1ccccc1)OB2O

Procedure:
To a solution of 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (400 mg, 1.8 mmol) in 30 mL toluene was added 4-methylbenzenesulfonic acid (68.5 mg, 0.36 mmol) and BnOH (583.8 mg, 5.4 mmol). The reaction mixture was refluxed for 5 h and concentrated to dryness. The residue was dissolved in 20 mL EtOAc and washed with H2O (15 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:3]\[C:4]#[N:5].[SH2:12]>CCO.C1COCC1>[C:6]1([C:2]2[CH:3]=[C:4]([NH2:5])[S:12][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: S
Reactant: N#C/C=C(\N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2ccccc2)ns1
Reaction time: 20 h

Procedure:
To a solution of (Z)-3-amino-3-phenylacrylonitrile (95 mg, 0.660 mmol) in EtOH (1.0 mL) and THF (1.0 mL) in a sealed tube, H2S gas was bubbled through for 5 min. It was then stirred at 90 C for 20 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (2.0 mL), aq. H2O2 (30%, 0.5 mL) was added. After being stirred at room temperature for 2 min, the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-phenylisothiazol-5-amine (22 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[O:15]=[C:12]1[NH:11][C:10]2[C:16]3[C:21]([CH:22]=[CH:23][C:9]=2[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)=[N:14][CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: Nc1cccc(C2=NCC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1CN=C(c2cccc(NS(=O)(=O)c3ccccc3)c2)c2ccc3ccccc3c2N1
Yield: 96.1 %

Procedure:
5-(3-Aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (10 mg, 0.033 mmol), and benzenesulfonyl chloride (13 μL, 0.1 mmol) were treated by heating in pyridine (1.0 mL). A post-treatment was performed in a conventional manner to give the title compound (14 mg, yield 95%) as white amorphous.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:21][CH2:20][CH2:19]1.O>C(O)C>[CH:18]1([CH2:17][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: OCc1ccc(O)cc1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCC2CCC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of 4-(hydroxymethyl)phenol (3.20 g, 25.8 mmol), potassium carbonate (7.12 g, 51.6 mmol) and (bromomethyl)cyclobutane (3.75 mL, 33.6 mmol) in ethanol (50 mL) was stirred at 70° C. overnight. Water was added thereto, ethanol was evaporated under reduced pressure, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and then purified by basic silica gel chromatography (hexane:ethyl acetate=19:1 to 13:7), and the solvent was evaporated to give the title compound (1.17 g, yield 23%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.C(#N)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: NC1CCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1cnc(NC2CCC2)nc1
Temperature: 50 °C

Procedure:
In a sealed tube 2.00 g (10.3 mmol) 5-bromo-2-chloropyrimidine, 1.15 mL (13.4 mmol) cyclobutylamin and 2.70 mL (15.5 mmol) DIPEA are added to 12 mL ACN. The reaction mixture is stirred at 50° C. over night, then diluted with EtOAc and washed with water (2×). The org. phase is dried with MgSO4 and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]([CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.ClCCl>[C:42]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:24]3[S:25][C:26]4[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=4[CH:28]=3)[C:9]=2[CH2:18][O:19][CH2:20][C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCNCC4)n4ncnc(N)c34)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C)cc2cc(-c3c(COCC(N)=O)c(CN4CCN(C(C)=O)CC4)n4ncnc(N)c34)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 33 (105 mg, 68% purity, 144 μmol) in THF/dichloromethane (1:2.5, 3.9 ml) was treated with sodium carbonate (179 mg, 1.6 mmol) and stirred at rt for 30 min. Acetyl chloride (30 μl, 424 μmol) was added, and the resulting mixture was stirred at rt for 30 min, then quenched with methanol (2 ml) and evaporated. Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 30 mg (85% purity, 34% of th.) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:24][CH:23]=[CH:22][C:4]=2[N:5]([N:14]=CC2C=CC=CC=2)[C:6](=[O:13])[C:7]=1[C:8](OCC)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33].[OH-].[K+].Cl>C1(C)C=CC=CC=1>[NH2:14][N:5]1[C:6](=[O:13])[C:7]([C:8]2[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:33])(=[O:34])[N:35]=2)=[C:2]([OH:1])[C:3]2[S:24][CH:23]=[CH:22][C:4]1=2
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2sccc2n(N=Cc2ccccc2)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 61.9 %

Procedure:
The product of Example 268C (2.29 g, 6.69 mmol) was reacted with 2-aminobenzenesulfonamide (1.15 g, 6.69 mmol) in toluene (60 mL), and stirred at reflux for 5 hours. The reaction was cooled to 25° C. and the resulting precipitate was collected by filtration and dried (1.95 g, 62%). The resulting solid (1.95 g, 4.2 mmol) was reacted with 10% aqueous KOH (60 mL) at reflux for 24 hours, cooled to 25° C. and acidified with concentrated hydrochloric acid to pH 2. The resulting solid was collected by filtration, washed repeatedly with water and dried to provide the title compound (1.5 g, 98%).(Any sodium salt made?) 1H NMR (300 MHz, DMSO-d6) δ ppm 6.12 (s, 2 H) 7.49 (d, J=5.52 Hz, 1 H) 7.57 (m, 2 H) 7.79 (t, J=7.17 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.34 (d, J=5.52 Hz, 1 H) 14.33 (s, 1 H) 14.68 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](NCOC)=[O:12])([CH3:4])[CH3:3].[CH3:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>>[CH3:4][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11]([C:23]1[N:19]([CH3:18])[N:20]=[CH:21][N:22]=1)=[O:12])([CH3:1])[CH3:3]
Reactant: Cn1cncn1
Reactant: COCNC(=O)CCCNC(=O)OC(C)(C)C
Product: Cn1ncnc1C(=O)CCCNC(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared according to the method of Example 43 step (b) using the product of Example 43 step (a) and 1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)(OP([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(O)=O)C)C.[Br-].[Li+].C(N(CC)CC)C>C1COCC1>[CH:1]1(/[CH:6]=[CH:16]/[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1CCCC1
Reactant: CCC(C)(CC)OP(=O)(O)CC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1CCCC1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono)acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 mL, 0.35 mmol) in THF (1 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 231 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH2:8][CH2:9][NH2:10])[N:7]=1)[CH3:2].O.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=O>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:14][CH:13]=2)[C:5]2[CH:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C=O
Reactant: CCc1nc(CCN)cn1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (5.30 g) in tetrahydrofuran (40 ml) is added ethyl glyoxylate hydrate (1.67 g). The reaction mixture is stirred overnight at room temperature and then refluxed for two hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.90 g) as a yellow oil.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH3:17]O>>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)CCCc1cccs1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1cccs1
Temperature: 70 °C
Yield: 89 %

Procedure:
A catalytic amount of conc. H2SO4 (1 MI) was added to a solution of 4-(thiophen-2-yl)butanoic acid (1.2 g, 7.05 mmol) in dry MeOH (30 MI) at 0° C. The resulting reaction mixture was heated to 70° C. for 4 h, cooled to room temperature, and concentrated under reduced pressure. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get methyl 4-(thiophen-2-yl)butanoate (1.1 g, yield 89%). 1H NMR (300 MHz, CDCl3) δ 7.14-7.12 (m, 1H), 6.94-6.91 (m, 1H), 6.81-6.80 (m, 1H), 3.68 (s, 3H), 2.91-2.86 (t, J=7.5 Hz, 2H), 2.41-2.36 (m, 2H), 2.07-1.97 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:39])[CH3:38])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:38])[CH3:39])[N:16]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 65 h
Yield: 99.6 %

Procedure:
To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (255 mg, 0.47 mmol) in EtOH (15 mL) and AcOH (5 mL) was added 10% Pd/C (55 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (256 mg, quant.). LCMS (method A): RT 3.16 min [M+H]+ 547.4
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[CH3:21][C:22]([CH3:27])([CH2:25]O)[CH2:23][OH:24].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:24][CH2:23][C:22]([CH3:27])([CH3:25])[CH2:21][O:8]2)[S:5][CH:6]=1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1cc(Br)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)COC(c2cc(Br)cs2)OC1
Temperature: 0 °C

Procedure:
4-bromothiophene-2-carbaldehyde (884 mg, 4.62 mmol), TsOH hydrate (44 mg, 0.231 mmol) and 2,2-dimethylpropane-1,3-diol (578 mg, 5.55 mmol) were dissolved in 9.2 mL benzene and refluxed in a Dean Stark apparatus for 5 hours. The mixture was cooled to 0° C. and aqueous sodium hydrogen carbonate was added. DCM was added and the phases separated with a phase extractor. The solvent was removed under reduced pressure to give the title compound.