Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)C1C=CC=CC=1>CCCCCC.C1COCC1>[CH:34]1([C:32]2([CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[CH:29][CH:28]=3)[O:33][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound was prepared as described in General Method 6 using 11.6 g (99.9 mmol) of methyl acetoacetate, 4.19 g (105 mmol) of NaH (60% dispersion in oil), 64.0 mL (102 mmol) of 1.6 M n-butyl lithium in hexane, 16.1 g (49.9 mmol) of 3-(4-benzyloxy-phenyl)-1-cyclohexyl-propan-1-one (prepared in Example G) and 550 mL of THF. After addition of the ketone, the reaction was stirred for 120 minutes at 0° C., then 1 hour at room temperature. The reaction was quenched with acetic acid (12 mL) and worked up in the usual manner. The crude product was carried on without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH2:25])[CH2:21][O:20]1)(=[O:16])[CH3:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:14]([O:17][CH2:18][CH:19]1[CH:24]=[CH:23][C@H:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:21][O:20]1)(=[O:16])[CH3:15]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(=O)OCC1C=C[C@H](N)CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)OCC1C=C[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Temperature: 90 °C
Yield: 82.7 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (156 mg, 0.727 mmol), [(5S)-5-amino-5,6-dihydro-2H-pyran-2-yl]methyl acetate (129 mg, 0.754 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in isopropyl alcohol (1.7 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified with flash chromatography to give the desired product (0.21 g 83%). LCMS calculated for C15H16N3O5S (M+H)+: m/z=350.1. Found: 350.0.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-:13])([OH:12])=[O:11].[N:14]#[C:15][NH2:16]>CCO>[N+:10]([O-:13])([OH:12])=[O:11].[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]([NH2:16])=[NH:14]
Reactant: N#CN
Reactant: Nc1ccc(F)cc1F
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccc(F)cc1F
Yield: 40 %

Procedure:
To a mixture of 2,4-difluoroaniline (25 mmol, 3.2 g) in EtOH (10 mL) in an ice bath was added nitric acid (69% aq soln.; 1.8 mL) dropwise. After completion of the addition cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a purple solid (2.32 g, 40%).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Li+].[F:10][C:11]([F:16])([F:15])[CH:12]1[CH2:14][O:13]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([NH:24][CH2:14][CH:12]([OH:13])[C:11]([F:16])([F:15])[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: OC(CNCc1ccccc1)C(F)(F)F
Temperature: -10 °C

Procedure:
Lithium triflate was suspended in CH3CN (15 mL) and the mixture is cooled to −10° C. 2-(Trifluoromethyl)oxirane is added and the suspension is allowed to warm to RT with stirring. Benzylamine (6.33 mL, 58 mmol, Aldrich) is added all-at-once and the resultant solution is stirred for 25 minutes. The reaction is quenched by pouring into CH2Cl2 (200 mL) and washing 3× with H2O (200 mL). The organic layer is dried over Na2SO4 and filtered. The product is purified on a Biotage Flash 75L using 20:70:10 CH2Cl2: pentane: triethylamine as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 100° C. yielding a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH:19]([P:22](Cl)(Cl)=[O:23])([CH3:21])[CH3:20]>>[CH:19]([P:22]1(=[O:23])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][N:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=1)([CH3:21])[CH3:20]
Reactant: FC(F)(F)c1cccc(NCc2ccccc2)c1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)P1(=O)c2ccccc2CN1c1cccc(C(F)(F)F)c1

Procedure:
The procedure of Example 1 was employed utilizing N-(3-trifluoromethylphenyl)-N-benzylamine and isopropyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was crystallized from methylcyclohexane to yield a tan precipitate. The tan precipitate was recrystallized from toluene and petroleum ether to yield 1-isopropyl-2-(3-trifluoromethylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as beige plates. A second crop was obtained to give a total yield of 5.9 g, (29% yield) of 1-isopropyl-2-(3-trifluoromethylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 117°-119° C. and the following analysis:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:28]1[C:31]2([CH2:34][O:33][CH2:32]2)[CH2:30][CH2:29]1.C([O-])(=O)C([O-])=O>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:14]([N:28]3[C:31]4([CH2:34][O:33][CH2:32]4)[CH2:30][CH2:29]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Reactant: C1CC2(COC2)N1
Agent: O=C([O-])C(=O)[O-]
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CCC23COC3)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and 6-Oxa-1-azaspiro[3.3]heptane, ethanedioate (1:2) (CAN 1380571-72-1) as starting materials and isolated (23 mg, 38%); MS (ESI, m/z): 470.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cnc(CN)cn1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: Cc1cnc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cn1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-(aminomethyl)-5-methyl-pyrazine (60 mg, 0.49 mmol). The title compound was obtained as a solid (40 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.48 (1H, m), 8.98 (2H, s), 8.48 (1H, s), 8.47 (2H, m), 4.50 (2H, m), 2.50 (3H, s). MS m/z: 454.00, 456.04 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CN(C=O)C.[Cl-].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[N:24][C:25]2[N:29]([CH3:30])[CH:28]=[CH:27][N+:26]=2[CH3:31])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl-:8].[NH2:1][C:2]1[N:7]=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]=[N:24][C:25]3[N:26]([CH3:31])[CH:27]=[CH:28][N+:29]=3[CH3:30])=[CH:21][CH:22]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Cn1cc[n+](C)c1N=Nc1ccc(N)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc[n+](C)c1N=Nc1ccc(Nc2cc(Cl)nc(N)n2)cc1

Procedure:
0.164 g of 2-amino-4,6-dichloropyrimidine (0.001 mol) and 3 ml of dry DMF, 0.251 g (0.001 mol) of 2-(4-amino-phenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and 0.138 g (0.001 mol) of potassium carbonate are charged to a fully equipped round-bottomed flask. The mixture is brought for 17 hours to 80° C. with stirring. After cooling, 4 ml of water are added and the precipitate is filtered off. 100 mg of a red powder containing the starting 2-(4-aminophenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and the expected product are obtained. The latter, purified by preparative HPLC, has the following UV absorption characteristics:
Reaction SMILES: ClN1C(=O)CCC1=O.[CH3:9][S:10][CH3:11].[CH:12]1([C:20]#[N:21])[CH2:16][CH2:15][N:14]2C=[CH:18][CH:19]=[C:13]12>ClCCl>[CH3:9][S:10][C:11]1[N:14]2[CH2:15][CH2:16][CH:12]([C:20]#[N:21])[C:13]2=[CH:19][CH:18]=1
Reactant: CSC
Reactant: N#CC1CCn2cccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CSc1ccc2n1CCC2C#N
Reaction time: 0.17 h

Procedure:
A solution of 1.15 g N-chlorosuccinimide in 40 ml of dry dichloromethane was cooled, in an atmosphere of nitrogen, to -10° C. (bath temp.) and a solution of 1 ml dimethylsulfide in 10 ml of anhydrous dichloromethane was added dropwise with stirring over a 10 min. period. After a further 10 min. at this temperature, the bath temperature was lowered to -55° C. and a solution of 1.08 g of 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbonitrile (I) in 10 ml of dry dichloromethane was added with stirring over a 10 min. period. The cooling bath was then removed and when the internal temperature had reached ambient the solvent was removed in vacuo. The residual solid sulfonium salt (II) was suspended in toluene (100 ml) and heated at reflux temperature in a nitrogen atmosphere for 5 min. The solvent was decanted from an insoluble tar, 100 ml of toluene was added to the tar and the mixture was heated at reflux temperature for 20 min. The toluene solutions were combined and evaporated. The residue was taken up in ether, the ether solution was washed with water, dried over sodium sulfate and evaporated in vacuo to give an oil which was passed through a short column of silica gel with dichloromethane. The nearly colorless oil obtained on evaporation of the solvent (1.20 g) was sufficiently pure for use in the next reaction. For analysis a sample was purified by HPLC (lichrosorb column, 50 cm×3/8 in.) using hexane-ethyl acetate (85:15) as the eluting solvent at 1100 p.s.i.g. and a flow rate of 9.7 ml/min. The sulfide (III) had a retention time of 13.5 min. On evaporation of the solvent it crystallized and then it was recrystallized from ether-hexane. m.p.: 58°-58.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([N:12]1[CH2:16][CH2:15][C:14]([F:19])([C:17]#[N:18])[CH2:13]1)=[O:11].Cl.N[C@H](C(C)(C)C)C(N1CCCC1)=O.[CH2:38]([N:40]1[CH:44]=[C:43]([C:45]2[N:50]=[C:49]3[C:51]([C:62](O)=[O:63])=[CH:52][N:53](COCC[Si](C)(C)C)[C:48]3=[N:47][CH:46]=2)[CH:42]=[N:41]1)[CH3:39]>>[C:17]([C:14]1([F:19])[CH2:15][CH2:16][N:12]([C:10]([C@H:9]([NH:8][C:62]([C:51]2[C:49]3[C:48](=[N:47][CH:46]=[C:45]([C:43]4[CH:42]=[N:41][N:40]([CH2:38][CH3:39])[CH:44]=4)[N:50]=3)[NH:53][CH:52]=2)=[O:63])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:11])[CH2:13]1)#[N:18]
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(F)(C#N)C1
Agent: CC(C)(C)[C@@H](N)C(=O)N1CCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(F)(C#N)C4)C(C)(C)C)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1, steps 3-4 substituting 1-((R)-2-amino-3,3-dimethylbutanoyl)-3-fluoropyrrolidine-3-carbonitrile trifluoroacetate for (R)-2-amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2, 3-1)]pyrazine-7-carboxylic acid. MS: (M+H)+=467.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: Fc1cccc(I)c1-c1nnn[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2c(F)cccc2I)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(2-fluoro-6-iodophenyl)-1H-tetrazole (23.48 g, 80.97 mmol), potassium carbonate (16.79 g, 0.121 mol), and iodomethane (16.09 g, 0.113 mol) in 25 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:32][CH2:33][C:34]1[CH:54]=[CH:53][C:37]([C:38]([NH:40][C:41]2[CH:42]=[C:43]3[C:48](=[CH:49][CH:50]=2)[N:47]=[C:46]([CH3:51])[CH:45]=[C:44]3[NH2:52])=[O:39])=[CH:36][CH:35]=1.C(N1CCOCC1)C>CN(C=O)C>[NH2:52][C:44]1[C:43]2[C:48](=[CH:49][CH:50]=[C:41]([NH:40][C:38]([C:37]3[CH:53]=[CH:54][C:34]([CH2:33][NH:32][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:9])=[CH:35][CH:36]=3)=[O:39])[CH:42]=2)[N:47]=[C:46]([CH3:51])[CH:45]=1
Reactant: O=C(O)c1cnccn1
Reactant: Cc1cc(N)c2cc(NC(=O)c3ccc(CN)cc3)ccc2n1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cc(NC(=O)c3ccc(CNC(=O)c4cnccn4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.2 %

Procedure:
To a solution of 10.5 mg (0.08 mmol) of 2-pyrazinecarboxylic acid in 1 ml of DMF were added 27.9 mg (0.085 mmol) TOTU. After 15 min at room temperature 55 mg (0.085 mmol) of 4-Aminomethyl-N-(4-amino-2-methyl-quinolin-6-yl)-benzamide and 39 mg (0.34 mmol) of N-ethylmorpholine were added. After 24 h stirring at room temperature the solution was evaporated and the residue was treated with acetonitrile and water containing 0.005% trifluoroacetic acid. The precipitate was filtered to give 36.7 mg (71%) of the title compound. MS 413.42 (M+1)+, 1H-NMR (DMSO-d6) δ 2.58 (s, 3H), 4.60 (d, 2H), 6.58 (s, NH), 7.55 (d, 2H), 7.81 (d, 1H), 8.00 (m, 3H), 8.65 (br.s., NH2), 8.78 (m, 2H), 8.90 (m, 1H), 9.20 (s, 1H), 9.62 (m, 1H), 10.80 (s, NH), 13.38 (br.s., NH).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH:13][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NCc1sc2ccccc2c1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2c(CNc3ncnc4[nH]cnc34)sc3ccccc23)cc1
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A mixture of C-(3-phenylbenzo[b]thiophen-2-yl)methylamine from Example 26 (230 mg, 0.961 mmol), 6-chloro-9H-purine (278 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.92 mmol) in n-butanol (10 mL) was heated at 100° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then sonicated in diethyl ether. Further purification by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) afforded 165 as a white solid (132 mg, 38%). LCMS: RT 4.22 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 12.96 (1H, s), 8.40 (1H, s), 8.23 (1H, s), 8.14 (1H, s), 7.94-7.85 (1H, m), 7.63-7.54 (4H, m), 7.51-7.43 (2H, m), 7.38-7.29 (2H, m), 4.94 (2H, s)
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:27]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:17]2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:30]>CO.O1CCOCC1>[ClH:30].[NH2:29][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:27])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(C4CCCC4)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(C4CCCC4)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(butyloxy)-9-[(1-cyclopentyl-3-piperidinyl)methyl]-8-(methyloxy)-9H-purin-6-amine (37.2 mg, 0.092 mmol) in methanol (3 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (0.578 ml). The reaction mixture was stirred at ambient temperature overnight. The reaction solution was evaporated under N2 in a Radleys blow down unit to give the title compound as an off-white solid (39 mg). LCMS (System B): tRET=1.39 min; MH+ 389
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:3][C:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]=2)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: OC1(c2cnccn2)CN2CCC1C2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: ClC1(c2cnccn2)CN2CCC1C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Thionyl chloride (1.5 g, 12.6 mmol) was added to a rapidly stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[ 2.2.1]heptan-3-ol (0.5 g, 2.6 mmol) in dichloromethane (30 ml) at room temperature. The solution was stirred for 1 h, heated at 60° C. for 0.5 h, and then cooled to room temperature, before adding water (20 ml) and basifying with potassium carbonate. Extraction into dichloromethane (3×75 mls), drying (Na2SO4) and chromatography of the residue remaining after removal of solvent through alumina, using ethyl acetate as eluant, gave 3-chloro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane as a pale yellow oil (0.18 g); m/e 209 (M+ of free base); δ (360 MHz,CDCl3) 0.84-0.92(1H,m,CH of CH2); 1.58-1.67(1H,m,CH of CH2); 2.42-2.48(1H,m,CH of CH2 --N); 2.69-2.72(1H,m,CH of CH2 --N); 2.78-2.86(1H,m,CH of CH2 --N); 3.22-3.24(1H,d, J=4.5 Hz, CH-bridgehead); 3.42-3.49(2H,m,2×CH of CH2 --N); 4.13(1H,dd J=3 and 14 Hz, CH of CH2); 8.48(2H,s,pyrazine-H); 8.91(1H,s,pyrazine-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[C:25]#[N:26])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,4-dichlorobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 91%).
Reaction SMILES: [C:1]1([CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]1[CH2:16][O:17][C:12]([CH3:13])([CH2:11][C:1]2[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:6]=2)[O:14]1
Reactant: CC(=O)Cc1ccc(CC(C)=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(CC2(C)OCCO2)cc1

Procedure:
A mixture of 1,4-phenylene bis(propan-2-one), (17.12 g), ethane-1,2-diol (1.72 g) and a trace of 4-toluene sulphonic acid was heated under reflux in benzene for 2 hr. using a Dean and Stark apparatus. The solvent was evaporated and the residue chromatographed on silica. Elution with 1:3 diethyl ether:petrolroleum ether (40-60) gave 4-(2,2-(ethylenedioxy)propyl)phenyl propan-2-one, as a white solid (3.5 g). Further elution gave starting material (12.9 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(S)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a suspension of 1-Amino-2-methylpropane-2-thiol hydrochloride (1.41 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.5 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and glutaric anhydride (1.14 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The solvent was evaporated at reduced pressure and the residue was extracted with ethyl acetate and water. The combined ethyl acetate extracts were washed with 1 N HCl, dried over sodium sulfate and solvent was evaporated at reduced pressure to give colorless oil, which upon trituration with ethyl ether/hexane gave 1.57 g of the title compound as a colorless powder in 72% yield, mp 101-104° C.; 1H NMR (CDCl3): δ1.31 (s, 6H), 1.94 (m, 2H), 2.22-2.38 (m, 4H), 3.33 (d, J=6.1 Hz, 2H), 6.28 (s, 1H), 9.2 (br s, 1H; LRMS (APIMS) (m/z) 220 (M+1).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26]
Reactant: BrC1CCCC1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 30.5 %

Procedure:
Cyclopentyl bromide (1.2 g, 8.1 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours under refluxing. After completion of the reaction, 1N hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.75 g, 2.06 mmol, 30.5% yield) was isolated by filtration. Spectral data and the like are as shown in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:24][C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ncccc2Cl)CC1
Yield: 39.7 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2,3-dichloropyridine (114 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (56 mg), a white solid, in 40% yield.