Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[N:32]=[C:31](B(O)O)[CH:30]=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[N:32]=[C:31]([C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:9][C:4]=2[C:3]([OH:2])=[O:24])[CH:30]=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1cccc(B(O)O)n1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: N#Cc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)n1
Yield: 15.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 6-cyanopyridine-2-boronic acid (available from CombiPhos Catalysts, Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(6-cyano-pyridin-2-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (14 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.24-8.32 (m, 1H), 8.00-8.16 (m, 3H), 7.73-7.88 (m, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:14][C:15]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16]2)=[N:11][C:10]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=[O:34])([O-])[OH:32].[Na+]>O1CCCC1>[CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:14][C:15]([N:19]3[CH2:20][CH2:21][N:22]([C:31]([O:32][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:34])[CH2:23][CH2:24]3)=[N:16]2)=[N:11][C:10]=1[Cl:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: Clc1nc2c(N3CCCC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCCC3)c3nc(Cl)c(NCc4ccccc4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.02 g (2.40 mmol) 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine are placed in 10 ml of tetrahydrofuran, 1.05 g (4.80 mmol) BOC-anhydride and 5 ml saturated sodium hydrogen carbonate solution are added. The mixture is stirred for 1.5 hours at ambient temperature, then evaporated down in vacuo. The aqueous residue is diluted with water, the precipitate is suction filtered, washed and dried.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:10]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=32)[CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>C(OC(=O)C)(=O)C>[N+:15]([C:8]1[CH:7]=[C:6]2[O:1][CH2:2][CH2:3][N:4]3[C:12](=[O:13])[C:11](=[O:14])[C:10]([CH:9]=1)=[C:5]23)([O-:17])=[O:16]
Reactant: O=C1C(=O)N2CCOc3cccc1c32
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=C1C(=O)N2CCOc3cc([N+](=O)[O-])cc1c32
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a stirred solution of 2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5,6-dione (33.1 g) in acetic acid-acetic anhydride (200 ml, 1:1) under ice-cooling was added fuming nitric acid (9.4 ml) dropwise. The mixture was stirred for 0.5 hours at the same temperature (0° C.) and for an hour at room temperature. The reaction mixture was poured into ice water (500 ml) and the resultant precipitate was collected by filtration. This precipitate was washed with water and dried to give 26.9 g (65.5%) of the title compound. The filtrate was extracted with chloroform, washed with water, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride solution successively and then dried over anhydrous sodium sulfate. Evaporation of chloroform further afforded 2.9 g of the title compound. This compound was recrystallized from acetonitrile to give yellow needles, mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH2:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH:19][S:35]([CH3:34])(=[O:37])=[O:36])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1nc(CN)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(CNS(C)(=O)=O)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 35 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methylamine in 3 ml of anhydrous dichloromethane at room temperature under nitrogen was treated with 0.024 ml of triethylamine and 0.007 ml of methane sulphonyl chloride. The mixture was stirred at room temperature for 0.5 h. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate then extracted three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:19) for the elution to give 21 mg of N-[[5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl]methanesulfonamide as a brown solid. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.90 (s, 3H), 3.92 (s, 2H), 4.20 (d, 2H), 4.73 (m, 1H), 6.89 (s, 2H), 7.11 (d, 2H), 7.38 (s, 1H), 7.56 (t, 1H), 8.30 (d, 2H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C1COCC1.[OH-].[Na+]>CO>[O:25]1[CH2:24][CH2:23][CH:22]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH:14]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCOCC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Add to a suspension of 4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methyl ester (16.7 g, 41.83 mmol) in methanol (200 mL) with stirring THF (600 mL). Treat the solution with 5N NaOH (23.5 ml, 2.8 eq.) and stir for 2 h at room temperature. Concentrate the solution to near dryness and treat with 1N HCl (125 mL), a solid separates. Dilute to 500 mL total volume with water, filter, back-wash with water, and dry (20 mm Hg, 60° C.) to give a resulting solid found to be pure title compound (15.8 g, 98%); 1H NMR (DMSO-d6) 13.57 (s, 1H), 8.08 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.27 (t, J=7.1 Hz, 1H), 3.95 (m, 2H), 3.47 (t, J=12.0 Hz, 2H), 3.03 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); MS (ESI) m/z 384 (m−H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([OH:15])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]=[C:19]=[O:20]>CS(O)(=O)=O.ClCCl>[CH3:17][NH:18][C:19]([O:15][CH:10]1[C:9]2[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=2[O:12][C:11]1=[O:14])=[O:20]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: CN=C=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CNC(=O)OC1C(=O)Oc2c1cc(C)cc2C(C)(C)C
Yield: 64.2 %

Procedure:
A mixture of 5.5 g (25.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (102), Example 2), 3 ml (50.0 mmol) of methyl isocyanate and 2 drops of methanesulfonic acid is refluxed for 31/4 hours. Then 3 ml (50.0 mmol) of methyl isocyanate and 2 drops of methanesulfonic acid are again added. The reaction mixture is refluxed for a further 16 hours, then cooled, diluted with dichloromethane and washed with water and 5% aqueous sodium hydrogencarbonate solution. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from toluene yields 4.45 g (65%) of 3-(N-methylcarbamoyloxy)-5-methyl-7-tert-butyl-3H-benzofuran-2-one (compound (112), Table 1), m.p. 138°-143° C.
Reaction SMILES: O1CCOCC1.Cl.C(OC([NH:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18])=O)(C)(C)C.C1(OC)C=CC=CC=1>O1CCOCC1>[NH2:15][CH2:16][C:17]([NH:19][C:20]1[N:28]=[C:27]2[C:23]([C:24]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[NH:26]2)=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reaction time: 0.5 h

Procedure:
An HCl dioxane solution (4N, anhydrous, 0.27 mL) was added to 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro-phenyl)-7-aza-indole (54) (50.0 mg, 0.11 mmol), anisole (59 ml, 0.55 mmol), and dioxane (4 mL) in one portion. After 30 min at 23° C., the reaction was concentrated with a stream of nitrogen in a hood. The residue was diluted with saturated bicarbonate (30 mL), extracted with ethyl acetate (3×50 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of preparative plate chromatography (two 2 mm silica gel plates, ethyl acetate:methanol 19:1) to afford 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (55): Mass Spectrum (CI) 362 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]3=[N:21][CH:22]=[CH:23][C:24]([Cl:25])=[C:19]3[CH:18]=2)=[CH:5]1.[Na+].[I-:38]>CC(=O)CC>[Cl:25][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[N:26]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:17]([C:6]3[C:7]4=[N:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=[C:12]4[N:4]([CH2:3][CH2:2][I:38])[CH:5]=3)=[CH:18][C:19]=12
Reactant: [I-]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Yield: 96.4 %

Procedure:
Dissolve chlorobisazaindole 31 (110 mg, 0.202 mmol) and NaI (33.5 mg, 0.222 mmol) in 2-butanone (10 mL) and reflux for 24 h. The reaction medium is then concentrated under vacuum, the residue is dissolved in EtOAc, washed with brine, dried (Na2SO4) and concentrated, to give 32 (124 mg, 96.6%) as a yellow solid: 1H NMR (CDCl3) δ 8.25 (d, 1H, J=5.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.65 (s, 1H), 7.10 (m, 5H), 4.53 (t, 2H, J=6.4 Hz), 4.03 (s, 3H), 3.99 (s, 3H), 3.50 (t, 2H, J=6.4 Hz), 2.31 (s, 3H), TLC (EtOAc at 40%/heptane) Rf=0.20, m/z obs.=636.9 (M+1), 638.9, 639.94.
Reaction SMILES: N1C=CC([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=CC=1.[Li+].[OH-].O>C1COCC1>[N:7]1[CH:12]=[CH:17][C:16]([O:15][C:13]([CH:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccncc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 33-1 (10 g, 42.7 mmol) in THF (50 mL) was treated with 1N LiOH (47 mL, 47.0 mmol) and water (50 mL). The resulting solution was stirred at ambient temperature for 12 h. The solution was concentrated and the aqueous residue was cooled to 0° C., then adjusted to pH=6 with 1N HCl. The resulting solid was collected by filtration and dried in vacuo to afford 33-2 as a white solid. 1H NMR (D2O) δ 7.95 (d, J=6.8 Hz, 2HO, 6.73 (d, J=6.8 Hz, 2h), 3.76 (d, J=12.8 Hz, 2HO, 2.81 (m, 2H), 2.20 (m, 1H), 1.85 (d, J=12.9 Hz, 2H), 1.55 (m, 2H). ##STR165## Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonylamino-3-methylphenoxyacetate (33-3)
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>C(O)CO>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:25][C:22]2=[N:23][N:24]=[C:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][CH:17]=3)[N:21]2[N:26]=1
Reactant: O=C1Nc2ccc(O)c(Cl)c2C1=O
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Solvent: OCCO
Product: Oc1ccc2[nH]c3nc4nnc(Cc5ccc(F)cc5)n4nc3c2c1Cl
Temperature: 125 °C
Reaction time: 16 h

Procedure:
According to a cyclization procedure for Example 30, 0.60 mmol of 4-chloro-5-hydroxy-1H-indole-2,3-dione (118.5 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (16 hr).
Reaction SMILES: C(OC(N1[CH2:35][CH2:34][C:11]2(OC[CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12]2)CC1)=O)(C)(C)C.[N:36]1(C2CCNCC2)[CH2:39][CH2:38][CH2:37]1>>[N:36]1([CH:34]2[CH2:35][CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12][CH2:11]2)[CH2:39][CH2:38][CH2:37]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCC4)CC3)cc2n1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 4-azetidin-1-yl-piperidine in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as an off-white solid (219 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(N=C(SC)SC)nc12
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of dimethyl 7-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (150 mg, 0.52 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (132 mg, 0.58 mmol) and cesium carbonate (427 mg, 1.31 mmol) in DMF (3 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (95 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (br. s., 1 H) 8.52 (s, 1 H) 4.16 (s, 3 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.40 (dd, J=14.93, 1.88 Hz, 1 H) 2.70-3.07 (m, 5 H) 2.08-2.27 (m, 2 H) 1.68-1.85 (m, 1 H) 1.48-1.66 (m, 2 H). MS (LC/MS) R.T.=0.90; [M+H]+=347.34.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>>[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:15][C@H:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]1)[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: O=[N+]([O-])c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 125 °C
Yield: 44.7 %

Procedure:
A stirred mixture of 2-chloro-6-nitro-quinoline (2.2 g, 11 mmol) and (R)-1-aminoindane (2.8 g, 21 mmol) was heated in a sealed tube for 20 h at 125° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane 0:1=>3:7) yielded (6-nitro-quinolin-2-yl)-(R)-indan-1-yl-amine as a brownish solid (1.5 g, 47%), MS 306.5 [(M+H)+].
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.S(=O)(=O)(O)O.S(=O)(=O)=O.[S:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])([OH:22])(=[O:21])=[O:20].[N+:32]([O-])([OH:34])=[O:33]>>[N+:32]([C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([S:19]([OH:22])(=[O:21])=[O:20])[CH:31]=1)[C:26]([OH:28])=[O:27])([O-:34])=[O:33]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1

Procedure:
Benzoic acid was sulfonated by heating it with concentrated sulfuric acid in the presence of sulfur trioxide. The 3-sulfobenzoic acid was nitrated with fuming nitric acid to yield 3-nitro-5-sulfobenzoic acid. Hydrogenation of this in 50% ethanol/water over palladium on charcoal easily afforded 3-amino-5-sulfobenzoic acid in good yield. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[O:5][C:6]=1[C:7](OC)=[O:8].[CH:15]([NH2:17])=O>>[N:1]1[C:2]2[C:3]3[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=3[O:5][C:6]=2[C:7](=[O:8])[NH:17][CH:15]=1
Reactant: NC=O
Reactant: COC(=O)c1oc2ccccc2c1N
Product: O=c1[nH]cnc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A solution of methyl 3-aminobenzo[b]furan-2-carboxylate (0.28 g, 1.36 mmol) in formamide (5 mL) is heated at 135 C. for 4 h, then the temperature is raised to 170 C. After 4 h the reaction is cooled to 25° C. and a dark purple solid precipitates. The solid is collected by vacuum filtration and air dried to give 3H-benzofurano[3,2-d]pyrimid-4-one (118 mg, 46.6%). 1H NMR (DMSO) δ13.0 (1H, brs), 8.25 (1H, s), 8.05 (1H, d, J =8.1 Hz), 7.84 (1H, d, J=8.3 Hz), 7.68 (1H, t, J=7.7 Hz), 7.51 (1H, t, J=7.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8](=O)[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1.[CH3:23][C:24]([S:27]([NH2:30])(=O)=[O:28])([CH3:26])[CH3:25]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8](=[N:30][S:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(F)(F)C(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)S(N)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-one (16.0 g, 40.4 mmol) in dry THF (350 mL) was added Ti(OEt)4 (16.7 mL, 80.4 mmol) and 2-Methyl-2-propane sulfonamide (5.8 g, 48.4 mmol) and refluxed for 16 h. Reaction mixture was concentrated under reduced pressure and the crude residue was directly purified by column chromatography on silica gel with 3% ethyl acetate in Hexane to furnish title compound as a colorless liquid. Yield=13.1 g (65.5%). TLC (10% ethyl acetate in Hexane): Rf=0.2),
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Na].[N:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CO>[OH:18][C:15]1([CH2:4][N+:1]([O-:3])=[O:2])[CH2:14][CH2:13][N:12]([C:9]2[CH:8]=[CH:7][N:6]=[CH:11][CH:10]=2)[CH2:17][CH2:16]1
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCN(c2ccncc2)CC1
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of nitromethane (2.31 ml) in methanol (5.4 ml) was added sodium (70 mg) at ice-cooled temperature. The resulting mixture was added dropwise to a solution of 1-(4-pyridyl)-4-piperidone (5.36 g) in methanol (10.7 ml) at ice-cooled temperature for 10 minutes, and stirred for 15 hours at room temperature. The precipitate was filtered, and washed with methanol to obtain the title compound (5.31 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reaction time: 2 h

Procedure:
Alternative preparation: To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (495.4 mg, 1.610 mmol, 1 eq), 1-piperidinepropanoic acid (335.4 mg, 2.133 mmol, 1.3 eq), and TBTU (624.4 mg, 1.945 mmol, 1.2 eq) in anhydrous DMF (15 mL), DiPEA (1.4 mL, 8 mmol, 5 eq) was added at rt, under N2, and stirred for 2 h. The solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 2%→5%→10%→7N NH3/MeOH:DCM 2%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].N1CCCN2CCCCCC=12.[N+:18]([CH:21]([CH3:23])[CH3:22])([O-:20])=[O:19]>>[CH3:22][C:21]([N+:18]([O-:20])=[O:19])([CH3:23])[CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CCS(C)(=O)=O)[N+](=O)[O-]
Yield: 72.8 %

Procedure:
A solution of (methylsulfonyl)ethene (1.51 mL, 17.24 mmol, Sigma-Aldrich) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (3.86 ml, 25.9 mmol) in 2-nitropropane (72.8 mL, 810 mmol, Sigma-Aldrich) was stirred at RT for 2 d. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM followed by 1% 2 M NH3 in MeOH/DCM to give 3-methyl-1-(methylsulfonyl)-3-nitrobutane (338a, 2.45 g, 12.55 mmol, 73% yield) as a white solid. 1H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 1.31 (s, 6H) 2.08 (d, J=17.02 Hz, 1H) 2.08 (dd, J=4.30, 3.52 Hz, 1H) 3.05 (s, 3H) 3.33 (d, J=17.02 Hz, 1H) 3.33 (t, J=3.91 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.CO.[BH4-].[Na+]>O1CCCC1>[OH:16][CH2:15][C:11]1[CH:10]=[C:9]([C:5]2[C:4]([CH3:17])=[CH:3][C:2]([OH:1])=[CH:7][C:6]=2[CH3:8])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.6 %

Procedure:
A solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (6.95 g, 30.7 mmol) in a mixed solvent of methanol (30 mL) and tetrahydrofuran (60 mL) was ice-cooled, sodium borohydride (90%, 1.29 g, 30.7 mmol) was added, and the mixture was stirred for 20 hr under nitrogen atmosphere, during which the mixture was allowed to gradually warm to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was treated with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (6.56 g, yield 93%) as colorless crystals.