Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:21]([CH2:23][C:24](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:25])#[N:22]>C(Cl)Cl>[C:2]1([C@@H:14]2[CH2:15][CH2:16][C@H:17]([NH:20][C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:18][CH2:19]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Agent: Cl
Solvent: ClCCl
Product: N#CCC(=O)N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (0.106 g, 0.206 mmol, Example #D.1.1) in DCM (4 mL) was added TEA (0.086 mL, 0.62 mmol). The reaction mixture was sonicated until the reaction was homogeneous. To the reaction solution was added perfluorophenyl 2-cyanoacetate (0.078 g, 0.31 mmol, Preparation #6). The resulting solution was stirred at ambient temperature for about 16 h. The crude reaction mixture was purified by silica gel chromatography (40 g) eluting with a gradient of 0-20% EtOAc in DCM and then further purified by RP-HPLC (Table 2, Method e) to give N-(cis-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)-2-cyanoacetamide with 3 equiv NH4OAc as an excipient (0.025 g, 22%). LC/MS (Table 2, Method a) Rt=1.33 min; MS m/z: 324 (M+H)+.
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].[OH-].[Na+].OO>O>[OH:22][C:9]1([CH2:6][CH2:7][CH2:8][OH:4])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.4 %

Procedure:
A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07 mmol) and THF (5 mL) at 0° C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carboxylate 13B (6:29 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.CCOC(C)=O>[NH:29]([C:30]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CCN(C(=O)Nc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To an ice cooled solution of 4-(piperidin-4-yloxy)benzaldehyde (2 g) and triethylamine (1.35 ml) in tetrahydrofuran (20 ml) was added phenyl isocyanate (1.3 ml). The mixture was stirred at room temperature for 3 h. At the end of this time, the reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3 solution followed by water, dried (Na2SO4) and concentrated to get 3.1 g (99%) of the title product as a gummy solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.Br[CH2:39][CH:40]([F:42])[F:41].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:39][CH:40]([F:42])[F:41])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(C3CCN(CC(F)F)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 2-bromo-1,1-difluoroethane (91 mg, 0.629 mmol), Potassium carbonate (87 mg, 0.629 mmol) and Sodium iodide (10 mg, 0.066 mmol) were mixed in DMF (3 mL). The reaction mixture was heated at 80° C. overnight. HPLC showed only about fifty percent conversion. The bath temperature was lowered to 55° C. and more 2-bromo-1,1-difluoroethane (0.1 mL) was added. After stirring at 55° C. overnight, more 2-bromo-1,1-difluoroethane (0.1 mL) was added and the reaction mixture was stirred at 55° C. overnight. HPLC showed most of starting material was converted to product. The crude reaction mixture was purified by reverse phase preparative HPLC using acetonitrile/water (50 mM ammonium acetate buffer) as mobile phase to give N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (227 mg, 81%). 1H NMR (DMSO-d6) δ 1.89 (m, 2H), 2.27 (m, 2H), 2.42 (m, 2H), 2.80 (m, 1H), 3.05 (m, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.69 (m, 1H), 6.17 (t t, J=55.81 Hz, J=4.35 Hz, 1H), 7.15 (m, 1H), 7.33 (m, 4H), 7.78 (d, J=7.94 Hz, 1H), 7.70 (d, J=7.94 Hz, 1H), 8.11 (d, J=8.19 Hz, 1H), 8.25 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=3.32 min. MH+=561.3.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20]C)=[O:19]>C1COCC1>[O:13]=[C:11]1[CH2:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C1CCCC(c2ccccc2)N1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-6-phenylpiperidin-2-one (155 mg, 0.885 mmol) in THF (10 mL), cooled to 0° C., was added NaH (30.0 mg, 1.24 mmol). The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 1 h at ambient temperature, the reaction was cooled to 0° C. prior to the introduction of methyl bromoacetate (149 mg, 0.973 mmol). After 40 minutes, the ice bath was removed and the reaction was stirred under nitrogen for 12 h. Additional quantities of NaH and methyl bromoacetate were then added in parts to nearly consume the lactam, as judged by LCMS analysis. After sufficient lactam was consumed, 1 M aqueous sodium hydroxide was added (1 mL, 1 mmol). After a majority of the methyl ester was saponified (˜3 h), the reaction was quenched with 1 M hydrochloric acid (5 mL), and EtOAc (50 mL). The organics were washed with saturated brine (twice), dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was used without further purification. MS: m/z=234 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:22])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]([CH3:22])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:10]=1)[C:3]([O:2][CH3:1])=[O:23]
Reactant: COC(=O)Cc1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Yield: 97.1 %

Procedure:
A mixture of 10.0 g of methyl{p-[2-(p-chlorophenoxy)-1-methylethoxy]phenyl}acetate, 5.87 g of N-bromosuccinimide and 120 ml of carbon tetrachloride is stirred and refluxed for 5 days. The mixture is cooled, filtered and the filtrate is passed through a short column of silica gel (125 ml cuts). The first two cuts are combined and the solvent removed to give 12.0 g of colorless gum.
Reaction SMILES: C([O:3][C:4]([CH:6]=[CH:7][C:8]1[N:9]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[CH3:25])[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=1)[C:12]([OH:14])=[O:13])=[O:5])C.Cl>C(OCC)C>[C:4]([CH:6]=[CH:7][C:8]1[N:9]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[CH3:25])[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=1)[C:12]([OH:14])=[O:13])([OH:5])=[O:3]
Reactant: CCOC(=O)C=Cc1cc(=O)c(C(=O)O)cn1-c1ccc(O)cc1C
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C=CC(=O)O
Yield: 96.8 %

Procedure:
To 0.09 g of 6-(2-ethoxycarbonylethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid was added 3 ml of 6N hydrochloric acid, and they were reacted at 100° C. for 1.5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and to the crystals thus formed were added 3 ml of diethyl ether, and the resulting mixture was filtered to obtain 0.08 g of 6-(2-carboxyethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 280° C. or more.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[C:36]4[C:31](=[CH:32][N:33]=[C:34](Br)[CH:35]=4)[N:30]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[N:29]=3)[N:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[C:6]([CH2:7][C:34]1[CH:35]=[C:36]2[C:28]([C:24]3[N:23]=[C:22]([N:19]4[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:17][CH2:18]4)[CH:27]=[CH:26][CH:25]=3)=[N:29][N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:31]2=[CH:32][N:33]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(CC#N)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
A solution of 0.940 mL of 1.6 M of n-Butyllithium in hexane was added dropwise to a solution of 0.102 mL, (1.95 mmol) of acetonitrile in tetrahydrofuran at −78° C. The mixture was stirred for 30 min and a solution of 272 mg (0.500 mmol) of 4-{6-[5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was added. The brown mixture was stirred for 30 min at −50° C. and 2 ml of saturated aqueous NH4Cl was added. The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 44 mg (17%) of tert-Butyl 4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 504.2 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:30])[C:7]([C:16]1[CH:29]=[CH:28][C:19]2[CH:20]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:22][C:18]=2[CH:17]=1)([F:15])C(OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([O:25][C:23]([C:21]1[S:22][C:18]2[CH:17]=[C:16]([CH:7]([C:6]([OH:30])=[O:5])[F:15])[CH:29]=[CH:28][C:19]=2[CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1cc2ccc(C(F)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2ccc(C(F)C(=O)O)cc2s1

Procedure:
Di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl](fluoro)malonate (9.3 g) was stirred in DCM (40 mL)/TFA (20 mL) at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was suspended in H2O (50 mL) and heated to reflux for 2 hours. Room temperature was attained and the products extracted into EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the product as a pale yellow solid. 1H NMR (DMSO-d6) δ 13.60 (br s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.14 (d, J=47.4 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=[CH:19]3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl-].[NH4+]>C1COCC1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][C:21]([CH2:6][CH2:1][CH2:2][CH3:3])([OH:24])[CH:20]=[CH:19]3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C2CCC(C3C=CC(=O)CC3)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](C2CCC(C3C=CC(O)(CCCC)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 4.0 g of 4-(4-(trans-4-pentylcyclohexyl)cyclohexyl)-2-cyclohexenone (r-9) was dissolved into 50 mL of THF, 14.5 mL of butylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=7:3 (in a volume ratio)), and thus 4.70 g of 4-(4-(trans-4-pentylcyclohexyl)cyclohexyl)-1-butyl-2-cyclohexene-1-ol (compound (r-10)) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.I[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(Cl)cc2Cl)c1
Yield: 36.3 %

Procedure:
2.0 g (10.4 mmol) of 2,4-dichlorophenylboronic acid, 2.4 g (11.0 mmol) of 3-iodoaniline, 3.2 g (30.0 mmol) of sodium carbonate and 1.6 g (1.4 mmol) of tetrakis(triphenylphosphine) palladium were added to a solvent mixture of 70 ml of toluene, 30 ml of ethanol and 30 ml of water, and the reaction was carried out under reflux with heating for 2 hours. The reaction mixture was poured into ice-cold water and extracted with toluene. The toluene layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.9 g of 3-(2,4-dichlorophenyl)aniline (yield 36.0%), which was used in Example 9 as the starting material.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:19]=[N:18][C:17]3[C:16](=[O:20])[N:15]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[C:14]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)=[N:13][C:12]2=3)[CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO.O.O>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:32]=[CH:33][C:28]([C:14]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:16](=[O:20])[C:17]3[N:18]=[CH:19][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:40])=[O:3])[C:12]=3[N:13]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid ethyl ester (200 mg, 0.37 mmol) in THF/MeOH/H2O 3:2:1 (5 mL) was cooled to 0° C. and treated with 3 N aqueous LiOH (183 μL, 0.55 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 4 h. The reaction was diluted with H2O, extracted with Et2O, and acidified with 1N aqueous HCl. The resulting white precipitate was collected by suction filtration to provide 3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (155 mg, 82%) as a white solid. HPLC-MS calculated for C30H19ClN4O3 (M+H+): 519.1. Found: 519.1.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([Cl:13])[C:5]=1[N+:14]([O-])=O)([O-])=O.O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:14][C:5]1[C:6]([Cl:13])=[C:7]([Cl:12])[C:8]([Cl:11])=[C:9]([Cl:10])[C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c(N)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
1,2-Diamino-3,4,5,6-tetrachlorobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 1,2-dinitro-3,4,5,6-tetrachlorobenzene (1.00 g, 3.27 mmol) and SnCl2.2H2O (3.69 g, 16.4 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 80° C. for 1 h. The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was adding (foaming!) to bring the pH to 6. The thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a brown solid 569 mg (71%). 1H NMR (CDCl3) δ3.96 (br s, 2(NH2)). 13C NMR (CDCl3) δ118.2, 127.0, 132.0.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C:8]1([OH:21])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(C)(C)C.O[Li].O.O.CO>CCO>[OH:21][C:8]1([CH2:7][C:6]([OH:22])=[O:5])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CC2CCC1C=C2c1cccs1
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C(O)CC1(O)CC2CCC1C=C2c1cccs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
276 mg of rac-(1R*,2R*,4R*)-(2-hydroxy-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester were dissolved in EtOH (1.7 mL) and treated with LiOH.H2O (181 mg), H2O (0.55 mL) and MeOH (1.65 mL). The reaction mixture was stirred at rt for 4 days and concentrated in vacuo. The resulting aq. residue was partitioned between water and Et2O. The aq. layer was separated, acidified with 25%-HCl, and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated to give 205 mg of rac-(1R*,2R*,4R*)-(2-hydroxy-5-thiophen-2-yl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2)(=[O:23])=[O:22]
Reactant: Cn1ncc2cc(CO)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc2cc(COS(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-methyl-1H-indazol-5-yl)methanol (0.15 g, 0.92 mmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. and treated with triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After stirring for 2 hours, the mixture was treated with additional triethylamine (0.14 mL, 1.0 mmol, 1.1 equiv) and methanesulfonyl chloride (0.079 mL, 1.0 mmol, 1.1 equiv). After an additional 1 hour, the mixture was diluted with dichloromethane (100 mL), washed with sodium bicarbonate (15 mL, aqueous saturated) and brine (15 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[N:4].[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>C1COCC1.C(OCCCC)CCC>[CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH:3]([NH2:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(C)(C(N)c1ccccc1)N1CCCC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (10.7 g; 77.54 mmol) in THF (400 ml) at −70° C. under argon was added over 10 minutes a solution of phenyllithium in dibutylether (86.3 ml of a 1.8M solution; 155 mmol). The reaction mixture was stirred at −70° C. for 2 hours then allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled in ice as saturated aqueous sodium hydrogen carbonate (400 ml) was added. After stirring for a further 30 minutes the layers were separated, and the aqueous layer extracted with ether (200 ml). Combined organics were dried (MgSO4) and evaporated. The residual amber oil was dissolved in methanol (400 ml), cooled in ice and sodium borohydride (5.2 g; 137 mmol) added in four portions over 5 minutes. The reaction mixture was stirred with ice cooling for 30 minutes, the ice removed and stirred at room temperature for 1.5 hours. The mixture was cooled in ice as water (50 ml) was added prior to concentration in vacuo to approx 70 ml. The mixture was partitioned between 2N HCl (100 ml) and ethyl acetate (400 ml) and the organics extracted with 2N HCl (2×100 ml). Combined acidic aqueous layers were washed with ethyl acetate (200 ml), basified with 50% NaOH and extracted with DCM (3×150 ml). Combined DCM organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless solid (15 g: 88%) 1H NMR (CDCl3), δ: 0.75 (3H, s), 0.99 (3H, s), 1.70-1.76 (4H, m), 1.80 (2H, bs), 2.65-2.70 (4H, m), 4.08 (1H, s), 7.20-7.42 (5H, m).