Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[CH:10][N:9]=1)=[O:7].O1CCCC1.[OH-].[Na+]>O.CO>[NH2:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=[C:11]([NH2:15])[N:12]=1
Reactant: COC(=O)c1ncc(N)nc1N
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(C(=O)O)c(N)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.4 %

Procedure:
Lithium hydroxide monohydrate (2.50 g, 59.5 mmol) was added to 3,5-diamino-pyrazine-2-carboxylic acid methyl ester (10.0 g, 59.5 mmol) described in Preparation Example AA-1 in a mixture solvent of tetrahydrofuran (100 mL), methanol (10 mL) and water (10 mL) at room temperature. The solution was stirred at room temperature for 17 hours, then, an aqueous solution of 5N sodium hydroxide (15 mL) was added thereto, followed by further stirring for 4.5 hours under reflux. The reaction solution was cooled to room temperature, and partitioned in 5N hydrochloric acid solution and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, and the title compound (3.34 g, 36%) was obtained as a crude product of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[N:31]1([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])[CH:35]=[CH:34][N:33]=[CH:32]1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCCC[C@@H]1n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3n3ccnc3)cc2F)c(OC)c1
Yield: 90.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (260 mg, 0.592 mmol) prepared in Example 14b, (1S*,2S*)-2-(1H-imidazol-1-yl)cyclohexanol (Tetrahedron, 2007, 63, 469-473; 100 mg, 0.602 mmol), sodium hydride (63%; 50 mg, 1.31 mmol) and DMF (3.0 mL), to yield the title compound (315 mg, 91%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Into a 100 mL, round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (200 mg, 0.40 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (10 g, 87.70 mmol, 221.25 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The pH value of the solution was adjusted to 8-10 with 10% aqueous sodium carbonate. The solution was extracted with dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.1 g (62%) of 3-[4-(2-fluorophenoxy)phenyl]-1-((3R)-piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOCC3)c2C1
Yield: 50 %

Procedure:
Method as described for example 47 using ethyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 27) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) as starting materials. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane was used as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (115 mg, 0.24 mmol, 50%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH3:27])[C:21]3=[O:26])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C1COCC1>C(O)C>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH3:27])[CH:21]3[OH:26])[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1Cc2c(cccc2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1Cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cccc2C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Sodium borohydride (2.35 g, 61.98 mmol, 1.5 equiv) was added in portions to a cold solution (0° C.) of compound 9 (13.8 g, 41.32 mmol, 1.0 equiv), THF (140 mL) and ethanol (140 mL). The reaction mixture was stirred at room temperature for 2 hours when LC/MS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL). 1M HCL was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 10 (15 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[C:8]([Si:12]([O:15][C@@H:16]1[C@H:25]2[C@@:20]([CH3:30])([C@@H:21]([C@H:26]([CH3:29])[CH2:27]I)[CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH2:17]1)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1.O1CCCC1.[Zn]>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][CH2:6][CH2:29][C@H:26]([C@@H:21]1[C@:20]2([CH3:30])[C@H:25]([C@@H:16]([O:15][Si:12]([C:8]([CH3:10])([CH3:9])[CH3:11])([CH3:14])[CH3:13])[CH2:17][CH2:18][CH2:19]2)[CH2:24][CH2:23][CH2:22]1)[CH3:27])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: C[C@H](CI)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [Zn]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCC[C@@H](C)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To 342.5 mg (5.24 mMol) of Zn powder are added 1.57 ml of tetrahydrofuran/pyridine 2/1. The reaction mixture is stirred under Argon, 247.2 mg (1.04 mMol) of NiCl2.6H2O and then 472.2 mg (4.72 mMol) of ethylacrylate are added. The reaction mixture is heated at 65° for 30 minutes, cooled to room temperature and 947 mg (2.10 mMol) of (1S,4aR,5R,8aR)-tert-Butyl[5-[(S)-2-iodo-1-methyl-ethyl]-4a-methyl-decahydronaphtalen-1-yloxy]-dimethylsilane dissolved in 1.57 ml of tetrahydrofuran pyridine 1/2 are added and the reaction mixture kept overnight at room temperature. Filtration through Speedex and washing of the filter cake with ethylacetate is followed by evaporation in vacuo to 1/3 of the volume. The solution is diluted with ethylacetate and the organic phase is washed 4 times with a disodium ethylene diamine tetraacetate dihydrate (EDTA) solution (8 g of EDTA and 8 g of NaHCO3 in 100 ml water) and twice with brine. The organic phase is dried over Na2SO4, filtered and evaporated in vacuo. The residue is chromatographed over 100 g of silicagel with hexane/ethylacetate 98/2 to yield 269 mg of starting material and 390 mg (44%) of (R)-5-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphtalen-1-yl)-hexanoic acid ethyl ester as an amorphous product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)cnn3c2=O)cc1
Temperature: 65 °C
Yield: 20.5 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (96 mg, 0.3 mmol), prepared as described in Example 244, K2CO3 (82 mg, 0.59 mmol), and α-bromo-p-toluonitrile (70 mg, 0.356 mmol) in DMF (1 mL) was heated at 65° C. for 2.5 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-Chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)benzonitrile (27 mg) as a yellow solid. HPLC RT: 2.45 min; M+H=439; 1H NMR (CDCl3): δ 8.63 (d, J=6.04 Hz, 2H), 8.21 (s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.33 (m, 2H), 7.21 (m, 2H), 7.08 (m, 2H), 5.25 (2H).
Reaction SMILES: [ClH:1].Cl.F[C:4]1C=CC(CCOC2C=CC(C3(O)CCCCC3CCN3CCN(C)CC3)=CC=2)=CC=1.Cl.Cl.[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH:53]([C:61]3([OH:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)[CH2:54][N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:49][CH:48]=2)=[CH:40][CH:39]=1>>[ClH:1].[ClH:1].[F:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][O:46][C:47]2[CH:48]=[CH:49][C:50]([CH:53]([C:61]3([OH:67])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]3)[CH2:54][N:55]3[CH2:60][CH2:59][N:58]([CH3:4])[CH2:57][CH2:56]3)=[CH:51][CH:52]=2)=[CH:42][CH:43]=1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCCc3ccc(F)cc3)cc2)CCCCC1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCCc3ccc(F)cc3)cc2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCCc3ccc(F)cc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-{4-[2-(4-fluorophenyl)ethoxy]phenyl}-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-(1-{4-[2-(4-fluorophenyl)ethoxy]phenyl}-2-piperazin-1-ylethyl)cyclohexanol (see Example 462). MS (ESI) m/z 441.
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[CH:4]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:3]=1.[H-].[Na+].I[CH3:28]>CN(C)C=O>[CH3:28][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:2]([CH3:1])=[N:3][CH:4]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:5]1=[O:13]
Reactant: CI
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of 1,3-dihydro-5-methyl-3(R,S)[-(benzyloxycarbonyl )-amino]-2H- 1,4-benzodiazepin-2-one (2 g, 6.2 mmol) in dimethylformamide (20 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.26 g of a 57% dispersion in mineral oil, 6.2 mmol) in one portion, at -10° C. After 30 min, iodomethane (0.39 ml, 6.2 mmol) was added and the resulting mixture stirred at room temperature for 3 h. The solvent was then evaporated and the crude residue partitioned between water (20 ml) and dichloromethane (3×20 ml). The combined organic phase was washed with brine (20 ml), dried (MgSO4) and evaporated. The residue was triturated with ether to afford the title compound (1.05 g, 50%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 2.52 (3H, s), 3.42 (3H, s), 5.0-5.25 (3H, m), 6.65 (1H, d, J=8 Hz), 7.2-7.7 (9H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([O:15][C:16](=[O:19])[NH:17][NH2:18])[CH3:14]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:18][NH:17][C:16]([O:15][CH2:13][CH3:14])=[O:19]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOC(=O)NN
Solvent: CO
Product: CCOC(=O)NN=Cc1ccc2ccccc2n1
Yield: 19.6 %

Procedure:
A mixture of 3.93 gm (0.025 mole) of 2-quinolinecarboxaldehyde, 2.60 gm (0.025 mole) of ethylcarbazate and 100 ml of methanol is refluxed for 8 hrs. The hot solvent is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/Skellysolve B to yield 1.19 gm (20%) of the title compound, having a melting point of 163°-165° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:27](=[O:29])[CH3:28])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(Indan-5-ylamino)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (Table A, Example A359; 0.3 g, 0.9 mmol) and 10% Pd/C (60 mg) in ethanol (25 mL) was hydrogenated at atmospheric temperature and pressure for 2 hours. The reaction mixture was filtered through Kieselguhr and the filtrate concentrated in vacuo to give an orange solid. The crude product was taken up in dichloromethane (5 mL) and treated with acetic anhydride (85 μL, 0.9 mmol) and stirred for 3 hours at ambient temperature. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution (10 mL) and extracted into ethyl acetate (3×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica gel using dichloromethane-methanol gave the desired compound as an orange powder.
Reaction SMILES: C(O[C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]1)(=O)C.[Cu]C#N.[C:14]1([Mg]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1>[C:14]1([C@@H:5]2[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(=O)O[C@@H]1C=C[C@H](O)C1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O[C@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
A solution of (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (491 mg, 3.45 mmol), THF (10 mL), and copper(I) cyanide (93 mg, 1.04 mmol) was cooled to <−20° C. and phenylmagnesium chloride (2.0 M in THF, 5.18 mL, 10.4 mmol) was added at the same temperature. After 10 minutes, TLC (50% EtOAc/hexanes) showed complete conversion. Saturated aqueous NH4Cl (50 mL) was added, extracted with EtOAc (3×50 mL), and dried (Na2SO4) the combined organic layers. Concentrated and purified the residue by flash column chromatography (10-50% EtOAc/hexanes, gradient elution), to provide the title compound (463 mg, 2.89 mmol, 84%). MS (DCI) m/z 143 (M−OH)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:17]1([O:23][C:10]2[C:11]([I:12])=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=[C:8]([NH2:16])[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OC1CCCCC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OC2CCCCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in THF. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: I[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])#[CH:9]>>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]#[C:9][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1
Reactant: C#Cc1ccccc1F
Reactant: Cn1ccnc1I
Product: Cn1ccnc1C#Cc1ccccc1F

Procedure:
The title compound, MS: m/e=201.2 (M+H+) was prepared in accordance with the general method of example 1b from 2-iodo-1-methyl-1H-imidazole and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][O:4][C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15]S[CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1.O[O:23][S:24]([O-:26])=O.[K+].O.CC(C)=O>CO>[CH3:21][CH:2]([CH3:1])[CH2:3][O:4][C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][S:24](=[O:26])(=[O:23])[CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)COC(=O)Nc1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reaction time: 3 h

Procedure:
2-Methylpropyl[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamate in methanol (250 ml) is added to a slurry of oxone (140.8 g, 229.1 mmol, 1.5 equiv.) in a slurry of water (250 ml). Acetone (375 ml) is added to the reaction mixture and an exotherm of 30° to give 53° is noticed. The reaction mixture is stirred for 3 hr, during which time the reaction gradually cooled to 25°. The slurry is quenched with aqueous sodium bisulfite (10%, 250 ml) and stirred 1 hr. The slurry is filtered to remove salts and the cake washed with methylene chloride (250 ml) followed by water (250 ml). The filtrate is separated into two phases and the lower organic phase is collected. The aqueous phase is washed with methylene chloride (2×250 ml). The combined organic phases are washed with saline (250 ml) and then concentrated. The concentrate is dried under reduced pressure overnight to give the title compound, TLC Rf=0.73 (methanol/methylene chloride, 5/95); mp=147-149°; NMR (CDCl3) d 7.36, 7.13, 7.03, 6.92, 5.75, 3.96, 3.80, 3.22, 3.10, 2.02-1.93 and 0.96; CMR (CDCl3) d 159.5, 153.4, 139.5, 134.1, 129.5, 123.0, 119.1, 113.9, 106.2, 71.6, 50.7, 47.8, 29.2, 27.9 and 18.9; MS (CI, NH3) m/z (relative intensity) 359 (100), 341 (5), 295 (18), 285 (20), 277 (23) and 178 (18).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:21](=[O:28])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[K+]>CN(C)C=O>[O:28]=[C:21]1[C:22]2([CH2:23][CH2:24][N:25]([CH2:2][CH2:3][NH:4][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[O:6])[CH2:26][CH2:27]2)[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][NH:20]1
Reactant: O=C(NCCCl)c1ccco1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccco1
Temperature: 25 °C

Procedure:
A member of 6.9 parts of N-(2-chloroethyl)-2-furancarboxamide, 9.2 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 6.6 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred first for 3 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The whole is alkalized and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 1.9 parts of N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro [4,5]dec-8-yl)ethyl]-2-furancarboxamide; mp. 196.3° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1Cl)[CH:2]=[CH2:3].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)/C=C/C(O)=O>>[CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: C=CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 1-[2-(allyloxy)ethyl]-2-chlorobenzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.16 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(allyloxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (3.18 g) as colorless plates, m.p. 161.5°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH:13]([CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18]4)[C:14](=[O:15])[C:7]3=[CH:6][C:5]=2[CH:4]=1.[H-].[Na+].[CH3:32]I>C1COCC1>[CH3:32][C:13]1([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[CH2:12][N:8]2[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:6]=[C:7]2[C:14]1=[O:15]
Reactant: COc1ccc2c(c1)cc1n2CC(CC2CCN(Cc3ccccc3)CC2)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)cc1n2CC(C)(CC2CCN(Cc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,3-dihydro-7-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-pyrrolo[1,2-a]indol-1-one (137 mg, 0.353 mmol) in dry THF (5 ml) was treated with NaH (35 mg, 0.875 mmol) at r.t. After 5 minutes, an excess of methyl iodide (0.1 ml) was added and the mixture was stirred at r.t. for 3 hours. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 140 mg of material which was purified through silica gel to give the title compound. 1HNMR (CDCl3)δ 1.36 (s, 3H), 1.6-2.2 (m, 7H), 2.4-2.7 (m, 2H), 3.2-3.4 (m, 2H), 3.8 (s, 3H), 4.05 (s, 2H), 4.18 (ABq, 2H), 6.9 (s, 1H), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.6 (m, 2H) ppm.