Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([O:19][CH3:24])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in example 1j) (10.03 g, 37.1 mmol) in toluene (100 mL) was added thionyl chloride (4.05 mL, 55.7 mmol, 1.5 eq). The reaction was heated to reflux monitoring gas evolution with a bubbler of mineral oil. Gas evolution ceased after 30 min at which time the reaction was cooled slightly under nitrogen and a large excess of methanol (10 mL) was added. The solution was again heated to reflux for 1 h, cooled to room temperature under nitrogen, and stirred for 18 h. Aqueous NaOH (2.5N, 60 mL) was added and the aqueous phase was extracted with ethyl acetate (2×70 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a solid. The reaction product was purified by flash chromatography over silica gel (250 mL, eluent: 15% ethyl acetate in hexane) to yield 10.2 g (97%) of the title compound as a highly crystalline white solid. TLC (Rf 0.45, 10% ethyl acetate in hexane). MS (CI, CH4) m/z 285 (M+1,100), 287 (31), 313 (M+29,11), 253 (14), 225 (14), 205 (8)
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.CO>[CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][CH:14]([N:23]([CH3:24])[CH3:22])[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(N(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)cyclohex-3-enone (0.1 mmol) and dimethylamine (0.11 mmol) in 2 mL of 1,2-dichloroethane, is added AcOH (0.1 mmol) and NaBH(OAc)3 (0.11 mmol). The reaction mixture is stirred at room temperature for 10 hours. After workup and silica flash chromatography (CH2Cl2/MeOH 9:1), 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3-enamine is obtained. MS (ES+): 319.19 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3cccc(F)c3)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.43 mmol, 100 mg), 3-fluorophenylboronic acid (0.47 mmol, 66 mg), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol, 18 mg), and potassium carbonate (1.72 mmol, 238 mg) were added to deoxygenated DME:water (1:1, 3 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 10 to 40% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 8.99 (s, 1H), 8.58 (d, 1H), 8.28 (d, 1H), 7.95 (s, 1H), 7.74 (m, 2H), 7.60 (m, 1H), 7.38 (m, 1H), 2.73 (s, 3H). MS (ESI) 295.13 (M+H+).
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][C:11]#[N:12].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[BH4-].[Na+].Cl>ClCCl.O1CCCC1.[Zn].C(O)C>[NH2:12][CH:11]([CH2:10][C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[O:7][CH3:6])[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccccc1CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C)C(N)Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 g of zinc in 1.5 L of absolute dichloromethane are combined with 15 mL of trimethylchlorosilane under nitrogen and stirred for 30 minutes at ambient temperature. Then 900 mL of absolute tetrahydrofuran (THF) are added and heated to 42° C. To this is added dropwise a mixture of 147 g (1.0 mol) of 2-methoxybenzylcyanide 11 and 362 g (2,0 mol) of ethyl 2-bromopropionate in 100 mL of THF and the resulting mixture is then refluxed for a further 2 h. It is left to cool, decanted off from the excess zinc and after cooling to about 5° C. combined with 70 g (1.8 mol) of sodium borohydride. Then 250 mL of ethanol are added dropwise (development of gas). The mixture is left to react for 3 h at 5° C., 1 liter of 2 N hydrochloric acid is slowly added, the phases are separated and the aqueous phase is extracted twice with 200 mL of dichloromethane. The solvent of the combined organic phase is eliminated in vacuo, the residue is combined with ice and toluene and made alkaline with conc. ammonia. The phases are separated and the aqueous phase is extracted twice more with 800 mL of toluene. The combined organic phases are dried over magnesium sulfate, and the solvent is eliminated in vacuo. Yield 149 g (61%) oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]Cl.[H-].[Na+].C1(C)C=CC=CC=1>O>[CH3:19][N:20]([CH2:21][CH2:22][CH2:23][O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:25]
Reactant: CN(C)CCCCl
Reactant: OC(CCCc1ccccc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 5.0 g of 1-(p-fluorophenyl)-4-phenyl-1-butanol, 10 g of γ-dimethylaminopropyl chloride, 2.0 g of sodium hydride (65%) and 100 ml of toluene was heated under refluxing for 30 minutes. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane. M.P., 80°-83° C. (fumarate).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][SH:11])=[CH:5][CH:4]=1.Cl[C:13]1[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]2[C:13]([S:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:20])=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Reactant: SCCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of 60% sodium hydride (35 mg, 0.88 mmol) in N,N-dimethylformamide (1 mL), a solution of 4-pyridineethanethiol (104 mg, 0.75 mmol) in N,N-dimethylformamide (1.5 mL) and a solution of 2-chloro-N-(4-chlorophenyl)pyridine-3-carboxamide (200 mg, 0.75 mmol, Reference compound No. 2-1) in N,N-dimethylformamide (1.5 mL) were added under ice-cooling successively. The reaction mixture was stirred at room temperature for 2 hours, and then ethyl acetate (40 mL) was added thereto. The ethyl acetate layer was washed with water (40 mL) and brine (40 mL) and dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The precipitated solid was filtered off and washed with diethyl ether :ethyl acetate (3:1). The solid was dried under reduced pressure to give 240 mg of the target compound as a white solid. (Yield 88%)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34](C(OC(C)(C)C)=O)[CH2:33]2)[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH2:33]2)[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)CNc3ccccc34)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
N-[7-Benzylamino-6-(1-(tert-butoxycarbonyl)spiro[indoline-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]methanesulfonamide (0.062 g, 0.094 mmol) obtained in step 3 was dissolved in 4 mol/L hydrogen chloride-dioxane solution, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained crystals and the mixture was suction-filtered to give the title compound (0.036 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[N:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:28]([CH3:30])[CH3:29])[CH:17]=1.[Cl-].[Na+]>CS(C)=O.C1(C)C=CC=CC=1.O>[CH:22]([C:20]1[C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:28]([CH3:30])[CH3:29])[CH:17]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:21]=1)([CH3:24])[CH3:23]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)c1cc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1[N+](=O)[O-]

Procedure:
0.77 g of 4-chlorophenol and 1.00 g of potassium carbonate are suspended in 6 ml of dimethyl sulfoxide and the suspension is heated for 1 hour at +60° C.; a solution of 1.46 g of 6-chloro-2,4-diisopropyl-3-nitropyridine in 4 ml of dimethyl sulfoxide is then added dropwise. When the addition is complete, the mixture is heated for 1 hour at +120° C. with vigorous stirring. After cooling, the reaction mixture is poured onto 100 ml of water and 50 ml of toluene and then saturated with sodium chloride. The resulting suspension is filtered over diatomaceous earth and the filtrate is extracted with toluene. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:30). 2,4-Diisopropyl-6-(4-chlorophenoxy)-3-nitropyridine is obtained in the form of a light-yellow crystalline powder, m.p. 102°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:28][C:29]1[C:30](=[O:43])[N:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[N:32]([CH3:35])[C:33]=1[CH3:34].C(N(CC)CC)C.CCCC(C)C>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:28][C:29]3[C:30](=[O:43])[N:31]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[F:42])[N:32]([CH3:35])[C:33]=3[CH3:34])=[O:16])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.421 mmol), oxalyl chloride (0.041 ml, 0.463 mmol) and DMF (0.065 ml, 0.842 mmol) in dry DCM (5 ml) was added a solution of 4-amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (102 mg, 0.463 mmol) in dry DCM (1 ml), followed by triethylamine (0.176 ml, 1.262 mmol) and the mixture was stirred at RT for 1 hr. The resulting mixture was diluted with DCM and washed with 0.1 M HCl(aq) and sat. NaHCO3(aq). The organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure. The resulting solid was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a glassy solid, which was suspended in 1:1 iso-hexane:Et2O, heated at 50° C. for 2 h, stoppered and allowed to cool for 16 hrs. The solid was collected by filtration and dried on the vacuum line to give the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[C@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:21][C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: N[C@@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(N[C@@H]2CCCc3ccccc32)nc1N
Yield: 51.5 %

Procedure:
0.25 g (1.61 mmol) of 4-amino-2-chloropyrimidine-5-carbonitrile, 0.31 g (2.10 mmol) of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine and 0.67 g (4.85 mmol) of potassium carbonate in 3 ml of N,N-dimethylformamide are heated at 120° C. for 4 hours, the crude mixture is concentrated by evaporation under a high vacuum, the remaining crude mixture is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.22 g of 4-amino-2-[(1R)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidine-5-carbonitrile (m.p. 167.6° C.) is obtained (yield 48% at 95% purity).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]2[N:17]=[C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)[S:19][C:15]=2[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][NH:20][C:18]2[S:19][C:15]3[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:31]=[CH:30][C:16]=3[N:17]=2)=[CH:24][CH:25]=1
Reactant: O=C(NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc2nc(NCCc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
1-Benzoyl-3-{2-[2-(4-bromo-phenyl)-ethylamino]-benzothiazol-6-yl}-thiourea (Example 38, 71.1 mg, 0.139 mmol) was dissolved in tetrahydrofuran (3 mL). Aqueous NaOH (2M, 0.3 mL) was added and the mixture refluxed under argon for 44 hours. The mixture was cooled to room temperature and the solvent evaporated. Water (2 mL) and ethyl acetate (10 mL) were added and the layers separated. The aqueous phase was saturated with NaCl before extraction. An additional 10 mL of ethyl acetate was added and the layers separated. The combined extracts were dried over MgSO4, filtered and evaporated to give a yellow solid (51.3 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:24][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and tetrahydro-4H-pyran-4-ol. White solid. MS (m/e): 264.1 ([M+H—Me2C═CH2]+, 100%)
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:40]=1[N:48]=[C:49]=[O:50])([CH3:38])[CH3:37].[K+].[Br-]>C(OCC)(=O)C>[CH3:38][CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:46])[CH3:47])[C:40]=1[NH:48][C:49]([N:19]([CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50])[CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)C(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 72 h

Procedure:
A mixture of 0.50 g of the product of Example 7, 0.22 g 2,6-diisopropylphenylisocyanate and a few mL ethyl acetate was allowed to sit 3 days at room temperature. The solvent was removed and the residue chromatographed on SiO2 (70-230 mesh) using hexane/EtoAc, 1/1, as eluant. The product was obtained as a white solid. 0.33 g (46%). NMR (CDCl3) δ 0.88 (3H, t), δ 1.15 (12H, d), δ 1.21-1.26 (22H, m) δ 1.78 (2H, m), δ 2.02 (4H, m), δ 3.10 (2H, m), δ 3.47 (2H, t), δ 3.75 (6H, s), δ 3.80 (3H, s), δ 4.17 (2H, s), δ 5.35 (2H, t), δ 6.07 (1H, s), δ 6.14 (2H, s), δ 7.13-7.25 (3H, m), δ 7.72 (1H, s). IR (KBr) 3242, 2959, 2525, 1675, 1627, 1508, 1156, 1135 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([CH2:26][CH2:27][CH2:28][OH:29])[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NCCCO
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3CCCO)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminopropane-1-ol, the desired compound was obtained.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][CH2:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][CH2:22][CH:23]([OH:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(O)Cc1cccc(Cl)c1
Yield: 90.9 %

Procedure:
Sodium borohydride (2 mg, 0.053 mmol) followed by MeOH (0.1 mL) was added to a solution of (4-{(R)-2-[4-(3-chlorophenyl)-3-oxo-butyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester (5 mg, 0.012 mmol) in CH2Cl2 (0.3 mL) at 0° C. After 10 min at 0° C. the reaction was quenched with aqueous HCl (0.25 M, 3 mL). The reaction mixture was extracted with CH2Cl2 (3×4 mL), then the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2) afforded 4.6 mg (92%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH:6]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:20]([Si:17]([CH3:19])([CH3:18])[O:11][CH:9]1[CH2:8][CH:7]([N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)[CH2:10]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: OC1CC(n2cc(I)cn2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(n2cc(I)cn2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
A mixture of 3-(4-Iodo-pyrazol-1-yl)-cyclobutanol (Compound 100C, 75.00 mg, 0.2840 mmol), 4-dimethylaminopyridine (6.940 mg, 0.05680 mmol), 1H-imidazole (58.01 mg, 0.8521 mmol), tert-butyldimethylsilyl chloride (0.08562 g, 0.5680 mmol) and DCM (4 mL) were stirred at room temperature for 20 minutes. The material was transferred to a separatory funnel extracting with DCM washing with aqueous saturated NaHCO3. The organic layer was dry-loaded on silica for column chromatography eluting with 3% EtOAc in hexanes to afford 59 mg (55% yield) of the title compound as colorless oil. MS (ES+): m/z 378.94 (100) [MH+]; HPLC: tR=4.35 min (Polar—5 min, ZQ3).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH:13]1[OH:21].CCOCC>ClCCl>[CH2:12]1[CH:20]2[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][C:13]1=[O:21]
Reactant: OC1CC2CCCCC2C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CC2CCCCC2C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 33.6 g (155 mmol) of finely ground pyridinium chlorochromate, stirred in 300 mL of dry dichloromethane, was added 7.0 g (50 mmol) of (2 alpha and 2 beta)-octahydro-1H-inden-2-ol in 30 mL of dichloromethane. After stirring for 2 h at 20° C., 300 mL of ether was added, the organic solution decanted from the gummy precipitate and the latter extracted with 5×100 mL of ether. The combined organic solutions were filtered through 450 g of silica gel and the latter washed with ether. Concentration of the filtrates and distillation gave 5.5 g (80%) of (3a alpha, 7a alpha)-octahydro-2H-inden-2-one bp 110°-112° C. (18 mm); TLC Rf of 0.29 (SiO2, dichloromethane, molybdophosphoric acid-colorless on blue-green).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 70.9 %

Procedure:
A solution of 0.84 g (1.2 mmol) bis(triphenylphosphine)palladium(II)chloride, 9.58 g (40 mmol) methyl 6-chloro-4-(trifluoromethyl)nicotinate and 10.08 g (52 mmol) of 4-(trifluoromethyl)benzeneboronic acid in 200 ml degassed toluene was treated with 40 ml aqueous 2M K3PO4 and heated at 80° C. for 16 h. The reaction was cooled to RT and extracted with H2O (0° C.)/Et2O (3x). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash-chromatography on silica gel (dichloromethane/heptane 2:1 to 1:1) gave 9.91 g of the title compound as an off-white powder.