Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:13]([N:15]1[C:19]([OH:20])=[CH:18][CH:17]=[N:16]1)[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C(OCC)(=O)C.C(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:19]2[N:15]([CH2:13][CH3:14])[N:16]=[CH:17][CH:18]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: CCn1nccc1O
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCn1nccc1Oc1cc(Br)cnc1C#N
Temperature: 25 °C
Yield: 53.3 %

Procedure:
5-Bromo-3-nitropicolinonitrile (24.0 g, 105 mmol), 1-ethyl-1H-pyrazol-5-ol (13.0 g, 116 mmol), and sodium carbonate (11.2 g, 105 mmol) were combined witb acetonitrile (400 ml). The mixture was heated to reflux for 20 hours. The mixture was then cooled to ambient temperature, filtered and evaporated. The residue was dissolved in ethyl acetate (800 ml) and washed with water (3×200 ml) and brine, dried (MgSO4), filtered and evaporated. The crude material was purified over silica gel (15:35:50, then 20:30:50 ethyl acetate/chloroform/hexane) to afford 5-bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.4 g, 53% yield) as a white solid.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:6]([OH:19])[CH:5]=1.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:6]([O:19][CH3:20])[CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
Methyl iodide (1.10 mL) was added to a suspension of (4-chloro-2-hydroxyphenyl)(4-fluorophenyl)methanone (3.00 g) and potassium carbonate (3.30 g) in N,N-dimethylformamide (50 mL) and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was filtered through Celite and the filtrate was poured into an aqueous saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=30/1) to give the titled compound (2.95 g) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br.[CH3:12][CH:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:14][CH2:15]Br.NC1C2C(=CC=CC=2Cl)NN=1.Br.BrCCCN(CC)CC>>[O:20]1[CH2:21][CH2:22][N:17]([CH:13]([CH3:12])[CH2:14][CH2:15][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH2:18][CH2:19]1
Reactant: CC(CCBr)N1CCOCC1
Reactant: Nc1n[nH]c2ccccc12
Agent: Br
Agent: CCN(CC)CCCBr
Agent: Nc1n[nH]c2cccc(Cl)c12
Product: CC(CCn1nc(N)c2ccccc21)N1CCOCC1
Yield: 48 %

Procedure:
The same procedures as described in Example 1 were repeated except that 4.50 g of 3-aminoindazole and 5.03 g of (1-methyl-3-bromopropyl)-morpholine hydrobromide were employed instead of the 5.66 g of 3-amino4-chloroindazole and the 4.83 g of 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 1-(3-morpholinobutyl)-3-aminoindazole having the following analytical values was obtained in a yield of 48 %.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=O)[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][OH:37]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:28])([F:30])[F:29])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10](/[C:32](=[N:36]\[OH:37])/[CH3:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(/C(C)=N\O)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (50 mg, 0.11 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol) in pyridine (1 mL) was stirred at rt overnight. The solution was concentrated and purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 488 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1)[CH3:10].C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:39]([C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)=[O:40])[C@H:22]([CH3:26])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc3nnn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a stirred solution of 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-benzo[d][1,2,3]triazole (0.075 g, 0.19 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.048 g, 0.22 mmol) in DMF (1.5 mL) was added HATU (0.090 g, 0.23 mmol) and iPr2NEt (0.064 mg, 0.48 mmol). The reaction mixture was stirred at room temperature for 30 min, and diluted with diethyl ether. The mixture was washed with deionized water, and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to afford the desired product (0.075 g, 0.13 mmol, 67%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:31][C:32]4[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=4)([CH3:30])[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@:18]([CH3:30])([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N:39]5[CH:43]=[N:42][CH:41]=[N:40]5)=[CH:34][CH:33]=4)[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: c1nc[nH]n1
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(I)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(-n4cncn4)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
An 8-mL vial was charged with 1-{[(R)-7-(3,5-dichloro-phenyl)-5-(4-iodo-benzyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (251 mg, 0.377 mmol), 1,2,4-triazole (39 mg, 0.57 mmol), and (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (16 mg, 0.11 mmol), K3PO4 (160 mg, 0.76 mmol), and 0.5 mL of DMF. The vial was purged with N2 and sealed with a screw cap. The green reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with 3 mL of EtOAc, and filtered through a small plug of Celite, washing with 20 mL of ethyl acetate. The filtrates were washed with 3×10 mL of water and 10 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (20 g, 0-3% MeOH/CH2Cl2) to provide 109 mg (48%) of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester as a pale orange foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][N:12]([CH:29]2[CH2:28][CH2:27][CH:26]([C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=4)[NH:22][CH:21]=3)[CH2:31][CH2:30]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCCNCC1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: COc1ccccc1N1CCCN(C2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Reaction time: 8 h
Yield: 80 %

Procedure:
1-(2-Methoxy-phenyl)-[1,4]diazepane (103 mg, 0.5 mmol), 4-(5-fluoro-1H-3-indolyl)-cyclohexanone (116 mg, 0.5 mmol) 5 mL 1,2-dichloroethane and 159 mg (0.75 mmol) of NaBH(OAc), were stirred at 23° C. in a 20 mL scintillation vial for 21 h. The reaction was quenched with 2 mL 1N NaOH, the vial capped, shaken and the organic layer (bottom layer) was removed with an automatic pipet. The organics were removed in a Speed Vac and pumped down overnight to afford 169 mg (0.4 mmol, an 80% yield) of the title compound as an off-white solid. MS (ES) m/z (relative intensity): 422 (M++H, 100).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[OH:9])=[O:2].[Br:15]N1C(=O)CCC1=O>>[Br:15][C:7]1[CH:6]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=[C:3]([CH:1]=[O:2])[C:8]=1[OH:9]
Reactant: COC(=O)Cc1ccc(O)c(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Yield: 80.1 %

Procedure:
Proceeding as in Reference 9, but substituting methyl 3-formyl-4-hydroxy-phenyl-acetate (50 g, 0.258 mol) and N-bromosuccinimide (45.92 g, 0.258 mole), gave methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (56.4 g, 80%) as a yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[CH:4][C:3]=1[N+:17]([O-])=O>CCO.[C].[Pd]>[NH2:17][C:3]1[CH:4]=[C:5]([CH:8]([NH:10][S:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(NS(=O)C(C)(C)C)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
A mixture of N-[1-(4-amino-3-nitrophenyl)ethyl]-2-methylpropane-2-sulfinamide (670 mg, 2.35 mmol) and 10% palladium-carbon (70 mg) in EtOH (50 ml) was stirred under hydrogen (4 atm) at room temperature for 6 hours. The mixture was filtered through a pad of Celite. The filtrate was concentrated to give 598 mg of the title compound as a brown solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (9H, s), 1.45 (3H, d, J=6.6 Hz), 3.50-3.32 (4H, m), 4.45-4.37 (1H, m), 6.71-6.65 (3H, m). A signal due to NH was not observed. MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: COc1ccc(CBr)cc1
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of crude (4-chloro-3-trifluoromethyl-phenyl)-methanol in DMF (anhydrous, 40 mL) at 0° C. is added NaH (600 mg, 15 mmol). After stirring for 30 min, 4-methoxy benzylbromide (2.21 g, 11 mmol) is added dropwise via syringe. After stirring at room temperature for 3 h, the reaction is quenched by pouring into a mixture of ice and saturated aqueous NH4Cl. The mixture is extracted with EtOAc (3×30 mL), and the combined organic layers are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the crude product is purified by silica gel chromatography (5% EtOAc in hexanes) to give 1-chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.BrC1C=C(C(OCC)=O)N(C2C(Cl)=CC=CN2)N=1>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: CCOC(=O)c1cc(Br)nn1C1NC=CC=C1Cl
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
The following Example 10 illustrates an alternative preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, which can be used to prepare, for example, ethyl 3-bromo-1-(3-chloro-2H-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. product of Example 9, Step B).
Reaction SMILES: [CH3:1][C:2]12[C:9](=NO)[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2.[OH2:12]>C(O)(=O)CCC(C)=O>[CH3:1][C:2]12[C:9](=[O:12])[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2
Reactant: CC12CCC=CC1CC2=NO
Reactant: O
Agent: CC(=O)CCC(=O)O
Product: CC12CCC=CC1CC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 120 mg of 6-methylbicyclo[4.2.0]oct-2-en-7-one oxime, prepared as shown in Preparation 19, in 4 ml of levulinic acid/1N hydrochloric acid (9/1) was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with hexane. The combined hexane extracts were washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Solvent was carefully removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 10% ethyl acetate in hexane, to give 6-methylbicyclo[4.2.0]oct-2-en-7-one, the compound of formula (8).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccco3)c2c1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part E) starting with 2 g (6.5 mmol) of 6-fluoro-1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole and 1.5 g (7.1 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography over silica gel, 0.9 g (30% of yield) of the expected acid were obtained.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]([CH:11]([CH2:17][CH:18]=[CH2:19])C(OCC)=O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCOCC>[CH:1]1([O:7][CH2:8][C:9](=[O:10])[CH2:11][CH2:17][CH:18]=[CH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCC(C(=O)COC1CCCCC1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C=CCCC(=O)COC1CCCCC1
Yield: 58.6 %

Procedure:
140 g of ethyl 2-(cyclohexyloxyacetyl)-4-pentenoate are heated under reflux in 650 g of 5% strength aqueous sodium hydroxide solution for 4 hours. 500 ml of ether are added to the reaction mixture. The organic phase is separated off and concentrated and the residue is distilled. About 60 g of 1-cyclohexyloxy-hex-5-en-2-one are obtained. (Temperature (bottom)=115°-155° C., temperature (top)=83° C.; 0.8 mbar).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23]Br>CS(C)=O.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 G, 5.2 mmol) in 30 mL of DMSO was added cesium carbonate (6.73 G, 20.6 mmol) and 2-chloroethylbromide (0.854 mL, 10.3 mmol). This reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with a large volume of EtOAc. The organic was washed with water ×1, saline ×1, then dried over Na2SO4 and conc. to give 1-(2-chloroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a solid.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[S:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[F:43][C:37]1[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=1[C:23]1[S:22][C:21]([CH2:20][CH2:19][OH:18])([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=1
Reactant: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Solvent: CC#N
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.070 g, 0.098 mmol) in 2 mL of anhydrous acetonitrile was added HF-TEA (0.160 mL, 0.99 mmol). The solution was stirred at room temperature for 16 hours then slowly quenched with saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) and the residue was dissolved in 2 mL of methanol and treated with 1N HCl/MeOH (2 mL). After stirring for 10 minutes, the solution was concentrated in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as a yellow powder, 0.023 g, 42%. MS ESI (+) m/z 473 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.44 (d, 2H, J=7.5 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 4.10 (m, 1H), 3.96 (m, 1H), 3.65 (m, 1H), 3.54 (q, 2H, J=30.2, 14.3 Hz), 2.83 (m, 1H), 2.72 (m, 2H), 2.57 (m, 2H), 2.48 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[S:18][C:6]2[NH:7][C:8](=[O:17])[N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]2[C:6]3[S:18][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=3[C:10](=[O:11])[N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:17])=[CH:26][CH:25]=1)#[N:34]
Reactant: CCc1cc2c(=O)n(CC(=O)OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(CC(=O)OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of methyl (6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)acetate (3.7 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (4.3 g), potassium carbonate (3.6 g) and acetonitrile (200 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give the title compound as a colorless solid (3.4 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]([O:14]C=O)[C:11]([NH2:13])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: COc1cccc(Cl)c1C(OC=O)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(Cl)c1C(O)C(N)=O

Procedure:
2-(2-Chloro-6-methoxyphenyl)-2-formoxyacetamide (10 g.) was dissolved in 50 ml. of ethyl acetate by brief warming. The resulting solution was equilibrated with 30 ml. of saturated sodium bicarbonate by stirring for 30 minutes. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered through a bed of diatomaceous earth and concentrated in vacuo to a foam. Trituration with hexane gave 2-(2-chloro-6-methoxyphenyl)-2-hydroxyacetamide [6.7 g., pnmr/CDCl3 /delta: 7.9 ppm peak gone, includes 2 doublets between 5.1 and 5.9 ppm (OH--CH splitting) which collapse to a singlet at 5.6 ppm (CH) on D2O exchange].
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 28.9 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-morpholin-4-yl-benzaldehyde (36.9 mg, 0.193 mmol) were reacted to produce 24 mg (29%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6): 12.83 (s, 1H), 8.00 (d, J=8 Hz, 2H), 7.86 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.16 (s, 1H), 7.06 (d, J=8 Hz, 2H), 6.77 (d, J=8 Hz, 1H), 6.38 (d, J=8 Hz, 1H), 6.33 (s, 2H), 3.88 (br s, 1H), 3.76 (s, 4H), 3.31 (s, 3H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 431 (M+H), HPLC: 1.99 min (G method).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]2[O:4][N:3]=[C:2]([CH2:1][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: Cc1cc2onc(C)c2cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2onc(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1C
Yield: 77.8 %

Procedure:
The procedure described in Example 1d was followed using 3,5,6-trimethyl-1,2-benzisoxazole (0.600 g, 3.73 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (1.30 g, 4.10 mmol), and 1M LDA (4.10 mL, 4.10 mmol) in dry THF (10 mL). After purification, the title compound (1.04 g, 78%) was obtained as a clear oil.