Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([Mg]Br)=[CH2:13].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>C1COCC1.CCOC(C)=O>[C:16]([O:11][CH:10]([CH:12]=[CH2:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C=C[Mg]Br
Reactant: O=CCOCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(COCc1ccccc1)OC(C)=O
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Benzyloxyacetaldehyde 1 (220 g, 1.46 mol) in anhydrous THF (140 mL) was added drop wise to a stirred 1 M solution of vinyl magnesium bromide in THF (1.89 L) previously cooled to −5° C. When the addition was complete, the mixture was allowed to stir at −5° C. for an additional 30 minutes after which time TLC analysis showed a complete reaction. Acetic anhydride (222 mL, 240 g, 2.35 mol, 1.6 eq) was then added and the mixture allowed to slowly warm-up to room temperature overnight. Iced water (1 L) was then added to the reaction followed by EtOAc (700 mL) and the mixture stirred for 10 min. The layers were separated and the aqueous layer extracted with EtOAc (700 mL). The combined organics were washed with brine (700 mL), dried (MgSO4) and concentrated in vacuo to give the crude product as an orange oil. Purification through a silica pad afforded the acetate 2 as a yellow oil (309 g, 97%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.CN(C)C=O.[C:35]([O:38][CH2:39][C:40](Cl)=[O:41])(=[O:37])[CH3:36]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:40](=[O:41])[CH2:39][O:38][C:35](=[O:37])[CH3:36])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-aminothiazole (1 g), triethylamine (1.3 g) and N,N-dimethylformamide (10 ml) was added dropwise a solution of 2-acetoxyacetyl chloride (0.87 g) in methylene chloride (1 ml) in a stream of nitrogen gas with ice-cooling and stirring over a period of 20 minutes. After 3 hours, the reaction mixture was filtered and the residue on the filter paper was washed with N,N-dimethylformamide (10 ml). The filtrate and washings were combined and concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure and the residue was recrystallized from a mixture of water and ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-(2-acetoxyacetylamino)thiazole (0.23 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:10]=1[CH2:11][NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:41](Br)[CH:42]=[CH2:43].O>C1COCC1>[CH2:43]([N:12]([C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[CH2:11][C:10]1[CH:26]=[C:27]([Br:30])[CH:28]=[CH:29][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:42]=[CH2:41]
Reactant: CCCCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nn1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OCCCC)nn1
Reaction time: 2 h

Procedure:
To a mixture of butyl 6-[N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (CF3CO2H salt) (1.2 g) in THF (100 ml) under argon, was added potassium di-(trimethylsilyl)amide [7.0 ml of 0.67M solution in toluene] to give a yellow solution. To the solution was added allyl bromide (0.5 ml). The mixture was stirred for 2 hours, poured into water and extracted with diethyl ether. The organic solution was dried (MgSO4), evaporated and the residue purified by HPLC, eluting with dichloromethane, to give butyl 6-[N-allyl-N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (460 mg) as a gum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8](=[O:20])[N:9]2[C:13](=[C:14]([C:16](=[O:19])CC)[CH:15]=1)[CH2:12][CH2:11][CH2:10]2)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=[O:34].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:7]1[C:8](=[O:20])[N:9]2[C:13](=[C:14]([C:16]([OH:19])=[O:34])[CH:15]=1)[CH2:12][CH2:11][CH2:10]2
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2
Reactant: OB(O)c1ccccc1F
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2F)c(=O)n2c1CCC2
Temperature: 160 °C
Yield: 63.9 %

Procedure:
A mixture of 5-oxo-8-propionyl-1,2,3,5-tetrahydroindolizin-6-yl trifluoromethanesulfonate (0.10 g, 0.292 mmol), 2-fluorophenylboronic acid (0.050 g, 0.38 mmol), and 2M Na2CO3 (0.75 mL, 1.46 mmol) in toluene/EtOH (4 mL, 4:1) was heated at 160° C. for 30 min. in a Microwave Synthesizer. The mixture was cooled, and the layers were separated. The aqueous layer was acidified and the precipitate was filtered and air dried to afford the title compound (0.051 g, 64%). MS (m/z, M+1): 274.1.
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[CH:27]([N:23]1[C:22]([C:16]2[N:15]=[C:14]3[C:13]4[CH:30]=[CH:31][C:10]([O:9][C@@H:7]([CH3:8])[C:6]([NH2:41])=[O:5])=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:26][CH:25]=[N:24]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester (64 mg, 0.15 mmol) in DCM (10 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the crude carboxylic acid 512 dissolved in DMF (2 mL). HATU (130 mg, 0.34 mmol), ammonium chloride (27 mg, 0.51 mmol) and triethylamine (71 μL, 0.51 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in ethyl acetate) to yield 436 as a white solid (50 mg, 90%). LCMS: RT=3.07 min; [M+H]+=383, 1H NMR (400 MHz, d6-DMSO) 8.26 (1H, d, J=8.6 Hz), 7.81 (1H, s), 7.85 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.72 (1H, dd, J=8.6, 2.6 Hz), 6.49 (1H, d, J=2.6 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.62 (1H, q, J=6.6 Hz), 4.55-4.36 (4H, m), 1.47-1.36 (9H, m)
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].N[NH:9][C:10]([NH2:12])=[S:11].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:2]([C:1]1[S:11][C:10]([NH2:12])=[N:9][N:7]=1)[CH2:3][CH2:4][C:5]1[S:11][C:10]([NH2:12])=[N:9][N:6]=1
Reactant: N#CCCCC#N
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCCc2nnc(N)s2)s1
Temperature: 85 °C
Yield: 106.6 %

Procedure:
A mixture of glutaronitrile (5.00 g, 53.13 mmol) and thiosemicarbazide (9.68 g, 106.26 mmol) in TFA (50 mL) was heated at 85° C. for 4 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(propane-1,3-diyl)-bis(1,3,4-thiadiazol-2-amine) (1004, 13.72 g). 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.03 (s, 4H), 2.87 (t, J=7.5 Hz, 4H), 2.02-1.95 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:25]2[CH:24]=[N:23][C:22]([O:21][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=2)=[N:7][CH:6]=1
Reactant: CCCCCCCCCCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 34.4 %

Procedure:
A reaction of 35 mmol of 2,5-dibromopyrimidine, 27 mmol of 2-dodecyloxypyridine-5-boronic acid, 64 mmol of sodium carbonate and 0.3 mmol of tetrakis(triphenylphosphine)palladium(0) in 210 ml of toluene, 135 ml of ethanol and 70 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 3.9 g (35%) of a colorless solid.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>C(O)C>[C:19]1([C:17]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C(N)=S
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Yield: 75.4 %

Procedure:
To ethyl 2-amino-2-thioxoacetate (4 g, 30 mmol) in ethanol (50 mL) was added pyridine (0.24 g, 3 mmol). 2-Bromo-1-phenylethanone (5 g, 25 mmol) was added after 10 minutes and the mixture was then heated at reflux for 6 hours. The resulting mixture was washed with water and extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give a crude product, which was purified by column chromatography to afford the title compound as a white solid (4.4 g). MS (ESI) m/z 233 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH:24]([CH3:26])[N:23]([C:27](=[O:29])[CH3:28])[CH:22]([CH3:30])[CH2:21]4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.C(Cl)Cl.CCN(C(C)C)C(C)C.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1Cl.CN1[C:54](=[O:55])CCC1>>[C:27]([N:23]1[CH:24]([CH3:26])[CH2:25][N:20]([C:16]2[CH:15]=[C:14]([N:11]3[CH:12]=[N:13][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:54]([C:44]5[O:43][CH:47]=[CH:46][CH:45]=5)=[O:55])=[CH:3][CH:4]=4)=[N:10]3)[CH:19]=[CH:18][N:17]=2)[CH2:21][CH:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CN1CCCC1=O
Reactant: Clc1ccco1
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N)cc4)n3)ccn2)CC1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(NC(=O)c5ccco5)cc4)n3)ccn2)CC1C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a solution of 50 mg of 1-(4-{4-[3-(4-Amino-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone (0.123 mMol. 1.00 equiv) in 2 mL of NMP was added 5 mL of CH2Cl2 and 500 μL of Hunig's base followed by 100 μL of 2-furanyl chloride (1.01 mMol, 8.13 equiv). The reaction mixture was stirred for 1 hr and concentrated. The resulting oil was purified via flash chromatography (EtOAc) to yield 1.4 mg of Furan-2-carboxylic acid (4-{1-[2-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-phenyl)-amide (0.0028 mMol, 2.3% yield). 1H NMR (500 MHz, MeOD-d4) ∂ 8.95 (1H, s), 8.18 (1H, d), 7.72 (1H, m), 7.61 (4H, m), 7.25 (2H, m), 7.15 (1H, m), 6.61 (1H, s), 4.30 (2H, m), 3.30 (2H, m), 3.15 (2H, m), 2.20 (3H, s), 1.35 (6H, m) ppm. LC/MS: 2.2 min/501.3 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17]C(C#N)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:23]([C:22]([OH:25])=[O:24])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
To 4-phenyl-1-(4-cyanophenyl)piperidine (0.39 g) are added acetic acid (10 ml) and conc. hydrochloric acid (10 ml), and the mixture is refluxed for five hours. The reaction solution is concentrated, and to the residue is added diethyl ether/methanol. The insoluble crystals are collected by filtration, and dried under reduced pressure to give 4-phenyl-1-(4-carboxyphenyl)piperidine (0.39 g) as white powder.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[NH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:42][C:39]1[CH:38]=[CH:37][C:36]([N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][N:6]3[C:7]([CH3:12])=[C:8]([N+:9]([O-:11])=[O:10])[C:4]([C:3]([F:13])([F:14])[C:2]([F:1])([F:19])[C:15]([F:17])([F:18])[F:16])=[N:5]3)[CH2:35][CH2:34]2)=[CH:41][CH:40]=1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c([N+](=O)[O-])c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as oil. 1H NMR (400 MHz, CDCl3): 6.9-7.0 (m, 2H), 6.8-6.9 (m, 2H), 5.06-5.14 (d, 2H), 3.6-3.8 (m, 4H), 3.06-3.18 (m, 4H), 2.56-2.66 (d, 3H). 13C NMR (400 MHz, CDCl3): 160, 146.2, 144, 119.2, 118, 52.2, 50.8, 50.4, 46, 42.2, 12.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: CO
Solvent: O
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Temperature: 45 °C
Yield: 47.2 %

Procedure:
A solution of 1.17 g (4.88 mmol) of (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid.
Reaction SMILES: [Mg].C(OCC)C.[CH2:7](Br)[CH2:8][CH2:9][CH3:10].Br[C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][C:15]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:16]3)[CH2:14]1)[CH2:20]2>ClCCl.O>[CH2:7]([C:19]12[CH2:20][CH:13]3[CH2:22][CH:17]([CH2:16][C:15]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:14]3)[CH2:21]1)[CH2:18]2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC12CC3CC(CC(Br)(C3)C1)C2
Reactant: CCCCBr
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCCCC12CC3CC(C1)CC(CCCC)(C3)C2
Yield: 33 %

Procedure:
Into a 1 liter egg plant-shaped flask, 4.9 g (0.2 moles) of magnesium was weighed and placed. Under the stream of nitrogen gas, 80 ml of diethyl ether was added and stirred. Then, a solution prepared by dissolving 27.4 g (0.2 moles) of n-butyl bromide into 20 ml of diethyl ether was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 30 minutes. The temperature was adjusted at the room temperature, and diethyl ether was completely removed using a vacuum pump. Then, a solution prepared by dissolving 27.1 g (0.1 mole) of 1-bromo-3-(n-butyl)adamantane obtained in accordance with the process described above in 1-2) into 300 ml of dichloromethane was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 5 hours. The reaction fluid was poured into 200 ml of ion-exchanged water and treated by extraction with dichloromethane using a separation funnel. The solvent was removed using an evaporator. The residue was dissolved into 20 ml of hexane and purified in accordance with the silica gel column chromatography (the solvent of development: hexane). The solvent was removed using an evaporator, and 8.20 g of 1,3-di(n-butyl)adamantane of the object compound was obtained (the yield: 33%).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:26]1CCCC1>>[N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Reactant: CCCC(c1ccc(C#N)cc1)n1ccnc1
Product: CCCC(c1ccc(C(=O)c2ccccc2)cc1)n1ccnc1

Procedure:
The 4-[1-(1-imidazolyl)-butyl]-benzonitrile is reacted with phenylmagnesium bromide under standard conditions analogously to example 11 in tetrahydrofuran. 0.83 g of 4-[1-(1-imidazolyl)-butyl]-benzophenone with a boiling point of 175° C./0.03 mbar is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.P(Br)(Br)([Br:25])=O>BrCBr>[Br:25][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(O)c1cnc(Cl)nc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: BrCBr
Product: CC(C)C(Br)c1cnc(Cl)nc1Cl
Reaction time: 0.17 h

Procedure:
(±)-1-(2,4-Dichloro-pyrimidin-5-yl)-2-methyl-propan-1-ol (0.18 g; 0.83 mmol) (from Example 11a supra) was combined with N,N-diisopropyl-ethylamine (0.37 mL; 2.10 mmol) (Aldrich) and a small volume of dibromomethane (50 μL) (Aldrich) to help solubilize the mixture. Only a small amount of material remained insoluble. Neat phosphorus oxybromide (0.22 g; 0.85 mmol) (Aldrich) was added in one portion. Reaction mixture was stirred for 10 minutes and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M) gave (±)-5-(1-bromo-2-methyl-propyl)-2,4-dichloro-pyrimidine as a colorless oil. (Yield 79.5 mg; 33.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.O.Cl>C(O)CCC>[OH2:4].[ClH:1].[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: OC(CCC1NCCc2ccccc21)COc1ccccc1Cl

Procedure:
A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetrahydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120° C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3 N hydrochloric acid and extracted twice with 100 ml. isopropyl ether. The aqueous acidic solution was made basic and extracted with isopropyl ether and treated with ethereal hydrogen chloride. Recrystallization with isopropanol yielded 6 g. of the hydrochloride hydrate of the product which melted at 118°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[Br:14]Br.[C:16](N)([CH3:19])(C)C>>[Br:14][C:3]1[C:2]([OH:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:16][CH3:19])=[O:6]
Reactant: BrBr
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)(C)N
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1Br
Yield: 70.1 %

Procedure:
A 0.1 mole of the ethyl ester of 3-hydroxy-4-nitrobenzoic acid was monobrominated using the procedure described in Example 1, except only one equivalent of bromine and two equivalents of t-butyl amine were used. This reaction yielded ethyl 2-bromo-3-hydroxy-4-nitrobenzoate in 70.1% yield. It had a melting point of 58°-61° C.
Reaction SMILES: ClC[C:3]([O:5][C:6](=[O:9])[CH2:7][Cl:8])=[O:4].[CH2:10]=[O:11].[CH2:12]([Cl:14])Cl>S(=O)(=O)(O)O>[Cl:8][CH2:7][C:6]([O:5][CH2:3][O:4][C:10](=[O:11])[CH2:12][Cl:14])=[O:9]
Reactant: C=O
Reactant: O=C(CCl)OC(=O)CCl
Reactant: ClCCl
Agent: O=S(=O)(O)O
Product: O=C(CCl)OCOC(=O)CCl
Reaction time: 24 h
Yield: 57 %

Procedure:
Chloroacetic anhydride (12.75 g, 75 mmol), paraformaldehyde (2.25 g, 75 mmol) and conc. sulfuric acid (15 drops) are added to methylene chloride (15 ml). The mixture is stirred for 24 hrs. at 50° C. under nitrogen, whereafter the reaction mixture is extracted with saturated aqueous potassium carbonate until carbon dioxide emission ends. The organic layer is dried (MgSO4), evaporated to dryness and the residue is distilled (80° C., 0.15 mmHg) to yield 10.2 g (57%) product. 1H NMR (200 MHz, CDCl3): δ 4.1 (2×CH2Cl,s), 5.9 (CH2,s). 13C NMR (200 MHz, CDCl3): δ 41.1 (CH2Cl), 81.4 (O--CH2 --O), 166.4 (CO).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N:11]1[N:15]2[CH2:16][CH2:17][CH2:18][NH:19][C:14]2=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]([N:19]1[CH2:18][CH2:17][CH2:16][N:15]2[N:11]=[CH:12][CH:13]=[C:14]12)=[O:7]
Reactant: c1cc2n(n1)CCCN2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: O=CN1CCCn2nccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (0.153 ml) was added formic acid (0.077 ml) at 15°-20° C. The mixture was stirred at ambient temperature for 30 minutes. To this solution was added 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a mixture of dichloromethane and aqueous sodium bicarbonate solution. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give 4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (79.9 mg).