Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[CH3:25][N:26]([CH3:28])[NH2:27].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][N:26]([CH3:28])[NH:27][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C:4]2[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:6][O:7][C:3]=2[CH2:2][OH:1])=[N:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added N,N-dimethylhydrazine (18 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4), filtered and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (49 mg, 62%) as a white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCCCCCCCC(=O)O
Yield: 94.7 %

Procedure:
10-Bromodecanoic acid (2.51 g, 10 mmol) in acetone (50 mL) is treated with sodium azide (0.75 g, 11 mmol) at reflux for 2 h. The reaction is then concentrated in vacuo to a gum that is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give 10-azidodecanoic acid (2.02 g, 95%).
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nn2c(Cl)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nn2c(N)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
20 ml of a 50% solution of NH3 in MeOH were added to a solution of 1.20 g (3 mmol) of (3-benzenesulphonyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-dimethyl-amine in 30 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 6:1) yielded 0.90 g (78%) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 216-218°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O.CCOC(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])([O-:17])=[O:16]
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-trifluoromethoxybenzoic acid (49.0 g, 0.24 mol) in sulfuric acid (500 mL) at less than 0° C. (ice-MeOH bath) was added a solution of potassium nitrate (31.3 g, 0.31 mol) in sulfuric acid (200 mL) over 20 minutes. The resulting solution was stirred at 0° C. for 2 hours, then warmed to room temperature and stirred for 18 hours. The reaction was poured into ice and the resulting acidic solution was extracted with EtOAc (5×). The combined organics were washed with H2O (1×), brine (2×), H2O (1×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (65.7 g) as a solid contaminated with HOAc. The crude sub-title compound was dissolved in EtOAc and toluene and concentrated in vacuo to give a HOAc free solid (58.4 g, 97%) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][SH:24]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: SCc1ccccn1
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccccn3)c21
Yield: 64.8 %

Procedure:
The title compound (cis/trans=20/80) was prepared as a yellow oil in 64.8% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans-22/78) and 2-pyridylmethanethiol.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na].I[CH3:29]>CO.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Reaction time: 0.08 h
Yield: 28 %

Procedure:
Indazole (T) (1.68 g.) was added to a solution of sodium (0.108 g.) in methanol (1.0 ml.). After stirring for 5 minutes, iodomethane (0.32 ml.) was added and stirring continued for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (130 g.), eluting with 2:98 v/v ethyl acetate:dichloromethane to give methyl 4-[3-methoxy-6-nitroindazol-1-ylmethyl]-3-methoxybenzoate (U) (0.481 g., 28%) as a yellow solid, with satisfactory NMR spectral data.
Reaction SMILES: N[CH2:2][C:3]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1([C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]1)=[O:17])=[CH:10][CH:9]=2)(C)[CH3:4].C(=O)([O-])[O-].[K+].[K+].IC.O.[CH3:39][N:40]([CH:42]=O)[CH3:41]>>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:18]3([C:16]([NH:15][C:11]4[CH:12]=[C:13]5[C:8](=[CH:9][CH:10]=4)[NH:7][C:6]([C:3]([CH3:4])([CH3:2])[CH2:42][N:40]([CH3:39])[CH3:41])=[CH:14]5)=[O:17])[CH2:20][CH2:19]3)=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CN(C)C=O
Reactant: CC(C)(CN)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN(C)CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF (1 mL) was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 μL, 0.11 mmol). The mixture was stirred for 2 h. Water was added and the mixture was extracted with dichloromethane. Combined organic phases were dried over magnesium sulfate, evaporated, coevaporated with toluene (3×) and purified by silica gel chromatography (0-30% EtOAc in hexane) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (7 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 7.15 (s, 1H), 7.01-6.95 (m, 3H), 6.85 (d, J=7.9 Hz, 1H), 6.10 (d, J=0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s, 2H), 2.24 (s, 6H), 1.68 (dd, J=3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J=3.7, 6.8 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]4[CH:28]=[CH:29][O:30][C:26]=4[CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOC(C)=O>CO>[ClH:32].[ClH:32].[ClH:32].[O:30]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:27]=2[CH:28]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C

Procedure:
trans-{4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (2.9 g, 7 mmol) was treated with 1 N HCl in EtOAc (100 ml, 100 mmol) and MeOH (1.9 ml) and the resulting mixture was stirred over night at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white powder (2.9 g, 96%), MS (ISP) m/z=329.1 [(M+H)+].
Reaction SMILES: [C:1]([C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])#[N:2].N>[Ni]>[NH2:2][CH2:1][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10]
Reactant: CO[Si](CCC(C)(C)C#N)(OC)OC
Agent: [Ni]
Agent: N
Product: CO[Si](CCC(C)(C)CN)(OC)OC

Procedure:
In accordance with the procedure in Example 7, 3-cyano-3-methylbutyltrimethoxysilane (600 grams, 2.76 moles) was hydrogenated in the presence of 10.0 grams of ammonia and 8.0 grams of nickel (5%) on kieselguhr. The yield after distillation (boiling point, 68° C. at 0.25 mm Hg) was 590 grams of 4-amino-3,3-dimethylbutyltrimethoxysilane (96.6%). The material was characterized by infra-red, 1H and 13C NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:19])[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:18][CH2:17][C@H:16]([CH3:19])[CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:32])=[O:31]
Reactant: C[C@@H](CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (R)-(-)-3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol (7.26 g, 24.8 mmol), triethylamine (3 ml, 30 mmol) in methylene chloride (DCM, 120 ml), methanesulfonyl chloride (3.13 g, 27.3 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 1 hour., then concentrated down to a crude mixture. Triethylamine hydrochloride salt was removed by filtration with DCM/ether as solvent. The crude oily mixture was purified with a flash chromatography column (SiO2, 90 g; eluted with DCM). The colorless oil, which is the methanesulfonate ester, weighed 6.48 g (70%), and was used directly in the following step.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:19](O)(=O)[CH3:20]>N1CCCCC1>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:5]3[CH2:20][CH2:19][CH2:2][CH2:3][CH2:4]3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(CN2CCC(O)CC2)o1
Reactant: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Yield: 151.8 %

Procedure:
In 30 ml of piperidine was dissolved 7.4 g (29.25 mmol) of Compound s followed by addition of 2.7 g (45 mmol) of acetic acid, and the mixture was heated under reflux for 27 hours. After cooling, the excess piperidine was distilled off under reduced pressure and the residue was diluted with 300 ml of chloroform and washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel column chromatography (acetone) to give 6.49 g (76.0%) of 1-[5-(4-hydroxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound t) as light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.FC(F)(F)C1N=C[N:17]=C(O)C=1.N>C(#N)C>[NH2:17][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: Oc1cc(C(F)(F)F)ncn1
Agent: N
Solvent: CC#N
Product: Nc1cc(C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 98 %

Procedure:
To a stirred mixture of 4-chloro-6-trifluoromethylpyrimidine (prepared from 6-trifluoromethyl-4-pyrimidinol as described in U.S. Pat. No. 5,714,438) (17.14 g, 93.9 mmol) in acetonitrile (282 ml) was added 25% aqueous ammonia solution (564 ml) and the mixture was stirred at room temperature for 23 h. The mixture was extracted with ethyl acetate (3×1 l), and the combined extracts were dried (MgSO4) and evaporated in vacuo to leave 14.97 g (98%) of the title compound as a white solid: 1H NMR (360 MHz, DMSO-d6) δ 6.80 (1H, s), 7.52 (2H, br s), 8.49 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12
Reactant: Clc1nncc2c1CCCO2
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nncc3c2CCCO3)c(OC)c1
Temperature: 115 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of 5-chloro-3,4-dihydro-2H-pyrano[2,3-d]pyridazine (150 mg, 0.879 mmol), N,N-diisopropylethylamine (0.154 mL, 114 mg, 0.879 mmol), and 2,4-dimethoxybenzylamine (294 mg, 1.76 mmol) in isopropanol (2 mL) was heated in a sealed tube 18 hours at 115° C. and then 4.5 hours at 145° C. before addition of excess 2,4-dimethoxybenzylamine (about 2 g, 12 mmol). The reaction was stirred at 145° C. for 18 hours. After cooling to room temperature, isopropanol was removed in vacuo. The crude was then treated with diethyl ether (30 mL). A tan solid was removed by filtration. The filtrate was washed twice with small amounts of saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography with a 0 to 10% methanol/dichloromethane gradient to afford the title compound (159 mg) as an amber foamy oil. MS (ESI) [m/e, (M)+]=301.8. 1H NMR (400 MHz, chloroform-d) δ ppm 8.22 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.36-6.56 (m, 2H), 4.73 (d, J=5.56 Hz, 2H), 4.37-4.56 (m, 1H), 4.11-4.24 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.27-2.31 (m, 2H), 2.04-2.11 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[I:10][CH2:11][CH2:12][CH2:13][CH2:14]I>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:14][CH2:13][CH2:12][CH2:11][I:10])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: ICCCCI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1nc(=O)n(CCCCI)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a suspension of 4-amino-5-fluoropyrimidin-2-ol (0.50 g, 3.87 mmol) in acetonitrile (CH3CN; 20 mL) was added BSA (1.58 g, 7.75 mmol), and the mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 1,4-diiodobutane (1.2 g, 3.87 mmol) was added, and the mixture was stirred for 16 h at room temperature and then at 70° C. for 3 h. The solvent was evaporated and the residue was purified by normal phase chromatography (24 g SiO2; gradient, 0 to 15% MeOH/CH2Cl2) to give an orange oil. The oil was dissolved in EtOAc and the solution was slowly cooled. The resulting solid was collected by filtration, washed with additional EtOAc, and dried to give 4-amino-5-fluoro-1-(4-iodobutyl)-1H-pyrimidin-2-one (0.52 g, 43%) as a tan solid: mp 181-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.25 (d, J=6.7 Hz, 1H), 3.70 (t, J=6.7 Hz, 2H), 3.29 (t, J=6.7 Hz, 2H), 1.73 (m, 4H); ESIMS m/z 312 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:10]3[N:11]([CH:17]=[CH:18][N:19]=3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(OCC)(=O)C>[NH2:16][CH2:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2[N:11]([CH:17]=[CH:18][N:19]=2)[N:12]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(C#N)nn3ccnc23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccccc2)c2cc(CN)nn3ccnc23)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a 25 ml round bottom flask was added 8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-6-carbonitrile (0.62 g, 1.7 mmol) from (1a) and toluene (3.4 ml, 0.5 M) and the solution cooled to −5° C. To this was added dropwise, a 1.0 M solution of diisobutylaluminum hydride [DIBAL] in toluene (3.5 ml, 3.5 mmol) over a period of 10 minutes. The reaction was stirred at −5° C. for 1 hour and then warmed to room temperature and allowed to stir for an additional 2 hours. Dilute 1N HCl and ethyl acetate were added and the layers separated. The acidic aqueous layer was extracted 1 additional time with ethyl acetate and then basified with a 50% NaOH solution. The aqueous layer was extracted 2× with ethyl acetate and the combined organics were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo to provide crude 6-(aminomethyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.44 g) which was used as such in the subsequent step. m/z=(360, M+1).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Yield: 80.3 %

Procedure:
To a solution of the Grignard reagent prepared from Magnesium turnings (2.33 g, 96 mmol) and 4-benzyloxybromobenzene (25 g, 95 mmol) in THF (150 ml), 1,4-Cyclohexanedione monoethylene ketal (10 g, 64 mmol) in THF (150 ml) was added. After completeion of the reaction, the solution was added to 200 ml of aq. NH4Cl and extracted with CH2Cl2. Drying and evaporation of the organic layer gave a residue which was crystallised from AcOEt-hexane to give 8-(4-benzyloxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (17.5 g, 54%, MS: m/e=340 (M+)).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH:11]O>C(O)(=O)C>[CH3:9][C:4]1[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:11])[CH:5]=1
Reactant: OO
Reactant: Cc1ccc(C)c(O)c1C
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
600 mg of the catalyst prepared in Example 6 and 10 g of 2,3,6-trimethylphenol were added to 90 ml of acetic acid. While cooling the solution with ice water, 20 g of a 30% hydrogen peroxide aqueous solution was dropwise added in about 40 minutes, and the mixture was stirred overnight. After completion of the reaction, the catalyst was removed by filtration, and the acetic acid solution was concentrated under reduced pressure to about 20 ml, diluted with ether, washed with an aqueous solution of NaHCO3 and then dried. The ether was distilled off, and the residue was subjected to distillation under reduced pressure, whereby 8.7 g of trimethylbenzoquinone (boiling point: 64° C./0.7 torr) was obtained. Further, the distillation residue was treated by column chromatography (SiO2 /CH2Cl2), whereby 0.5 g of trimethylbenzoquinone was additionally obtained. The total amount was 9.2 g (84% yield).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH2:6][CH2:5]1
Reactant: Clc1ncccn1
Reactant: c1ccn(CCCCN2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccc3)CC2)nc1

Procedure:
A mixture of 4.14 g (20 mmol) of 1-[4-(piperazinyl)-butyl)pyrrole, 2.29 g (20 mmol) of 2-chloropyrimidine and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide is refluxed for 5 hours. The reaction mixture is evaporated under vacuum, chloroform is added and the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 3.3 of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}pyrrole are obtained in the form of a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1C(=O)N([Cl:21])C(=O)C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH2:13][Cl:21])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(Cl)c(Cl)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Product: ClCc1ccc2cc(Cl)c(Cl)cc2n1

Procedure:
MS (ESI) 246 (M+H)+. Prepared from 6,7-dichloro-quinaldine and NCS in place of NBS.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:3].[NH:12]1C=CN=[CH:13]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:1]=[CH:13][N:12]=[CH:3]1
Reactant: c1c[nH]cn1
Reactant: CN(C)Cc1ncccc1O
Solvent: Cc1ccccc1C
Product: Oc1cccnc1Cn1ccnc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution consisting of 2-dimethylaminomethyl-3-hydroxypyridine (30.4 g.) and imidazole (13.6 g.) dissolved in xylene (100 ml.) was heated under reflux for a period of five hours and then allowed to cool to room temperature (~25° C.). The resulting precipitated oil was then scratched so as to induce crystallization and the solid product so obtained was thereafter crystallized from isopropanol/petroleum ether (b.p. 60°-80° C.) to afford pure 2-(imidazol-1-ylmethyl)-3-hydroxypyridine (yield, 24.9 g.), m.p. 154°-155° C.