Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH:26]([CH3:34])[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH3:34])[CH2:29][CH2:30]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1c(C(C)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-(2-{4-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (58 mg, 0.31 mmol, 1.2 mmol) and 4-methyl-5-(1-methyl-2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]#[N:26])=[CH:23][C:22]([CH3:27])=[N:21]2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:26][CH2:25][C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([CH3:27])[CH:23]=1)=[S:11]
Reactant: COc1ccc(-n2nc(C)cc2C#N)cc1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: COc1ccc(-n2nc(C)cc2CNC(=S)Nc2cccc(Cl)c2Cl)cc1
Yield: 76 %

Procedure:
Prepared in 76% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 204A according to the procedure described for Example 153B. MS (ESI+) m/z 421.1 (M+H)+; 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 3.81 (s, 3H), 4.65 (s, 2H), 6.25 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.34 (dd, J=8.1, 8.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.46-7.50 (m, 1H), 7.71 (d, J=7.5 Hz, 1H), 8.43 (br s, 1H), 9.41 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CN(C=O)C.P(Cl)(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Yield: 95.9 %

Procedure:
3-Bromo-2-hydroxy-5-nitropyridine (8.5 g, 39 mmol) and N,N′-dimethylformamide (0.5 ml) in chloroform (75 ml) were treated dropwise with phosphorous oxychloride (7.3 ml, 80.2 mmol) and heated at reflux for 24 hrs. The mixture was then cooled and concentrated, before being partitioned between ethyl acetate (80 ml) and sodium hydrogen carbonate solution (50 ml). The organic phase was washed with brine (100 ml), dried Na2SO4) and concentrated to give the product as a yellow solid (8.88 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:28](Br)[CH:29]=[CH2:30]>C1COCC1>[CH2:30]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)[CH:29]=[CH2:28]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a −78° C. solution of N-Boc-4-piperidinecarboxylic acid methyl ester (5.70 g, 23.4 mmol) in THF (80 mL) was added potassium hexamethyldisilazide (0.5 M in toluene, 70.2 mL, 35.1 mmol). After 2 h allyl bromide (6.69 mL, 77.3 mmol) was added, the reaction stirred at this temperature for 0.5 h, then warmed to 0° C. After 3 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 8% methanol:dichloromethane to give the title compound (6.0 g). MS: m/z=284.2 (M+1).
Reaction SMILES: [OH-].[Na+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13]>O.CO>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])/[CH:11]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
To an ice-cooled solution of sodium hydroxide (2.34 g, 58.6 mmol) in water (17.0 mL) was added benzaldehyde (0.746 g, 7.03 mmol) and then a solution of 5-chloro-2-hydroxyacetophenone (1.00 g, 5.86 mmol) in methanol (17.0 mL). The reaction mixture was allowed to warm to room temperature, and it was stirred for 24 hours. The bulk of the organic solvent was removed by evaporation in vacuo. The aqueous residue was extracted with EtOAc (3×30 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated to dryness in vacuo. The residue was dissolved in a minimum volume of CH2Cl2, and n-pentane was added which resulted in precipitation. The obtained suspension was filtered and the precipitate was washed with little cold pentane, and dried in vacuo to afford Compound (XVI) (695 mg, 46%) as an orange solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:11]1([C:14]2[O:15][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=2)[CH2:13][CH2:12]1
Reactant: NC(=O)C1CC1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1coc(C2CC2)n1
Temperature: 120 °C
Yield: 50 %

Procedure:
Ethyl 4-chloroacetoacetate (20.0 g, 122.0 mmol) was added to cyclopropanecarboxamide (3.52 g, 41.5 mmol) in toluene (100 mL) and 1,4-dioxane (100 mL). The mixture was refluxed at 120° C. for 17 hours then evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 petroleum ether: EtOAc) to afford the title compound as a white solid in 50% yield, 4.00 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Si:20]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10.0 g (49.7 mmol) of tert-butyl 4-hydroxypiperidine-1-carboxylate and 4.06 g (59.7 mmol) of imidazole were initially charged in 100 ml of anhydrous DMF, and 15.02 g (54.7 mmol) of tert-butyl(diphenyl)silyl chloride were added at 0° C. After the reaction mixture had been stirred at RT for 48 h, it was poured into 1.6 liters of water and then extracted three times with approx. 500 ml each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was roughly purified by means of suction filtration (approx. 300 g of silica gel, eluent: cyclohexane→2:1 cyclohexane/ethyl acetate). 22.21 g (91% of theory, approx. 90% purity) of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14](Cl)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(C)=O>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Reactant: NCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(C)c2nc3ccccc3c(NCc3ccccc3)c12
Temperature: 85 °C

Procedure:
A mixture of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b] quinoline (1.2 g, 0.005 mol), benzylamine (1.2 ml) and DMSO (3 ml) was heated at 80-90° C. for 3-4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×50 ml) and then the CH2Cl2 layers were combined and evaporated. The residue was purified by column chromatography on silca gel eluting with ethyl acetate to afford the product which was crystallized from ether/hexane to afford 1.2 g of 1,3-dimethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 105° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[CH:6][CH:5]=1.O[NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[NH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:34]1([C:32]2[N:33]=[C:26]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]4)=[O:17])[CH2:13]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: N=C(NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
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: CN(C)C=O
Product: O=C(N1CCS(=O)(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.23 mmol) of the compound from Example 37A and 46 mg (0.46 mmol) of N-hydroxycyclopropanecarboximidamide were initially charged in 0.8 ml of DMF and reacted with 132 mg (0.35 mmol) of HATU and 0.12 ml (90 mg, 0.69 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 46 mg (37% of theory)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[O:40]1[CH2:41][CH2:42][CH:37]([NH:36][C:29](=[O:30])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38][CH2:39]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: NC1CCOCC1
Agent: Cl
Product: CC(C(=O)NC1CCOCC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 4-aminotetrahydropyran hydrochloride (Combi-Blocks and Cat. No. AM-1014). LCMS (M+H)+: m/z=557.3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][CH2:14]O)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18][CH2:14][CH2:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: OCCCOc1cccc2cccnc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCOc1cccc2cccnc12
Temperature: 25 °C

Procedure:
A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thionyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4 A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chloroform and extracted with the potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, the hexane layer was filtered off. The solid was dried in vacuo at room temperature overnight to give 26.69 g (76.2%) of white cyrstalline solid, m.p. 69°-71° C.
Reaction SMILES: [Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+].O=C1C[CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31]C1.O>C1COCC1>[CH2:22]=[C:23]1[CH2:26][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:24]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of THF, and potassium tert-butoxide (16.8 g, 0.15 mol) was added at −20° C. Reacted for 0.5 h after the temperature was raised to 0° C. Subsequently, ethyl 4-oxo-cyclohexylcarboxylate (Compound 8-1) (17 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise to the flask under nitrogen, reacted at room temperature for 3 hours, then a small amount of water was added to dissolve the solid, and rotary evaporated to remove THF, extracted with anhydrous diethyl ether, dried, and concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 8-2 as a colorless liquid (16.1 g, 95.7% yield).
Reaction SMILES: [C:1]([NH:5][NH:6]C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[C:20](=[O:21])[NH:19][C:17]([C:16]2[CH:22]=[C:23]([CH:24]=[CH:25][C:15]=2[Cl:14])[CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Yield: 22.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-tert-butylhydrazinecarboxylate (Intermediate-74, 0.233 g, 1.2 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.400 g, 1.2 mmol), DCM (10 mL), trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.52 (s, 9H), 4.42 (s, 2H), 7.39 (d, 1H), 7.41 (s, 1H), 7.58 (d, J=2.1 Hz, 2H), 10.0 (br s, 1H), 12.0 (br s, 1H); MS (m/z): 377.20 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[C:13]1([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[CH:27]=[CH:31][CH:30]=[CH:29]3)[CH2:7][CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC1CCC(OC)O1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCCn3cccc3)CC2)cc1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
Under reflux, for 20 minutes is heated a solution of 1.28 g (3.96 mmoles) of 1-(4-aminobutyl)-4-diphenylmethylpiperazine and 0.77 g (5.8 mmoles) of 2.5-dimethoxytetrahydrofurane in 25 ml of acetic acid. It is cooled, it is poured over ice water, neutralized with NaCHO3 and extracted with chloroform. It is dried with Na2SO4, and evaporated under vacuum to dryness. 1.7 g of crude oil is obtained which is purified on a silica chromatographic column (eluant: ethyl acetate). 0.95 g of 1-[4-(4-Diphenylmethyl-1-piperazinyl)butyl]pyrrole is obtained in solid form, with a melting point 80°-84° C.
Reaction SMILES: Cl.[CH3:2][CH:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1.C(#N)CC.CCN(C(C)C)C(C)C>>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][C@H:5]2[CH:3]([CH3:4])[CH3:2])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=1
Reactant: CC(C)[C@@H]1COCCN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNc1nc(Cl)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 110 °C
Yield: 44.3 %

Procedure:
(3R)-3-(1-Methylethyl)morpholine hydrochloride salt (3.0 g, 18.11 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (3.22 g, 18.11 mmol, 1 equiv) were charged into a 60 mL sealable tube, followed with addition of propionitrile (25 mL) and Hunig's base (9.49 mL, 54.3 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 96 hours. The mixture was concentrated in vacuo. The residue was partitioned between cold 2N HCl (100 mL) and EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The acidic aqueous phase was basified with 6N NaOH to pH=10, followed by extraction with EtOAc (2×100 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark brownish oil. Both samples were purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3. The combined fractions were concentrated in vacuo. The residue was dried under vacuum at room temperature for 7 hours to give the title compound (2.17 g). LC-MS (ES) m/z=271 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[C:4]([CH:15]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>CN(C=O)C>[NH:17]1[CH2:16][CH:15]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:7]=[C:2]([NH:32][C:29]3[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=3)[CH:3]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(-c3ccccc3Cl)n2)C1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C3CNC3)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 12.7 %

Procedure:
A mixture of tert-butyl 3-(6-chloro-2-(2-chlorophenyl)pyrimidin-4-yl)azetidine-1-carboxylate (280 mg, 0.74 mmol), 5-methyl-1H-pyrazol-3-amine (86 mg, 0.88 mmol), DIPEA (124 mg, 0.96 mmol) and sodium iodide (122 mg, 0.81 mmol) in DMF (5 mL) was heated at 120° C. overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and brine. After a further extraction with EtOAc, the combined organics were dried (MgSO4), filtered and concentrated. Purification was achieved by column chromatography (eluting with petroleum ether/ethyl acetate, 1/1). The residue was dissolved in TFA (1 mL) and DCM (3 mL) and stirred for 45 min and then concentrated. Purification by Gilson preparatory HPLC gave the azetidine as a white solid (32 mg, 13%). MS (ES+) m/e=341. 1H NMR: (DMSO) 2.23 (3H, s), 4.05-4.28 (5H, m), 6.25 (1H, s), 7.11 (1H, s), 7.43-7.65 (3H, m), 7.78 (1H, d), 8.97 (1H, s), 9.61 (1H, s), 10.47 (1H, s).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]([CH3:13])([CH3:12])[CH:9]1[O:11][CH2:10]1>CO.O>[N:1]([CH2:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[CH3:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(O)CN=[N+]=[N-]
Temperature: 0 °C
Yield: 93.8 %

Procedure:
Sodium azide (10 g, 154 mmol) and ammonium chloride (3.7 g, 070 mmol) are added to a solution of 3,3-dimethyl-1,2-epoxybutane (4.26 ml, 35 mmol) in methanol:water (8:1, 315 ml), and the mixture is heated at reflux for 7 hours. The reaction is poured into ice/water (400 ml) and extracted with dichloromethane (3×200 ml). The combined organics are dried (MgSO4), filtered and evaporated to yield a clear oil (4.7 g, 94 %).
Reaction SMILES: [C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])O1)=[O:2].[NH3:15]>C(O)C>[C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[NH:15]1)=[O:2]
Reactant: N
Reactant: O=C(O)c1cc2ccccc2c(=O)o1
Solvent: CCO
Product: O=C(O)c1cc2ccccc2c(=O)[nH]1
Reaction time: 24 h

Procedure:
Isocoumarin-3-carboxylic acid (1.40g.) was added to a solution of ammonia (d. 0.88, 10ml.) in ethanol (40ml.) at 0° and allowed to stand for 24 hours. After removal of solvent in vacuo, 6N hydrochloric acid (70ml.) was added and allowed to stand for 1 hour at 0°. Filtration gave the product as a white solid, mp. 327°-330° (lit mp. 326°-8°), (Found: C, 62.91; H, 3.69; N, 7.46. C10H7NO3 requires C, 63.49; H, 3.73; N, 7.40).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].CCCCCC.Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:20][CH2:21][OH:22])[N:3]=1
Reactant: OCCBr
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 3,5-dibromo-4-nitropyrazole (2) (11.0 g, 41 mmol) in DMF (52 ml) was added dropwise over 20 min to a stirred solution of NaH (1.76 g, 46 mmol; 60% dispersion in oil, prewashed with hexane under an inert atmosphere) in DMF (88 ml). After stirring for 10 minutes, a solution of 2-bromoethanol (6.4 g, 49 mmol) in DMF (14 ml) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 2 hours and then the DMF was evaporated off under reduced pressure. A mixture of DCM/water (100 ml, 1/1) is added to the residue and the organic phase is washed with water (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude brown solid obtained was subsequently purified by column chromatography (5%/95% EtOAc/hexane). The yellow solid product (3.4 g) was recrystallized from a mixture of toluene/hexane (20 ml, 55%/45%) to give the 2-(3,5-dibromo-4-nitropyrazol-1-yl)ethanol (3) in the form of a white solid (2.8 g, 22%).