Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([NH2:37])[CH2:36][CH2:35]1.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:37][C:34]4([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=5)[CH2:36][CH2:35]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1(c2ccccn2)CC1
Reaction time: 2 h

Procedure:
Into a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl chloride in 10 mL of dichloromethane, 0.20 g of 1-(2-pyridyl)cyclopropylamine was dropped while stirring and ice-cooling the solution and after the completion of the dropping, the stirring was continued at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL×2). The organic phase was cleaned with water (10 mL×1) and then was dehydrated and dried with saturated brine and over anhydrous sodium sulfate, respectively, in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:1) to obtain 0.16 g of the objective substance as a yellow resin-state substance.
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]=2.[CH3:24][OH:25]>>[CH2:14]([O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:25][CH3:24])[N:4]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:9]([NH2:12])[N:8]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CO
Reactant: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na]
Product: CCCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 65 °C
Reaction time: 9 h

Procedure:
Sodium (3.7 g) was added to absolute methanol (400 ml) under a nitrogen atmosphere. To this solution was added the product from step (iii) (28.5 g) and the mixture was stirred at 65° C. for 9 hours. The mixture was concentrated in vacuo and 500 ml of water added. The aqueous phase was extracted with ethyl acetate, washed with brine and dried. The subtitle compound was obtained after crystallisation from diethyl ether. Yield 14.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[C:26]([Br:28])[S:27][C:21]=2[N:20]=[C:19]1[CH:29]([N:32]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (19 mg, 0.085 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8, 38 mg, 0.085 mmol, 1 equiv) and N,N-diisopropylethylamine (11 mg, 0.085 mmol, 1 equiv) in dichloromethane (5 mL), and the resulting reaction mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]bromo-N-[2-(dimethylamino)ethyl]benzamide (2-10) as a colorless foam. 1H NMR (500 MHz, CDCl3) δ 7.55 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.04 (d, J=15.4 Hz, 1H), 5.92 (m, 1H), 5.12 (d, J=15.4 Hz, 1H), 3.37 (m, 2H), 2.05 (m, 4 H), 1.83 (m, 6H), 0.65 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[CH:3]=2)[N:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: OB(O)c1cccnc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.392 g, 1.00 mmol) and commercially available 3-pyridineboronic acid (0.122 g, 0.99 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 27%). MS (ISP) 391.1 [(M+H)+]; mp 89-106° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C1COCC1>[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[CH2:1])=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1
Reactant: [Li]CCCC
Reactant: CN1CCCN(C2CCCc3cc(C=O)ccc32)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)CCCC2N1CCCN(C)CC1
Reaction time: 2 h

Procedure:
A dry flask under nitrogen was charged with 0.25 g (0.69 mmol) of methyltriphenyl phosphonium bromide and 2.1 ml of anhydrous THF. To this suspension at ambient temperature was added 0.30 ml (0.69 mmol) of a 2.3 M solution of n-butyllithium in hexane. This was followed by the addition of a solution of 0.18 g (0.67 mmol) of 1-methyl-4-(6-formyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine in 1.4 ml THF. After two hours, analysis by 1H-NMR of a worked-up aliquot revealed the presence of the desired product (vinyl proton resonances) as well as residual aldehyde (CHO resonance). A second portion of the triphenylphosphonium ylid (0.070 mmol) was generated in 4 ml THF and added to the mixture containing the residual aldehyde. After four hours, analysis by 1H-NMR of a worked-up aliquot indicated only a trace of aldehyde. The reaction mixture was concentrated invacuo to semisolid which was treated with water and extracted several times with ether. The combined ether extract was dried (MgSO4), filtered and concentrated invacuo to a semisolid, 0.34 g. This material was triturated with hexane, filtered and the hexane was removed invacuo. The resulting residue was again titurated with hexane, filtered and concentrated invacuo to give the title compound, 0.18 g, as a yellow oil; 1H-NMR(300 Hz, CDCl3) δ 5.17-5.20 (1H, d), 5.68-5.74 (1H, d), 6.62-6.71 (1H, q).
Reaction SMILES: [CH3:1][NH2:2].O.[Br:4][CH:5]([CH2:9][CH2:10][Br:11])[C:6](Br)=[O:7]>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:6](=[O:7])[CH:5]([Br:4])[CH2:9][CH2:10][Br:11]
Reactant: CN
Reactant: O=C(Br)C(Br)CCBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution mixture consisting of 40% aqueous methylamine solution (7.9 g, 0.10 mol, manufactured by JUNSEI CHEMICAL CO., LTD.) and water (3.3 g) was cooled to not more than 10° C. To the solution mixture, 2,4-dibromobutyric acid bromide (38 g, 0.12 mol) was added dropwise over a period of 15 minutes while keeping the temperature at not more than 10° C. After the completion of the dropwise addition, the mixture was heated to 30° C. and stirred for 30 minutes. The reaction liquid was combined with 50 g of chloroform, and the organic phase was extracted. The organic phase was separated and dried over magnesium sulfate, and the magnesium sulfate was filtered out. The organic phase obtained was concentrated to afford a crude crystal, which was then washed with a 1:1 solution of diethyl ether and hexane to give N-methyl-2,4-dibromobutyric acid amide (21.4 g, 0.083 mol, mp: 54° C., yield: 69%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[CH2:14]([NH2:16])[CH3:15].[NH4+].[OH-]>O>[CH2:14]([NH:16][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:15]
Reactant: CCN
Reactant: COC(=O)c1cccnc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1ncccc1C(=O)OC

Procedure:
To 10 g. (0.06 mole) of methyl 2-chloronicotinate in 50 ml. of methanol was added 6.0 g. (0.13 mole) of ethylamine in 25 ml. of methanol and this was placed into an autoclave and heated on a steam bath for 4 hours. Then the reaction solution was stripped, water added, made very basic via NH4OH, extracted into CHCl3, washed with water, dried and then stripped to dryness to yield 2-ethylaminonicotinic acid, methyl ester. An HCl-salt was prepared by adding the crude residue to ethyl acetate and then adding ethereal-HCl. The product precipitated out of solution and was collected on a filter and rinsed with petroleum ether to give 7 g. of product with a m.p. of 140°-5° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][NH2:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH2:25]([N:27]([CH2:34][CH3:35])[CH2:28][CH2:29][NH:30][CH:31]([CH3:33])[CH3:32])[CH3:26]>O1CCCC1>[CH2:34]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][N:30]([CH:31]([CH3:33])[CH3:32])[C:13]([NH:12][CH2:11][CH2:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])=[O:14])[CH3:35]
Reactant: NCCS(=O)(=O)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCNC(C)C
Solvent: C1CCOC1
Product: CCN(CC)CCN(C(=O)NCCS(=O)(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6.96 g (0.0376 mole) of 2-phenylsulfonylethanamine and 6.64 g (0.041 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 6.16 g (0.039 mole) of N-[2-(diethylamino)ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed for 13 hr. The solvent was removed in vacuo, and the residue was dissolved in a 50/50 mixture of ether and methylene chloride. The solution was extracted with water and was dried over magnesium sulfate. The solvent was removed in vacuo in give an oil. Flash chromatography on silica gel (methanol) gave 5.74 g (41.36%) of clear, colorless oil:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]#[N:15].[N:16]1([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]([C:14]#[N:15])=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: N#Cc1c(Cl)c2cc(Cl)cnc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Yield: 74 %

Procedure:
This compound was prepared from 4,6-dichloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (97) and piperazin-1-yl-thiophene-2-yl-methanone according to general procedure E to yield 6.8 g (74%) of 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) as yellow solids. MP 158° C.; 1H-NMR (DMSO-d6): δ 3.64 (m, 4H), 3.90 (m, 4H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.49 (dd, J=1.2, 3.6 Hz, 1H), 7.81 (dd, J=1.2, 5.2 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H); EIMS: 400 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:19]O>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)cc1
Reactant: OO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cnc3c[n+]([O-])ccc32)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
In 15 mL of acetic acid, 483 mg (2.01 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine prepared in Step A of Example 1 was dissolved, and 2 mL of a 30% hydrogen peroxide aqueous solution was added thereto and the mixture solution was stirred at 50° C. for 14 hours. The solvent was distilled under reduced pressure, and the obtained residue was separated by a silica gel column (Si-10, a product of Kusano Co., Ltd., column 30 cm, dichloromethane:methanol=9:1) to obtain 298 mg (57%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine 5-oxide as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:26]([NH:28][C:29]1[CH:30]=[N:31][C:32]([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)=[C:33]([CH3:35])[CH:34]=1)=[O:27].O>N1C=CC=CC=1>[C:1]([N:39]1[CH2:40][CH:41]=[C:36]([C:32]2[N:31]=[CH:30][C:29]([NH:28][C:26]([C:12]3[CH:13]=[N:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=4)[C:11]=3[CH3:10])=[O:27])=[CH:34][C:33]=2[CH3:35])[CH2:37][CH2:38]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Benzoyl chloride (75 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (221 mg) in pyridine (2.5 ml), and stirred at 40° C. for six hours. Water was added to the reaction solution, the precipitated solid was washed with ethanol and water to give the titled compound (218 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCS(N)(=O)=O
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(c1ccc(F)cc1)c1cncc(Br)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 52.8 %

Procedure:
A mixture of 5-bromo-pyridine-3-carbaldehyde (0.930 g, 5 mmol), ethanesulfonamide (0.682 g, 6.25 mmol) and titanium(IV) isopropoxide (2.93 ml, 10.00 mmol) in toluene (10 mL) was heated to 100° C. for 4 h. After concentration, the residue was dissolved in THF (12.5 ml), and (4-fluorophenyl)magnesium bromide (1 M in THF, 12.50 mL, 12.50 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 45 min. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via Biotage (10-40% AcOEt/heptane; SNAP25 column) giving the title compound (986 mg, 53%) as a beige solid. LC-MS (M+1) 375.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])O.[Na+].Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>C(O)(C)C>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: CN(C)CCCCl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
Prepared according to a slightly modified procedure from U.S. Pat. No. 3,331,845. A mixture of 4-nitrophenylpiperazine (2.1 g, 10 mmol), sodium hydrogen carbonate (2.5 g, 30 mmol), N,N-dimethyl-N-(3-chloropropyl)amine hydrochloride (1.9 g, 12 mmol) in isopropanol (80 mL) was heated at 80° C. for 18 h. The mixture was then allowed to cool, the solid filtered off and the solvent removed under reduced pressure. Ethyl acetate (ca. 200 mL) was added and the residue was washed with saturated brine twice (50 mL each time). The organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The crude compound was purified by column, eluting with dichloromethane/methanol 9/1 (containing 1% N,N-dimethylethylamine) to give the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz): 1.6 (2H, m); 2.15 (6H, s); 2.25 (2H, m); 2.35 (2H, m); 2.5-2.55 (4H, m); 3.35-3.4 (4H, m); 6.75 (2H, d, J 8 Hz); 8.05 (2H, d, J 8 Hz) MS: 293, 248.
Reaction SMILES: C[O:2][C:3]1[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([CH:13]=[CH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:20])[CH:4]=1.[OH-].[Na+].Cl>CO>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][C:12]1([CH:13]=[CH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:20])[CH2:4][C:3]1=[O:2]
Reactant: C=CC1(CCC(C)C)C(OC)=CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 60 °C
Reaction time: 96 h
Yield: 58.5 %

Procedure:
To a solution of Example 181C (42 mg, 0.16 mmol) in methanol (1 mL) was added a solution of 1 N NaOH (0.5 mL, 0.5 mmol). The reaction solution was stirred at 60° C. for 96 h. The solution was cooled to room temperature, acidified with 0.1 N HCl, and extracted with ethyl acetate (3×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (20%-40% ethyl acetate/hexane) afforded product as an off-white solid (24 mg, 60%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10]>>[C:13]([O:12][C:8]([NH:9][N:10]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NN
Product: CC(C)(C)OC(=O)NN=C1CCOCC1
Temperature: 67.5 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
Tetrahydro-4H-pyran-4-one (1.002 g, 10.01 mmol, CAS #29943-42-8, purchased from Fluka) was combined with tert-butyl carbazate (1.322 g, 10.00 mmol) in hexanes (10 mL). The mixture was heated in an oil bath at 65-70° C. for 75 minutes. A new precipitate began to precipitate out of solution before the carbazate completely went into solution. The mixture became very thick with the solid precipitate. Diluted with additional hexanes and heated another 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo. Isopropanol was added to the residue and the mixture was stirred vigorously for 5 minutes and then diluted with ether and chilled. The solid was collected by filtration and dried in vacuo to give N′-(tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester 1.326 g, 62%). A second crop (0.373 g, 17%) was collected from the mother liquor.
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:28]([OH:31])[CH2:29][Br:30])=[C:21]2[C:26]=1[NH:25][C:24](=[O:27])[CH:23]=[CH:22]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:28]([O:31][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:29][Br:30])=[C:21]2[C:26]=1[NH:25][C:24](=[O:27])[CH:23]=[CH:22]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of (R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one (10.1 g, 27.0 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred for 5 minutes and then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0° C. for 30 minutes, followed by RT overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (×3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Iso-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40:60) to afford the title compound (11.3 g, 85%).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([O:22]C)=O)[C@@H:13]([CH3:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.[NH2:25][NH2:26]>CO.C(OCC)(=O)C>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:20]([NH:25][NH2:26])=[O:22])[C@@H:13]([CH3:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: NN
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)COC(C)(C)C)[C@@H](C)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)COC(C)(C)C)C(=O)NN
Reaction time: 2 h

Procedure:
4.253 g (7.4 mmols) of DPC-Ser(tBu)-Thr(tBu)-OMe in 18 ml of methanol are mixed with 5.55 ml (about 110 mmols) of hydrazine hydrate and left to stand for 10 hours at room temperature and 2 hours at 40°C. The reaction solution is taken up in 450 ml of ethyl acetate and washed 4 times with half-saturated sodium chloride solution. The solution is dried over sodium sulphate, concentrated to about 15 ml, and mixed with about 5 ml of petroleum ether. Overnight 3.17 g of a hydrazide of melting point 132°-134°C crystallise out.
Reaction SMILES: I.CS[C:4](=[N:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:23][NH2:24]>C(O)C>[CH2:19]([NH:18][C:4]([NH:24][CH3:23])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CN
Reactant: CCCCN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Solvent: CCO
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC
Reaction time: 504 h

Procedure:
A mixture of 2-methyl-3-(n-butyl)-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (4.0 g) and 33% methylamine in absolute ethanol solution (200 ml) was heated initially for 24 hours at 45° and then left at room temperature for 21 days to yield 1-(n-butyl)-2-(2 -morpholinophenyl)-3-methylguanidine as an oil; a solution of which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether to give 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine monofumarate (m.p. 170°-172° C.).