Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[ClH:28].[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:28].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:42])=[CH:40][CH:39]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CN(C)CCCOc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (4.22 g) and 4-(3-dimethylaminopropoxy)phenol hydrochloride, (2.3 g) in dimethylsulfoxide (100 ml) was stirred under nitrogen and warmed to 55° C. Then a solution of sodium hydroxide (0.8 g) in water (3 ml) was added and the reaction was stirred at 55°-65° for 2 hours. The usual work-up furnished the crude salt, which was crystallized from methanol-ethyl acetate to give 1.5 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy] -N,N-dimethylpropanamine trihydrochloride, mp 228°-230°.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[CH3:26][C@H:27]1[O:32][C@H:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.O>O1CCCC1>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][N:29]2[CH2:28][C@H:27]([CH3:26])[O:32][C@@H:31]([CH3:33])[CH2:30]2)[CH2:12]1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(CC(=O)[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)C[C@H](C)O1
Yield: 14 %

Procedure:
21-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (1 g.) was dissolved in dry tetrahydrofuran (50 ml.) and cis/trans-2,6-dimethylmorpholine (1 ml.) added to the solution. The mixture was refluxed for 4 hours. The mixture was poured into water, the emulsion extracted into ether, and the combined extracts washed with water, dried over anhydrous sodium sulphate and evaporated to a pale yellow foam (1.07 g.) which was purified by preparative T.L.C. in ethyl acetate. The faster running band (Rf ~0.6) gave 3α-hydroxy-21-(trans-2',6'-dimethylmorpholino)-5α-pregnane-11,20-dione (150 mg., 14%) as a white foam. [α]D + 70.5° (c 0.42).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[CH2:13]CCl.CO.S(=O)(=O)(O)O>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: ClCCCl
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(O)c(F)c1
Yield: 91.6 %

Procedure:
10.0 g (64.1 mM) of 3-fluoro-4-hydroxybenzoic acid, 150 ml of 1,2-dichloroethane, 80 ml of methanol and 10 ml of concentrated sulfuric acid were mixed, followed by refluxing for 5.5 hours under stirring and further stirring for 12 hours at room temperature. After the reaction, a solution of salt was added to the reaction mixture, followed by sufficient shaking to separate the reaction mixture. The organic layer was recovered from the reaction mixture and the water layer was subjected to extraction with methylene chloride to be added thereto. The resultant organic layer was washed with a 5%-aqueous solution of sodium hydrogencarbonate in a solution of salt and further washed with a solution of salt, followed by drying with anhydrous sodium sulfate. The sodium sulfate was recovered by filtration and the filtrate was condensed into a solid. Hexane was added to the solid and subjected to filtration to obtain 9.98 g of methyl 3-fluoro-4-hydroxybenzoate (Yield: 91.6%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].[OH:27][CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[OH:27][CH2:28][C:29]1([CH2:34][NH:35][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: N#CC1(CO)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(CO)CCCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (200 mg, 0.56 mmol), 1-hydroxymethyl-cyclopentanecarbonitrile (145 mg, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (117 mg, 0.61 mmol) and 1-hydroxybenzotriazole hydrate (83 mg, 0.61 mmol) were stirred in DCM (20 ml) for 66 h at room temperature. The reaction was poured into water (25 ml) and diluted with DCM (25 ml). The organic layer was isolated using a hydrophobic filter tube and the DCM removed under reduced pressure and purified by semi-preparative HPLC followed by purification on neutral alumina giving the title compound (75 mg, 28%) as a glassy solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].[C:14](Cl)(=O)[CH3:15].[Cl-].[NH4+]>C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Br:12][C:7]1[C:8]([F:11])=[C:9]2[O:10][C:14]([CH3:15])=[N:1][C:2]2=[C:3]([C:4]#[N:5])[C:6]=1[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
Diisopropylethylamine (22 ml, 0.126 mmol) was added to an ethyl acetate (400 ml) solution of 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (8.85 g, 36.1 mmol), cooled with ice, then acetyl chloride (3.85 ml, 54.2 mmol) was dropwise added, followed by stirring as such for 14 hours with gradually heating up to room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added, and the organic layer was collected. This was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was suspended in toluene (500 ml), a catalytic amount of p-toluenesulfonic acid was added, followed by heating under reflux for 3 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, the resulting residue was dissolved in ethyl acetate, washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, the precipitated crystal was washed with isopropyl ether, then collected by filtration to obtain the entitled compound (7.07 g, 73%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]([CH2:34][CH3:35])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1.[CH2:41]([NH2:45])[CH2:42][CH2:43][CH3:44]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:45][CH2:41][CH2:42][CH2:43][CH3:44])[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]([CH2:34][CH3:35])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1
Reactant: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Reactant: CCCCN
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Yield: 66 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of example 1 step (vii) (150 mg) and 1-butylamine (56 mg). The sub-title compound (77 mg) was obtained as a yellow oil; 1H NMR (CDCl3); 6.94 (1H, s), 6.86 (1H, d), 6.77 (1H, d), 4.84 (1H, t), 4.55 (2H, br s), 4.13 (2H, q), 3.88 (3H, s), 3.70 (2H, s), 3.64 (2H, s), 3.30-3.23 (4H, m), 2.66 (2H, q), 2.30 (3H, s), 1.43-1.34 (2H, m), 1.24 (3H, t), 1.19-1.12 (2H, m), 1.06 (3H, t), 0.83 (3H, t).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH2:6]1)=O.O1CCCC1.[BH4-].[Na+].CO>O>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]3=[O:10])=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: COC(=O)C1CC(=O)N(c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CO)CC4=O)cc3)CC2)c(C)c1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To 1-{4-[4-(2,4-dimethylphenyl)piperazine-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid methyl ester (1.3 g) described in Example 337 were added tetrahydrofuran (5 mL) and sodium borohydride (124 mg), methanol (0.9 mL) was added with heating under reflux, and the mixture was stirred for 1 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (1.06 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[CH:5][N:4]=1)#[N:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:14])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(O)nc1C#N
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1ncc(Cl)nc1C#N
Yield: 76.6 %

Procedure:
2,3-Dicyano-5-hydroxypyrazine (7.30 g; 0.05 mole) was dissolved in 70 g (0.59 mole) of thionyl chloride, and the solution was cooled to 0° to 5° C. With stirring, 4.80 g (0.06 mole) of pyridine was added dropwise over the period of 15 minutes. Then, the mixture was stirred at 70° C. for 2 hours. After the reaction, the excess of thionyl chloride was distilled off under reduced pressure, and the residue was extracted with 150 ml of chloroform. The chloroform solution was washed twice with 50 ml of water, and dried over anhydrous calcium chloride, and then the solvent was distilled off to afford a red solid. Recrystallization of the solid from benzene afforded 6.30 g (yield 77%) of 2,3-dicyano-5-chloropyrazine.
Reaction SMILES: ClC1N=C(Cl)N=C(Cl)N=1.[CH2:10]([O:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[CH:30]=[N:31]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:10]([O:17][C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]2=[N:20][C:19]=1[C:30]#[N:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc2nc(C=NO)c(OCc3ccccc3)c(=O)n2c1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(C#N)c(OCc3ccccc3)c(=O)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Trichloro-1,3,5-triazine (576 mg, 3.15 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (1 mL) and stirred at room temperature for 30 min. To this solution was added dropwise a solution of the product from Example 11.1 (927 mg, 3 mmol) in DMF (5 mL). The mixture was kept at room temperature for 2 h, then ethyl acetate (50 mL) was added and the organic phase separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by short flash chromatography afforded the desired compound (530 mg, 60.7%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCCC)=[N+:2]=[N-:3].[I:22]C1C=CC=CC=1C(Cl)=O.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[I:22])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1I
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Yield: 74 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-iodobenzoyl chloride (0.312 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-iodobenzamide (0.272 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1H), 7.33 (m, 2H), δ 7.08 (t, 1H), δ 6.51 (s, 1H), δ 3.54 (s, 2H), δ 3.53 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 169.9, 141.9, 140.0, 131.5, 128.4, 128.4, 92.7, 50.8, 39.6 ppm; HRMS (ESI) calcd for C9H9IN4O (M+) 315.9821. Found 315.9820.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cnn(C2CCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCC2)c1C(F)(F)F
Yield: 88.3 %

Procedure:
To a solution of 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (117 mg, 0.45 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (13 mg, 0.54 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (93 mg, 89%), which was used without further purification.
Reaction SMILES: O.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])O.[Na+].[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32](ON2C(=O)CCC2=O)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]>O1CCOCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1cccc(C=CC(=O)ON2C(=O)CCC2=O)c1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To water (80 mL)-dioxane (80 mL) solution of L-tryptophan (3.0 g) was added sodium hydrogencarbonate (1.3 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Next, dioxane (80 mL) solution of the compound obtained in Example 117 (4.2 g) was added to the mixture solution at 0° C., the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, thereafter the solution was made acidic with a 10% aqueous citric acid solution, and the crystals precipitated were filtered. The crystals were washed with water, to give the captioned compound (4.6 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[C:13](OCC)(=[O:16])[NH:14][NH2:15]>CCO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]3[C:13](=[O:16])[NH:14][N:15]=[C:9]32)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Clc1nccc2ccc(Br)cc12
Solvent: CCO
Product: O=c1[nH]nc2c3cc(Br)ccc3ccn12

Procedure:
7-Bromo-1-chloroisoquinoline (1-1) (79 mg, 0.327 mmol, 1.0 equiv) and Ethyl carbazate (34 mg, 0.33 mmol, 1.0 equiv) were suspended in EtOH (1.5 mL). The reaction mixture was irradiated in microwave at 170° C. for 40 minutes. The crude mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to yield 9-bromo[1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (1-2). LRMS m/z (M+H) 263.9 and 264.9 found, 264.1 and 265.1 required.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][S:7]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])(=[O:9])=[O:8].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C)C=O.O>[CH2:24]([N:10]([CH2:11][C:12]([NH2:14])=[O:13])[S:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=1)(=[O:9])=[O:8])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: NC(=O)CNS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(CC(N)=O)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.96 g of 3-trifluoromethylbenzylsulfonamidoacetamide was dissolved in 10 ml of dry dimethylformamide. To this ice-cooled solution was added 0.24 g of sodium hydride. The reaction mixture was stirred for 15 minutes at room temperature and then 0.95 ml of allyl bromide dissolved in 5 ml of dimethylformamide was added dropwise. Reaction was essentially instantaneous. After about 30 minutes, the reaction mixture was diluted with 150 ml of water and extracted twice with 75 ml portions of diethyl ether. Petroleum ether was added to the combined ether phases until cloudiness occurred, and this solution was washed with 100 ml of water. The organic phase was dried over magnesium sulfate and stripped to a white solid. Trituration with carbon tetrachloride afforded 2.8 g of the title compound, m.p. 91° to 92° C.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>CO>[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC
Reaction time: 4 h

Procedure:
Cyclopentylcarbonyl chloride (0.1 mole) is added to 0.1 mole of 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline in 300 ml. of methanol with vigorous stirring at room temperature. Stirring is continued for a period of 2 to 6 hours and the product is isolated according to the procedure of Example 127(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline. If the hydrochloride salt is desired, the base treatment is omitted and evaporation of the solvent provides 4-amino-2-[4-(cyclopentylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride, m.p. 279°-280° C. (dec.)(corr.) crystallized from methanol-isopropanol.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:9]1[S:13][C:12]([NH:14][N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][NH:2][C:3](=[O:4])[N:14]([C:12]1[S:13][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[N:10][N:11]=1)[N:15]=[CH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1nnc(NN=Cc2ccccc2)s1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)N(N=Cc1ccccc1)c1nnc(C(C)(C)C)s1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Methyl isocyanate (1.88 g) was added to a stirred suspension of benzaldehyde 5-t-butyl-1,3,4-thiadiazolyl hydrazone (7.8 g) in ethyl acetate (60 ml). Triethylamine (3 drops) was then added and the mixture was stirred for 2 hours. The solvent was evaporated to give a white solid, purified by chromatography. The pure fractions were combined and recrystallised from a mixture of ethyl acetate and hexane to give benzaldehyde 4-methyl-2-(5-t-butyl-1,3,4-thiadiazol-2-yl)semicarbazone (2.1 g, 22%) as a white powder, mp 115°-116° C.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[H][H]>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(C)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CCNC(=O)c1ccc(N)cc1

Procedure:
N-Isopentyl-4-nitrobenzamide (1 g, 4.23 mmol) and methanol (40 ml) were added to palladium on carbon (0.200 g, 1.879 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 6 hours with hydrogen at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:4]=2[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(N(C)C)=O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:12]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:14])[C:4]=2[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(Cc1cccc2[nH]c(=O)n(Cc3ccccc3)c12)NCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
2-(2-oxo-3-benzylbenzimidazolyl)acetic acid (1.77 mmol, 0.5 g) (example 2) in DMA (5 ml) is charged with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (2.66 mmol, 0.51 g). Benzylamine (2.48 mmol, 0.27 ml) is added to the suspension, and the mixture is stirred at room temperature for 17 hours. The solution is added dropwise into ice (50 g) and the colorless precipitate is filtered off and dried in vacuo. Recrystallisation from ethyl acetate yields the title product (47%) (R1=CH2—C(O)—NHR5, R5=benzyl, R2=benzyl, n=0).
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]12.CCN(CC)CC.[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50](Cl)=[O:51])[N:48]=1)=[O:42]>C(Cl)Cl>[Cl:39][CH2:40][C:41]([NH:43][C:44]1[S:45][CH:46]=[C:47](/[C:49](=[N:53]/[O:54][CH3:55])/[C:50]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[C:5]([C:14]([O:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:15])=[C:6]([CH:10]=[N:11][O:12][CH3:13])[C@@H:7]([CH3:9])[S:8][C@H:3]23)=[O:51])[N:48]=1)=[O:42]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@@H]1C
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2S[C@@H]1C
Yield: 81.7 %

Procedure:
To a solution of 656 mg of diphenylmethyl 7-amino-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 30 ml of CH2Cl2 were added, at -20° C., 0.2 ml of Et3N and 407 mg of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetylchloride, and the mixture was stirred at from -20° C. to -15° C. for 1.5 hours. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (15:1) were collected to distill off the solvent under reduced pressure, thus yielding 783 mg (75%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.