Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCSc2ccc(Cl)c(Cl)c2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichlorothiophenol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[O:21][N:20]=1)(=[O:12])=[O:11].Cl.[CH3:35][NH2:36]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:36][CH3:35])=[CH:32][CH:33]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: O=Cc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Reactant: CN
Agent: Cl
Product: CNCc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 13 from 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzaldehyde [see Preparation 22] and methylamine hydrochloride to afford N-[4-(3-[1l-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-N-methylamine as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH:16]1[CH3:15])=[O:14]
Reactant: CC1CCc2ccccc2N1
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: CC1CCc2ccccc2N1C(=O)CSc1nc2ccccc2s1
Yield: 40 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 2-methyl-1,2,3,4-tetrahydroquinoline to yield 40 as a pale yellow solid (0.32 g, 40%); MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.38; H, 5.22; N, 7.85; S, 17.93.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][OH:19]>>[CH3:18][O:19][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17]
Reactant: CO
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Product: COC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and methanol in an analogous manner to Example 1426a. Product isolated as a yellow oil (388 mg, 66%). LCMS (m/e) 253 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91-7.81 (m, 2H), 7.56-7.37 (m, 1H), 4.32-4.18 (m, 2H), 3.95-3.80 (m, 2H), 3.79 (s, 3H), 2.22-2.12 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (52%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40].[OH-].[NH4+:43].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:12][CH:13]([CH3:41])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][C:23]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=4)=[CH:22][C:21]=3[N:20]=[C:19]([NH2:43])[C:18]=2[N:17]=[C:16]1[CH2:38][CH2:39][CH3:40]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Reaction time: 16 h

Procedure:
Part B of the general methods described for Examples 35-40 was followed using 2.00 g of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol to provide 2.33 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid. Parts C and D of the general methods described for Examples 35-40 were replaced by the following procedure. mCPBA (0.853 g, 2.97 mmol) was added in one portion to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinoline (1.00 g, 2.47 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes Ammonium hydroxide (17 mL) was then added, followed by p-toluenesulfonyl chloride (0.710 g, 3.70 mmol). The reaction was stirred for 16 hours and then diluted with dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic solutions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown solid. The solid was recrystallized from acetonitrile to provide 0.680 g of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a reddish-brown, crystalline solid, mp 209-211° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[C:32]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OCc2ccccc2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2OCc2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
Piperidine (0.038 g, 0.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.129 g, 0.68 mmol) were added to a methylene chloride solution (10 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.095 g, 0.23 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.060 g, 0.12 mmol, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Product: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2,6-dichloro-4-iodobenzoic acid (65 mg, 0.21 mmol) in SOCl2 (3 mL) was heated to reflux under nitrogen atmosphere overnight and then cooled to room temperature. The reaction was conentrated under reduced pressure to afford 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 100% yield).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)(=O)=[O:25].C(O)C>C(Cl)Cl>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Solvent: CCO
Solvent: ClCCl
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
3.3 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 50 ml of methylene chloride, the solution cooled to -70° C., and a solution of 1.5 gm of sulfuryl chloride in 5 ml of methylene chloride was added dropwise. After 15 hours, 20 ml of 95% ethanol were added, and the mixture was heated to room temperature by removing the cooling bath, neutralized with an aqueous sodium carbonate solution. The methylene chloride phase was dried with sodium sulfate, and the solvent was evaporated. The residue was recrystallized from toluene.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][C:16]1[N:20]=[C:19]([CH3:21])[NH:18][N:17]=1>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:17]2[C:16]([CH3:15])=[N:20][C:19]([CH3:21])=[N:18]2)[N:3]=[N:4][CH:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Clc1cnnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(C)n(-c2cc(Cl)cnn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3,5-dichloropyridazine (23-1, 5.00 g, 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 ml) at 0° C. was added cesium carbonate (17.7 g, 50.3 mmol, 1.5 eq.), followed by 3,5-dimethyl-1H-1,2,4-triazole (3.25 g, 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 mL) dropwise. The resulting reaction mixture was stirred for 1 hour at the same temperature and then warmed to room temperature and stirred for another 3 hours, then heated to 60° C. and stirred for 6 hours. The solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and extracted with DCM (3×80 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (70% ethyl acetate in hexanes) to afford 5-chloro-3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazine (23-2) as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.11 (d, 1H, J=2.1 Hz), 8.20 (d, 1H, J=2.1 Hz), 2.96 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][CH:14]=O.C(OCC)(=O)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: O=CCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccc(Nc2nccs2)cc1
Temperature: 80 °C

Procedure:
1-(4-fluorophenyl)thiourea (2.00 g, 11.7 mmol) and 2-chloroacetaldehyde (3.72 mL, 58.6 mmol) in anhydrous ethanol (5 mL) were added to a microwave vial. The reaction mixture was heated to 80° C. in a microwave reactor for 20 min. On cooling, ethyl acetate (2 mL) was added to the crude product reaction mixture and pure product crystallized out. This filtered off, washed with hexane and air-dried to afford the title compound as a crystalline brown solid, 1.568 g. MS (M+H)+ 195.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyanobenzenesulfonyl chloride (0.51 g, 2.5 mmol) and piperidine (0.60 mL, 517 mg, 6.04 mmol) in 10 mL methylene chloride was stirred overnight at ambient temperature. The organic layer was washed successively with water, 5% HCl and brine, dried (Na2SO4) and concentrated. The resulting white solid (0.61 g, 96%) was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>O1CCCC1>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
To a solution of 3-aminopyridine (1.0 g, 11 mmol) and triethylamine (1.3 g, 13 mmol) in tetrahydrofuran (30 mL) was added at 0° C. trichloroacetyl chloride (1.4 mL, 13 mmol), and the mixture was stirred at 0° C. for 20 minutes. The reaction solution was concentrated, and ethyl acetate was added to the residue. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (2.3 g, yield 89%) as colorless powder.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[O:25][CH3:26])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2CCOCC2)cc1NC(N)=S
Reaction time: 1 h

Procedure:
To a solution of 1-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea (X) in methanol is added sodium methylate solution and stirring continued for about 1 h at room temperature. The product (XI) [2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea is isolated by conventional means.
Reaction SMILES: [CH2:1]([C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>C(O)C.C(O)=O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[N:15][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([CH2:1][C:2]2[CH:3]=[C:4]([CH3:10])[C:5]([N:6]=[CH:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[C:7]([CH3:9])[CH:8]=2)=[CH:17][C:16]=1[CH3:18]
Reactant: O=Cc1ccccn1
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Solvent: CCO
Solvent: O=CO
Product: Cc1cc(Cc2cc(C)c(N=Cc3ccccn3)c(C)c2)cc(C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a suspension of 2a (0.50 g, 1.97 mmol) in absolute ethanol (2 ml) was added 2-pyridinecarboxaldehyde (0.56 ml, 5.91 mmol, 3 eq.) and one drop of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 17 as a yellow solid (0.28 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:24]C)[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26].Br.[C:32](O)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:24])[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][O:21][C:32](=[O:34])[CH3:33])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26]
Reactant: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-3-(hydroxymethyl)-7-methoxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (50 mg, 0.11 mmol) and 33% hydrogen bromide in acetic acid (0.1 g) in acetic acid (1 μL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[Cl:11][CH2:12][C:13](Cl)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:11][CH2:12][C:13]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:4]=1
Reactant: NC(=NO)c1ccccn1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: ClCc1nc(-c2ccccn2)no1
Reaction time: 24 h

Procedure:
The title compound was prepared by a modification of a reported method: a) Mylari, B. L.; Beyer, T. A.; Scott, P. J.; Aldinger, C. E.; Dee, M. F.; Siegel, T. W.; Zembrowski, W. J. J. Med. Chem. 1992, 35, 457, and b) Palazzo, G.; Tavella, M.; Strani, G.; Silvestrini, B.; J. Med. Pharm. Chem. 1961, 4, 351. To a suspension of N′-hydroxypyridine-2-carboximidamide (25.0 g, 0.182 mol) in chloroform (350 mL) was added chloroacetyl chloride (20.5 g, 0.182 mol, 1 equiv) and triethylamine (20.23 g, 0.2 mol, 1.1 equiv). When most of the triethylamine had been added, the suspension turned to a clear light-yellow solution. The solution was allowed to stand at room temperature for 1 d. The mixture was extracted with water (3×75 mL), resulting in the precipitation of a crystalline solid. The resulting slurry was filtered, and filter cake triturated with ethanol, re-filtered, and dried, affording 29.62 g (73%) of the O-chloracetyl amidoxime intermediate. This intermediate was refluxed in xylenes (300 mL) for 3 h, and the volatiles removed completely in vacuo, affording 25.55 g (72% overall) of the pure 1,2,4-oxadiazole. 1H NMR (DMSO-d6) □ 5.20 (s, 2H), 7.62 (m, 1H), 8.06 (m, 2H), 8.76 (m, 1H). LC-MS (APCI) calcd for C8H6ClN3O: 195.02. found (M+H+): 196.0 m/z.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: Nc1cccc2nc3ccccc3nc12
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2nc3ccccc3nc12

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NCC1CC1
Product: CSc1nc(Cl)c(C=O)c(NCC2CC2)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and (aminomethyl)cyclopropane to give the title compound 4-chloro-6-(cyclopropylmethyl-amino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.32 (m, 2H), 0.59 (m, 2H), 1.12 (m, 1H), 2.55 (s, 3H), 3.46 (m, 2H), 9.35 (br s, 1H), 10.28 (s, 1H). LC MS (m/e)=258 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1.Br[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[N:13][CH:12]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccnnc2)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccnnc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridazin-4-yl)phenylboronic acid (100 mg, 0.46 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (117 mg, 0.46 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 5% methanol then trituration with diethyl ether gave 2-[3-(4-fluoro-3-(pyridazin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid: δH (400 MHz, CDCl3) 1.63 (6H, s), 7.11 (1H, d, J 7), 7.43-7.48 (1H, m), 7.64-7.69 (2H, m), 7.71-7.74 (1H, m), 7.88 (1H, s), 8.54 (1H, d, J 7), 9.33 (1H, dd, J 5 and 1), 9.46-9.47 (1H, m); m/z (ES+) 350 (M++H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH2:25])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:29](=[O:30])[N:12]2[C:13]([C:26]([OH:28])=[O:27])=[C:14]([CH2:17][S:18][C:19]3[S:20][C:21]([CH2:24][NH:25][S:32]([CH3:31])(=[O:34])=[O:33])=[N:22][N:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)s1
Yield: 31.8 %

Procedure:
7-(2-Thienyl)acetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.46 g.) was suspended in methylene chloride (100 ml.). To the suspension was added bis(trimethylsilyl)acetamido (4.06 g.) and the mixture was stirred to give a solution. To the solution was added methanesulfonyl chloride (1.15 g.) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was added to 5% hydrochloric acid at 0°-5° C. White precipitates in the solution were collected by filtration, dried and then recrystallized with aqueous acetone to give 7-(2-thienyl)acetamido-3-(5-mesylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (910 mg.). m.p. 139°-145° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)#[N:2].C([SH:10])C.[ClH:11]>>[ClH:11].[ClH:11].[NH:6]1[CH:7]=[C:3]([C:1](=[NH:2])[SH:10])[N:4]=[CH:5]1
Reactant: N#Cc1c[nH]cn1
Reactant: CCS
Agent: Cl
Product: N=C(S)c1c[nH]cn1
Reaction time: 0.33 h

Procedure:
To 900 mg. of 4-cyanoimidazole in 30 ml. of ethyl mercaptan cooled to 0° C. in a glass pressure bottle is added over 15 min. sufficient hydrogen chloride gas to saturate the solution. The sealed bottle is allowed to remain at room temperature for 20 min., and its contents then treated with 100 ml. of diethyl ether and filtered to give 1.7 g. of the product, m.p. 155°-158° C., dec.