Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[C:7]2[CH:25]=[CH:24][N:23](CO)[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:17]=2)[N:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[C:7]2[CH:25]=[CH:24][NH:23][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:17]=2)[N:11]=1
Reactant: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3ccn(CO)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3cc[nH]c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(3-aminophenoxy)-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methanol in MeOH (10 mL) and water (2 mL) was added K2CO3 until the pH of the reaction mixture was about 12. The reaction mixture was then stirred at rt for 2 hrs. Water was added and extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a dark oil to give the title compound as a dark oil that was taken on to the next step with no purification. m/z (ESI+) for C19H22N8O 379.15 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH3:18])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Li+]>C1COCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]([CH3:18])[N:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1nnn(C)c1-c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnc(C(=O)O)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
Ethyl 5-(4-bromophenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylate (from step 3b, 2.0 g, 6.45 mmol) was dissolved in 30 mL of THF and 0.5N lithium hydroxide solution (15 mL) was added. The mixture was stirred at room temperature for 10 hrs and solvents were evaporated. The residue was dissolved in water (30 mL) and filtered. The filtrate was treated with hydrochloric acid (2N, 4 mL). The white solid was filtered and dried to give 5-(4-bromo-phenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylic acid (1.82 g, 100% yield). LC-MS calcd for C10H8BrN3O2 (m/e) 283.0, obsd 282.0 (M−H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 3H), 7.50 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 12.95 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])(=O)C.[Na+].[C:16]([N:35]1[CH:39]=[C:38]([C:40](=O)[CH2:41][CH3:42])[N:37]=[CH:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CO.CCOCC>[C:16]([N:35]1[CH:39]=[C:38]([CH:40]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:41][CH3:42])[N:37]=[CH:36]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)CCCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)CCCNC(CC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, ethyl 4-aminobutanoate hydrochloride a17 (1.75 g, 0.0104 mol) is dissolved in MeOH (30 ml). Sodium acetate (1.28 g, 0.0156 mol), a solution of 1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89 (0.96 g, 2.6 mmol) in a mixture of MeOH (7 ml) and Et2O (20 ml), NaBH3CN (0.15 g, 2.34 mmol) and finally Na2SO4 are added. After stirring for 48 h at room temperature, the mixture is poured on Et2O/H2O. The organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude ethyl 4-{[1-(1-trityl-H-imidazol-4-yl)propyl]amino}butanoate x90 (0.814 g) is used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:16])[CH2:14][OH:15])[CH2:8]1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:16])[CH2:14][O:15][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH2:8]1
Reactant: C[C@@H](CO)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 66.9 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 0.46 g of 2(S)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propanol (prepared as described in Preparation 36), 0.90 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.39 g of tributylphosphine, 0.49 g of azodicarbonyldipiperidine and 30 ml of anhydrous benzene were used, to give 0.79 g of the title compound having an Rf value of 0.26 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-35.3° (methanol, c=1.015).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@H:41]([CH3:44])[CH2:42][OH:43].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: C[C@H](CO)OC1CCCCO1
Reactant: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](O)COc1ccc2nc(C(=O)Nc3nc4cc(-c5ccc(C(F)(F)F)c(Cl)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) in dry DMF (1 mL) was added NaH (40 mg, dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. Then, water (10 mL) was added and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and dissolved in 1:1 mixture of methanol and DCM (5 mL). To this was added 2 M solution of hydrochloric acid in methanol (1 mL) and stirred at room temperature for 2 h. After air drying, the product was purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (37 mg). LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.15 (1H, d) 7.92 (1H, brs) 7.87-7.93 (3H, m) 7.55-7.63 (2H, m) 7.08 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.03-4.07 (1H, m) 1.18 (3H, d).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH:9]([Br:13])[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1>C1CCCCC1>[N+:10]([C:9]([Br:13])=[CH:8][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])C(Br)C(Br)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: O=[N+]([O-])C(Br)=Cc1ccccc1

Procedure:
To a refluxing solution of 1-(4-chlorophenyl)-1,2-dibromo-2-nitroethane (from example 1) in cyclohexane (200 mL) is added a solution of pyridine (6 mL, 74 mmoles) in cyclohexane (200 mL) over a 1 hour period. The mixture is refluxed for an additional hour. The refluxing mixture is then extracted with approximately 200 mL of dilute HCl and 2×200 mL H2O. The organic layer is dried over magnesium sulfate (anhydrous) filtered, and the solvent removed from the filtrate by evaporation to yield a yellow solid. The solid is recrystallized from cyclohexane to give beta-nitrobromostyrene.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(Cl)Cl.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH-].[Na+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Ni+2]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: c1ccc2c(c1)CCNC2
Agent: [Ni+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: C1=NCCc2ccccc21

Procedure:
Into a 5000 ml, 3-neck round-bottom flask equipped with a mechanical stirrer is placed 1,2,3,4-tetrahydroisoquinoline (1) (25.005 g) and methylene chloride (750 ml). A solution of potassium persulfate (71.376 g) and sodium hydroxide (18.0456 g) in deionized water (1650 ml) is added. While vigorously stirring the biphasic mixture, a solution of nickel sulfate hexahydrate (0.6499 g) in deionized water (75 ml) is added dropwise to the mixture. The reaction is allowed to stir overnight at room temperature. The biphasic mixture is vacuum filtered through Celite, the phases separated and the water layer extracted (3×300 ml) with methylene chloride. The organics are combined, dried with MgSO4 and reduced by rotary evaporation to a thick, dark brown oil. The desired product is isolated from the oil by Kugelrohr distillation (0.1 mm Hg, 75° C.). The preparation is represented by the following reaction: ##STR26##
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH:15](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:15]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2
Reactant: NNc1nc2cc(F)ccc2nc1Cl
Reactant: CCOC(OCC)OCC
Product: Fc1ccc2nc(Cl)c3nncn3c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 10 g. (0.047 mole) of 2-chloro-6-fluoro-3-hydrazinoquinoxaline and 80 ml. (0.47 mole) of triethyl orthoformate was heated under a nitrogen atmosphere with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration, washed with three-50 ml. portions of ethanol and air-dried to constant weight to ultimately afford 9.42 g. (91%) of pure 4-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 310°-312° C. (decomp.). Mass Spectrum: m/e, 224, 223, 222 (P+).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15](O)=[O:16])[C@H:13]3[CH2:18][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[NH2:31][OH:32].C(N(CC)CC)C>ClCCl.O1CCCC1.O>[OH:32][NH:31][C:15]([C@H:14]1[C@H:13]2[CH2:18][C@H:10]([CH2:11][CH2:12]2)[N:9]1[C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:16]
Reactant: C[C@@H](c1ccccc1)N1[C@H]2CC[C@H](C2)[C@@H]1C(=O)O
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@@H](c1ccccc1)N1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (224 mg, 0.913 mmol) in dichloromethane (3.5 ml) were added oxalyl chloride (0.17 ml, 1.92 mmol) and N,N-dimethylformamide (0.07 ml, 0.913 mmol) while being cooled with ice, and the mixture was stirred at room temperature for 30 minutes. Separately, to a suspension of hydroxylamine hydrochloride (254 mg, 3.65 mmol) in tetrahydrofuran (1.0 ml)-water (0.2 ml) was added triethylamine (0.78 ml, 5.57 mmol) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. To this reaction mixture was added the acid chloride solution at 0° C., and the mixture was stirred at room temperature for 14 hours. The reaction mixture, with water added thereto, was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (1% methanol/chloroform), to give the entitled compound (126 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
(3,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10 ml). The mixture was heated at 70° C. for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate). The desired fractions were concentrated to yield N-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7% yield) as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (m, 1H), 7.40 (m, 1H), 7.19 (dd, J=8.09, 1.98 Hz, 1H), 4.94 (s, 1H), 4.43 (s, 2H), 3.47-3.77 (m, 4H), 1.41-1.79 (m, 6H). LC/MS RT=2.15; [M+H]+=305.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:18]([O:17][CH:12]([C:11]#[C:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]([F:16])([F:15])[F:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OC(C#CCOCc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C#CCOCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
In a three-necked flask of 50 ml in internal volume which was well dried under reduced pressure in nitrogen stream were charged 20 ml of methylene chloride, 3.57 g (13.0 mmol) of the above alcohol (3) and 1.20 ml (16.9 mmol) of acetyl chloride and then 1.37 ml (16.9 mmol) of pyridine was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction was stopped by adding 1N aqueous hydrochloric acid solution and the reaction mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. Solvent was distilled off to obtain a crude product, which was purified by silica gel column chromatography to obtain the above acetate (4).
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][C:20](=[O:23])[S:21][CH:22]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.[S-]C#N.[K+].C(=O)(O)[O-].[Na+].[C:38]1([N:44]2[C:48](=[S:49])[NH:47][N:46]=[N:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(OC(C)C)(C)C>O.O1CCCC1>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:49][C:48]1[N:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[N:46][N:47]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][C:20](=[O:23])[S:21][CH:22]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: S=c1[nH]nnn1-c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1csc(=O)s1)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3ccccc3)CSC12
Temperature: 60 °C
Yield: 42.4 %

Procedure:
The sodium salt of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (10 g.) is dissolved in water (51 cc.). Potassium thiocyanate (60 g.), sodium bicarbonate (2.24 g.) and 1-phenyl-5-thioxo-1,2,3,4-tetrazoline (4.75 g.) are added to this solution and the mixture is heated to 60° C. for 8 hours. After cooling, the reaction mixture is diluted with water (250 cc.) and washed with ethyl acetate (200 cc.) after acidification to pH 5.5 by adding 4 N hydrochloric acid. The mixture is then acidified to pH 1.5 by adding 4 N hydrochloric acid in the presence of ethyl acetate (100 cc.). After decanting the organic phase, the aqueous phase is extracted four times with ethyl acetate (a total of 400 cc.). The organic extracts are combined, washed three times with an 0.1 N hydrochloric acid solution (a total of 300 cc.) and then twice with water (a total of 300 cc.), dried over sodium sulphate, treated with decolourising charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is dissolved in tetrahydrofuran (50 cc.) and this solution is then added to isopropyl ether (1 liter). A product precipitates, which is isolated by filtration and dried under reduced pressure (0.1 mm Hg). 2-Carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-3-[(1-phenyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (5.4 g.) is thus obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[C:10]([CH:16]=[O:17])[NH:11][C:12](=[O:15])[C:13]=1[I:14].O>CO>[CH3:23][C:21]1[CH:20]=[C:6]([CH:5]=[C:4]([CH3:3])[CH:22]=1)[O:7][C:8]1[C:9]([CH2:18][CH3:19])=[C:10]([CH2:16][OH:17])[NH:11][C:12](=[O:15])[C:13]=1[I:14]
Reactant: CCc1c(C=O)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1c(CO)[nH]c(=O)c(I)c1Oc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (0.047 g; 1.3 mmol) was added to a mixture of compound 159 (0.5 g; 0.013 mol) in methanol (3 ml). The mixture was stirred at room temperature for 1 hour. Water was added. The precipitate was filtered off, taken up in diisopropyl ether and dried to yield 0.26 g (52%), m.p.=70° C.).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)[CH3:3].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc(C=O)nc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc(CO)nc1
Yield: 84 %

Procedure:
5-(prop-1-en-2-yl)picolinaldehyde (0.600 g, 4.08 mmol) was dissolved in methanol (15 mL). To this was added Pd(OH)2 (0.600 mgs, 20% catalyst on carbon, 50% water by weight) and the mixture was hydrogenated under a balloon of hydrogen for 2 hours. The mixture was then filtered through GF/F filter paper and the filtrate was concentrated under reduced pressure to give the title compound (84%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)=O.Cl.[OH:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>CC#N>[CH3:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:5]2[CH:4]=[CH:3][N:29]=[C:27]([NH:26][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[N:28]=2)=[CH:8]1
Reactant: N=C(N)Nc1cccc(O)c1
Reactant: CN(C)/C=C/C(=O)c1cn(C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(-c2ccnc(Nc3cccc(O)c3)n2)c2ccccc21

Procedure:
To a mixture of (E)-3-(dimethylamino)-1-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (1.0 mmol, 0.21 g) in MeCN (3.5 mL) was added 1.0 mmol 1-(3-hydroxyphenyl)guanidine hydrogen chloride salt in the presence of NaOH (1.0 mmol). The mixture was irradiated at 150° C. for 20 minutes in microwave. The mixture was purified by chromatography using EtOAc/PE (1:1, v/v) to elute the titled product as a off-white solid. 1H-NMR (DMSO-d6) δ: 3.89 (s, 3H, CH3), 6.38 (m 1H, Ph-H), 7.07 (m, 1H, Ph-H), 7.19 (d, 1H, J=5.6 Hz, Pyrimidin-H), 7.25 (m, 1H, Ar—H), 7.38 (s, 1H, Ph-H), 7.53 (d, 1H, J=8.0 Hz, Ph-H), 8.32 (m, 2H, Ar—H and Pyrimidin-H), 8.64 (d, 1H, J=8.0 Hz, OH), 9.23 (s, 1H, Ar—H), 9.27 (s, 1H, Ar—H). MS (ESI+) m/z 317.1311 (M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([OH:20])=[C:18]([S:21][C:22]([F:25])([F:24])[F:23])[C:17]([C:26]#[N:27])=[N:16]1.S(OCC)(O[CH2:32][CH3:33])(=O)=O.S([O-])(O)(=O)=O.[K+]>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([O:20][CH2:32][CH3:33])=[C:18]([S:21][C:22]([F:25])([F:23])[F:24])[C:17]([C:26]#[N:27])=[N:16]1
Reactant: CCOS(=O)(=O)OCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 69.8 %

Procedure:
To a stirred suspension of sodium hydride (0.41 g, 60%, 10.3 mmol) in dioxane (150 ml) was added a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxy-4-trifluoromethylthio-1H-pyrazole-3-carbonitrile (4.00 g, 8.53 mmol) in dioxane (50 ml). After gas evolution had ceased the mixture was heated to reflux and diethyl sulfate (1.25 ml, 9.47 mmol) added, and then heated under reflux for 6 hours. The cooled mixture was acidified with aqueous potassium hydrogensulfate (5%), extracted with dichloromethane, and the organic phase dried over magnesium sulfate and evaporated. The resulting gum was triturated with pentane to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxy-4-trifluoromethylthio-1 H-pyrazole-3-carbonitrile (2.68 g, yield 70 %) as off-white crystals, mp 106° C., 1H NMR (CDCl3): 1.36 (t, 3H, CH3), 4.71 (q, 2H, OCH2), and 7.76 (s, 2H, Ar—H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([NH:18][C:19]3[O:20][C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:22][N:23]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(C)(C)C.C(OC(=O)NC1CCC2C(=C(NC3OC(C4C=CC(C)=CC=4)=CN=3)C=CC=2)C1)(C)(C)C>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:21]2[O:20][C:19]([NH:18][C:11]3[C:10]4[CH2:9][CH:8]([NH2:7])[CH2:17][CH2:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[N:23][CH:22]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Agent: Cc1ccc(-c2cnc(Nc3cccc4c3CC(NC(=O)OC(C)(C)C)CC4)o2)cc1
Product: NC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Yield: 38.1 %

Procedure:
The title compound was prepared using the procedure as described in Example 20H substituting the product of Example 21A (120 mg, 0.253 mmol) for the product of Example 20G. The crude product was purified by trituration with Et2O/hexanes which resulted in 36 mg (38%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 9.32 (br s, 1H), 7.75 (m, 4H), 7.60 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 3.05-2.70 (m, 4H), 2.30 (m, 1H), 1.82 (m, 3H), 1.43 (m, 1H); MS (ESI+) m/z 374 (M+H)+.