Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1ccccn1
Reactant: Cc1cccc(N)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccn2)n1

Procedure:
To a flask were added 3.2 g of 2-amino-6-methylpyridine, 4.9 g of 2-bromopyridine, 3.5 g of sodium tert-butoxide, and 120 ml toluene. The mixture was purged thoroughly with nitrogen and 83 mg of 1,1′-bis(diphenylphosphino)ferrocene and 34 mg of palladium acetate were added. The reaction mixture was heated to 65 C for 3 hours, to 75 C for 2 hours, and then cooled to 22 C. After quenching with 75 ml of water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 50 ml of 1M hydrochloric acid, and washed with 30 ml of ethyl acetate. After basifying with 3M sodium hydroxide, the product was extracted with 75 ml of ethyl acetate and washed with 30 ml of water. Following solvent removal, the product was purified by silica gel chromatography using 38% ethyl acetate, 50% hexane, and 12% methanol resulting in an orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][S-:21].[Na+]>C1COCC1>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:3][C:2]=1[S:21][CH3:20]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(C(F)(F)F)c2)nnc1SC
Yield: 88.3 %

Procedure:
3-Chloro-4-methoxy-6-[3-(trifluoromethyl)phenyl]pyridazine (2.0 g, 0.0069 mole, Compound No. 48) and sodium thiomethoxide (0.5 g, 0.0069 mole) were refluxed overnight under N2 in THF (50 mL). After this time no starting material was present by TLC. The mixture was partitioned between EtOAc-water. The aqueous layer was extracted again with EtOAc. The EtOAc layers were combined, washed with brine, dried (MgSO4), filtered and evaporated to give a crude oil. The oil was chromatographed on a Prep-500 using EtOAc-cyclohexane (3:17) to give 4-methoxy-3-(methylthio)-6-[3-(trifluoromethyl)phenyl]pyridazine (1.83 g, 88% yield, Compound No. 64) as a white solid.
Reaction SMILES: [C:1](O)(=O)C#C.[C:6]1([C:12]#[C:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:6]1([C:12]#[C:13][C:14]([O:16][CH3:1])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CC(=O)O
Reactant: O=C(O)C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Typical Procedure for Methylation of Propiolic Acid with Iodomethane (1b as Example) CH3I (2.2 mmol) and K2CO3 (2.2 mmol) were added to the solution of Propiolic acid (1b, 2 mmol) in acetonitrile and the obtained mixture was stirred at room temperature. The reaction was monitored by TLC until the starting 1b disappeared. After 3 hours, the mixture was extracted with ether (3×5 mL). The combined ether part was purified by column chromatography on silica gel (dichloromethane:hexane=1:3) to give pure methyl 3-phenylpropiolate in 98% yield. GC/Ms: m/z: 160. Data for 1H and 13C NMR of methyl 3-phenylpropiolate was conducted in CDCl3 and consistent with the data in reported literature.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][N:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[O:22][N:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccccc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 5.5 g of m-chloroperoxybenzoic acid (85%) in 125 ml of CH2Cl2 was added dropwise at -70° C. under N2 to a solution of 7.5 g of 3-benzoyl-5-phenylthiomethyl-1,2,4-oxadiazole in 150 ml of CH2Cl2. The temperature of the reaction was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was added directly to a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 3.7 g (44%) of needles, m.p. 79°-81°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:14]=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Reactant: Brc1ccccn1
Product: Fc1ccc(-c2cn(CCC#Cc3ccccn3)nn2)cc1
Yield: 25945.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (80 mg, 0.37 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography DCM/MeOH 98.5:1.5) to yield 28 mg (96 mmol, 26%) of 2-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a brown solid (M.P.=120-122° C.).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N+:7]([O-:32])=[N:8][C:9]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH3:5].C=O.O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[CH2:2]([C:6]1[N+:7]([O-:32])=[N:8][C:9]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:36])[CH2:28][CH2:27]2)=[CH:10][C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1c(-c2ccc(OC3CCCCC3)cc2)cc(OC2CCNCC2)n[n+]1[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCc1c(-c2ccc(OC3CCCCC3)cc2)cc(OC2CCN(C)CC2)n[n+]1[O-]
Reaction time: 1.33 h
Yield: 89.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine 2-oxide hydrochloride (0.162 mmol, 74.8 mg) in DCM (1.5 mL) was added formaldehyde solution in water (37%, 0.5 mmol, 0.372 mL), and 1 drop of acetic acid. It was stirred for 80 min. and sodium triacetoxyborohydride (0.65 mmol, 145 mg, 95%) was added. The reaction mixture was stirred at room temperature for 80 min. and partitioned between ethyl acetate (8 mL) and saturated aq. sodium bicarbonate solution (8 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The organic solvent was removed in vacuo and the residue was dissolved in DCM and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The off-white solid was dried overnight under high vacuum to provide the title compound (69.3 mg). LCMS: m/z 441 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.28-7.32 (2H, m), 7.05-7.07 (2H, m), 6.79 and 6.88 (1H, s), 5.15-5.34 (1H, m), 4.38-4.43 (1H, m), 3.23-3.65 (4H, m), 2.92 (3H, s), 2.80-2.84 (2H, m), 2.47-2.56 (1H, m), 2.38 (1H, d), 2.08-2.21 (1H, m), 1.89-2.05 (3H, m), 1.81 (2H, m), 1.21-1.66 (10H, m) 0.82 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([CH:30]=O)[NH:21][C:20]=1[CH3:32])=[O:18]>>[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:32])=[O:18]
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCN(C)C
Yield: 56 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (46 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 60 mg (55%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzoyl chloride (4.3 g, 20.5 mmol) was added all at once to 4-fluoro-3-nitroaniline (3.14 g, 20.1 mmol) and triethylamine (3 mL, 21.5 mmol) in ethyl acetate (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature then diluted to ˜500 mL with ethyl acetate. The ethyl acetate was washed successively with 1N HCl (100 mL), saturated sodium bicarbonate (100 mL), and brine (100 mL), then dried (magnesium sulfate), filtered, and stripped of solvent under reduced pressure. Trituration of the residue in hexanes (125 mL) and a few milliliters of ethyl acetate afforded the product by filtration (5.6 g); m.p. 202-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11](O)=[O:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].CSC.B.CO>C1COCC1>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][OH:12])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S*,4S*)-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3-ethyl ester (10 g, 34.8 mmol) in THF (180 mL), a solution of borane dimethylsulfide complex (2N in THF, 24.4 mL, 48.7 mmol) is added slowly at −10° C. The mixture is stirred at −10° C. for 20 min, then allowed to reach RT and further stirred for 4 h. MeOH is carefully added (exothermic!), and the mixture is concentrated under reduced pressure. MeOH is again added, and the mixture is concentrated. This operation is repeated 3 times, then the mixture is finally taken up into a saturated aqueous solution of NaHCO3 and extracted 3 times with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH from 100:0 to 95:5) to give the title compound as product. TLC, Rf (AcOEt)=0.52. MS (LC-MS): 174.1 [M+H-Boc]+.
Reaction SMILES: C([NH:4]C(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1)#[N:14].[C:32](Cl)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[C:13]([C:15]1[CH:31]=[CH:30][C:18]([C:19]2[N:21]([CH3:29])[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:4]=2)=[CH:17][CH:16]=1)#[N:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(Cc1ccncc1)C(=O)c1ccc(C#N)cc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(C#N)cc2)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C

Procedure:
4-Cyano-N-[N"-a-dibenzoyl-1,4-dihydropyridyl-methylenyl]-N-methylbenzarmide--To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF at -78° C. was added n-butyllithium (6.7 mL of 2.5M solution, 17 mmol). To the resulting mixture was added a solution of 4-cyano-N-methyl-N-(4-picolyl)benzamide (3.5 g, 14 mmol) in THF. The resulting dark purple solution was stirred at -78° C. for 10 min, at which time benzoyl chloride (4.1 mL, 35 mmol) was added. The mixture was warmed to room temperature over 30 min, then poured into aqueous NH4Cl. The mixture was extracted with Et2O, and the organic extract was evaporated under reduced pressure. The residue was triturated with Et2O to provide an orange solid which was washed sparingly with acetone and copiously with Et2O. The title compound was obtained as a bright yellow solid (1.6 g, 25%): 1H NMR (CDCl3): d 7.81-7.09 (m, 16H); 6.49 (m, 2H); 3.32 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.Br[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1.C(N(CC)CC)C>CC#N>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][C:32]4[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=4)[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1ccc(OCCCBr)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4ccc(C=O)cc4)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.244 g), 4-(3-bromopropoxy)benzaldehyde (example 8, step a) (0.15 g) and triethylamine (0.344 mL) in MeCN (2 mL) was heated at 60° C. After 16 h, the reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:triethylamine, 10:1 to give the subtitled compound as an oil. Yield 0.24 g.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[N+:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:28]=O)([O-:18])=[O:17].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:28][C:22]3[C:21]4[C:25](=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=4)[NH:24][CH:23]=3)[C:36]([C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: Cn1ccnc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc([N+](=O)[O-])cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-nitro-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. Mass: 477.19 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(C)(C)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(C)(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (330 mL) is added dropwise to a solution of 3-methoxy-2,2-dimethylpropan-1-ol (250 mg) and N,N-diisopropylethylamine (1.1 mL) in dichloromethane (3 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is washed with twice with 1 N hydrochloric acid, saturated aqueous NaHCO3 solution and brine. Then the organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 407 mg; TLC: rf=0.75 (silicagel, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
NaBH4 (1.18 g, 31.1 mmol) was added carefully in portions (exothermic) to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)-piperazine (3.54 g, 8.9 mmol), nickel(II)chloride hexahydrate (1.06 g, 4.4 mmol), MeOH (100 mL) and THF (50 mL) at 0° C. The ice bath was removed and the reaction mixture was warmed to rt. TLC analysis indicated the complete consumption of the starting material. The reaction mixture was concentrated onto silica gel and flash chromatography afforded the title compound of step B (2.93 g, 90%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.46 (m, 2H), 6.27 (dd, J=8.5, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.44-3.38 (m, 2H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.61-2.54 (m, 4H), 2.35-2.26 (m, 1H), 1.80-1.77 (m, 2H), 1.56-1.46 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[C:26]([C:23]1[C:22]([C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[C:21]([NH:20][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-c1cncs1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1cncs1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17 mmol) and 5-amino-4-(thiazol-5-yl)thiophene-3-carbonitrile (0.055, 0.26 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min)=5.989, method [7], MS(ESI) 461.1 (M+H). 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.91-7.85 (m, 4H) 7.78 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 5.06 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH3:30].[Li+].[Br-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)([OH:16])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -90 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 11.7 g (32.0 mmol) of 17 in 260 mL of THF, 37 mL (33.6 mmol) of 0.91 M MeLi*LiBr in THF was added dropwise with vigorous stirring for 20 min at −90° C. The reaction mixture was slowly warmed to room temperature and 50 mL of water was added. The organic solvent was evaporated using a rotary evaporator. The crude product was extracted from the residue with 2×100 mL of dichloromethane. The combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 12.0 g (98%) of 18.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)C.N1CCOCC1>CN(C)C=O.O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:14])=[CH:4][N:3]=1
Reactant: CCN1CCOCC1
Reactant: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (660 mg) in dimethylformamide (10 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.21 g), 1-hydroxybenzotriazole (0.86 g), N-ethylmorpholine (0.8 ml) and morpholine (0.55 ml). The solution was stirred at room temperature overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated sodium chloride solution and dried (MgSO4) then evaporated to afford the title compound as an off-white solid (783 mg). This was carried through without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 4-chloro-2-fluorobenzoic acid (1 eq) in CH2Cl2 (1.6 M) was added N,O-dimethylhydroxylamine hydrochloride (1.5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0.5M aqueous citric acid was added. The mixture was extracted with 1:1 EtOAc:Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N-methylbenzamide, which was used as such for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])[CH:11]([N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]2=[O:41])[C:12](=[CH2:14])C)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(O)[O-:46].[Na+]>C(OC)(=O)C.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:44]=[CH:43][C:7]([CH2:8][O:9][C:10](=[O:42])/[C:11](/[N:15]2[CH:18]([S:19][S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[CH:17]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:16]2=[O:41])=[C:12](\[OH:46])/[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)=O
Solvent: CCOC(C)=O
Product: C/C(O)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
(di) The crude 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylenebutyric acid p-nitrobenzyl ester, obtained according to Example 1.(cvii), is dissolved in 20 ml of methyl acetate and ozonised at -70° C. until no further starting material is present, according to a thin layer chromatogram. A stream of nitrogen is then passed through the solution and the latter is warmed to 0°-5° C. A solution of 300 mg of sodium bisulphite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no further ozonide can be detected with potassium iodide/starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated off, and the organic phase is washed with water, dried over magnesium sulphate and freed from solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is recrystallised from methanol and gives 2 -[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159°-160° C.