Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27](OC)=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4ccc(OCCCN5CCS(=O)(=O)CC5)cc34)c2)no1
Yield: 43 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from the previous step (230 mg, 0.45 mmol), thiomorpholine 1,1-dioxide (182 mg, 1.35 mmol), tetrabutylammonium iodide (166 mg, 0.45 mmol) and N,N′-diisopropylethylamine (160 μL, 0.89 mmol) in N,N′-dimethylformamide (3 mL) to afford 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea (117 mg, 43%) as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.03 (s, 1H), 8.75 (s, 1H), 7.94-7.86 (m, 2H), 7.68 (d, 1H), 7.51-7.41 (m, 3H), 7.30 (d, 1H), 6.49 (s, 1H), 4.26-4.23 (m, 2H), 3.11 (bs, 4H), 2.95 (bs, 4H), 2.71-2.67 (m, 2H), 2.00-1.96 (m, 2H), 1.27 (s, m 9H); LC-MS (ESI) m/z 611 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Yield: 82.5 %

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid (10.0 g, 0.048 mol) in ethanol (50 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 7 h. The reaction was concentrated in vacuo, diluted with diethyl ether, and poured into water. The ether layer was washed with a saturated aqueous sodium bicarbonate solution and water. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. Vacuum distillation (bath temperature: 175° C.; head temperature: 125° C.) afforded (3,4-dichloro-phenyl)-acetic acid ethyl ester (9.38 g, 82.5%) as a clear oil: EI-HRMS m/e calcd for C10H10Cl2O2 (M+) 232.0058, found 232.0066.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]Br>C(O)(=O)C>[Br:11][C:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc2ccccc2s1
Solvent: CC(=O)O
Product: Cc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (50 mL) of 2-methyl-1-benzothiophene (5.00 g) in acetic acid was added dropwise bromine (1.90 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (8.02 g, quantitative) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(OCC)(=O)C>[CH3:23][S:24]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2.00 g (10.1 mmol) of 2-methyl-5-phenylbenzyl alcohol was dissolved in 100 ml of ethyl acetate, and to this solution was added 4.2 ml (30.3 mmol) of triethylamine and the mixture was cooled to 0° C. To the reaction mixture was slowly dropped 1.73 g (15.1 mmol) of methanesulfonyl chloride, and the reaction mixture was controlled to room temperature. After stirring for 1 hours at room temperature, the reaction mixture was made acidic by addition of 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and saturated saline sequentially, dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=4/1 (v/v)), to obtain 2.79 g of 2-methyl-5-phenylbenzyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:27]([C:30]1[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:35]/[C:33]4[O:34][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)nn1Cc1ccccc1
Yield: 88 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 0.35 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-benzyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9d, 416 mg, 88%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]([F:16])([F:15])[CH2:9]OCC(O)=O>ClCCl.CN(C)C=O>[F:7][C:8]([F:16])([F:15])[CH2:9][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COCC(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCC(F)(F)F

Procedure:
A solution of oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichloromethane (50 mL) was added dropwise at room temperature, with stirring, to a solution of (2,2,2-trifluoroethoxy)ethanoic acid (int. Patent Appl., Publication No. WO 87/07270, 31.6 g, 0.2 mol) and N,N-dimethylformamide (5 drops) in dry dichloromethane (400 mL). The mixture was stirred for an additional hour, then heated under reflux for 2 hours, cooled and the bulk of the solvent removed by distillation (bp 40-45° C./760 mm Hg). The residue was transferred to a Claisen distillation flask and the remaining solvent and oxalyl chloride removed by distillation (bp 45-60° C./760 mm Hg). Vacuum distillation of the residue then afforded the product, bp 50-55°/25-32 mm Hg. δH (CDCl3) 4.00 (2H, q, 3JHF 8.3) and 4.57 (2H, s).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:18])[F:17])[NH:7][C:6](=O)[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C2CC2)nc(-c2ccccc2C(F)(F)F)[nH]1
Product: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Temperature: 0 °C
Yield: 76 %

Procedure:
6-Cyclopropyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (12.0 g, 42.8 mmol) in phosphorous oxychloride (40 mL, 428 mmol) was heated at 75-80° C. for 1 hour. The solvent was removed by evaporation and azeotroping three times with toluene. The residue was cooled to 0° C., taken up in ethyl acetate, treated with ice chips and water. The mixture was then washed sequentially with sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, 5:95 ethyl acetate:hexanes (5:95)] provided the title compound (9.71 g, 76% yield) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.12 (m, 2H), 1.30 (m, 2H). 2.02 (m, 1H), 7.24 (s, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.79 (m, 2H) ppm; MS (FIA) 299.1/300.9 (M+H); Rt (Method A) 3.882 minutes.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@H]1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-fluoropiperidin-3-ylcarbamate (0.28 g, 0.91 mmol) and 10% Pd/C (0.097 g, 0.091 mmol) in MeOH (10 mL) was charged 1 atmosphere of hydrogen and stirred at room temperature for 4 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-fluoropiperidin-3-ylcarbamate (0.19 g, 96%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C:10]([O:13][Si](C)(C)C)=[CH:9]2)=[CH:4][N:3]=1.Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OC1=CC(c2ccc(Cl)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
2-Chloro-5-(3-trimethylsilanyloxycyclopent-2-enyl)pyridine (0.58 g, 2.2 mmol) was dissolved in THF (10 mL) in a 100 mL round bottom flask and treated with 1N HCl (2 mL) with stirring at room temperature. After 1 h, the mixture was diluted with EtOAc and sat. NaHCO3 and the layers separated. The aqueous phase was extracted with EtOAc and the combined organic layers dried (Na2SO4), filtered, concentrated, and purified by flash silica gel chromatography (hexanes: EtOAc/2:1) to give 3-(6-chloropyridin-3-yl)cyclopentanone (0.16 g, 37%) as a dark oil: LC/MS (ESI) m/z 195, 1H NMR (300 MHz, CDCl3) δ 8.31 (d, 1H, J=2.7 Hz), 7.54 (dd, 1H, J=8.4, 2.7 Hz), 7.31 (d, 1H, J=8.4 Hz), 3.43 (m, 1H), 2.70 (m, 1H), 2.56-2.22 (m, 4H), 1.97 (m, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH:28]2[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: Nc1ccc(OS(=O)(=O)C2CC2)cc1
Product: O=C1N(c2ccc(OS(=O)(=O)C3CC3)cc2)CCC12CCC(O)CC2

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with cyclopropanesulfonic acid 4-amino-phenyl ester as a mixture of cis and trans diastereomers. MS (m/e): 366.137 [MH+].
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5](=[O:30])[C@H:6]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:7][C:8](=[O:21])[CH2:9][NH:10]C(OCC1C=CC=CC=1)=O)[CH3:3].C(OCC)C>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:30])[C@H:6]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:7][C:8](=[O:21])[CH2:9][NH2:10])[CH3:3].[BrH:1]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 ml of 25% HBr in glacial acetic acid was added to carbobenzoxyglycyl-L-tyrosine ethyl ester obtained above, and after the mixture was stirred for 30 minutes at room temperature, 5 l of absolute ethyl ether was added to the mixture to produce a precipitate. The precipitate was washed with ethyl ether to obtain glycyl-L-tyrosine ethyl ester·HBr.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].Cl.C(NCC)C>O>[CH2:8]([N:10]([CH2:11][CH3:12])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[O:14][CH3:13])[CH3:9]
Reactant: CCNCC
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1OC
Temperature: 0 °C
Yield: 94 %

Procedure:
Into a three-necked flask (200 ml), a toluene solution (56 g) containing diethylamine (25.80 g; 0.352 moles) was placed. While the flask was cooled with ice water and the solution was stirred, a toluene solution (30 g) of 2-methoxybenzoyl chloride (2.00 g; 0.117 moles) was added dropwise over 30 minutes. After the addition was completed, water was added to the resultant mixture, and diethylamine and diethylamine hydrochloride in excess amounts were removed. The obtained toluene layer was dehydrated with MgSO4. Then, the solvent was removed by distillation, and a light yellow liquid was obtained (the obtained amount: 22.81 g; the yield: 94%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:9]=C[C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=1)C(O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:7][C:8]1[CH:16]=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[C:1]([CH:9]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Temperature: 50 °C

Procedure:
Oxalyl chloride (1.23 ml, 14.24 mmol) was added dropwise to a solution of 5-fluoro 2-trifluoromethyl benzoic acid (1 gm, 4.81 mmol) in HPLC grade DCM (15 ml), containing DMAP. The reaction mixture was heated to 50° C. for 40 min. The reaction mass was cooled to room temperature and solvent evaporated to dryness under a nitrogen atmosphere to get crude 5-fluoro 2-trifluoromethyl benzoyl chloride.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH3:26])[C:21]([OH:25])=[CH:22][C:23]=3[CH3:24])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(NC(=O)c2cc(NC3CCCCC3)ncn2)c(C)cc1O

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,5-dimethylphenol (Aldrich), the title compound was obtained as a white solid yield after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11]O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].C(OC(=O)C)(=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc(C=NO)cc1Br
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: N#Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 4-bromo-5-nitro-thiophene-2-carbaldehyde oxime (216 g, 0.86 mol, Example 286: step b) and acetic anhydride (1 L, 10.6 mol) was heated to reflux for 4 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude reaction mixture was diluted in methylene chloride and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo resulting in a residue, which was stirred in diethyl ether/hexanes and filtered to afford the title compound as a yellow solid (170.2 g, 85%). 1H-NMR (DMSO-d6): δ 8.25 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27][CH:21]2[CH2:20][CH2:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:36]>C(O)C>[CH2:2]([O:4][C:5]([CH:7]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27](=[O:36])[CH:21]2[CH2:20][CH2:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCC2SCC(C(=O)O)N2C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Reaction time: 3 h

Procedure:
To a solution of [3R-[3α,6α(S*R*),9aα]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid hydrochloride (1 mmole) in 50 ml of absolute ethanol at 0° under nitrogen, purified meta-chloroperoxybenzoic acid (1.05 mmole) can be added. The reaction mixture can be stirred for 3 hours at 0° and then absorbed onto a Dowex 50 X-2 ion-exchange column. Elution with ethanol-water (1:1) and then 4% pyridine-water will permit recovery of the product. The product can then be freeze-dried to afford a mixture of diastereomeric sulfoxides which can be separated by preparative chromatography on a reverse-phase column.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=C)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH2:15]>C(Cl)Cl.C(#N)C>[F:1][C:2]1[C:3]([C:8]2([C:13]#[N:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CC(C#N)(c2ncccc2F)C1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: N#CC1(c2ncccc2F)CC(=O)C1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuCl3.H2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1.5 L) was added solid NaIO4 (1235 g, 5.8 mol) portionwise at 10-30° C. Upon completion of the addition, the reaction was stirred 1 h at 15° C. and overnight at rt. The solid precipitate was filtered off and washed with DCM (1 L×2). The organic layer was washed with water (500 mL×2) and brine (500 mL), dried over Na2SO4, and concentrated to provide the title compound as a crude dark solid (238 g, 86.3%), LRMS (M+H+) m/z 191.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1I.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]3[C:3]=2[C:22]2[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)Cn1nc2c(I)c(Br)ccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1nc2c(-c3ccc(C#N)cc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-iodo-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.13 mmol), 4-cyanophenylboronic acid (40 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in dioxane (1.0 mL) at 20° C. was added K2CO3 (40 mg, 0.25 mmol) in water (0.3 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (15 mg, 0.038 mmol) as a yellow solid. MS: [M+H]+=394.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:14][NH:13][C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[N:14][N:13]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[N:31][CH:30]=4)[C:12](=[O:21])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: COc1ccc(Br)cn1
Reactant: CN(C)C(=O)c1n[nH]c(=O)c2c1c1ccc(F)cc1n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N(C)C)c3c4ccc(F)cc4n(C)c3c2=O)cn1

Procedure:
A solution of 0.3 g (1.04 mmol) of 7-fluoro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-carboxamide (obtained in stage 3.2.), of 0.120 g (0.63 mmol) of cuprous iodide, of 0.20 g (1.45 mmol) of potassium carbonate and of 0.60 g (3.19 mmol) of 3-bromo-6-methoxypyridine in 50 ml of N,N-dimethylformamide is heated at 150° C. for 20 h. The reaction mixture is cooled and concentrated under reduced pressure. Dichloromethane, water and a sodium hydroxide solution (1M) are added. The organic phase is separated by settling, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/ethyl acetate: 100/0 to 0/100; then ethyl acetate/methanol: 95/5). The white solid obtained is recrystallized from a dichloromethane/ethyl acetate mixture and washed with diethyl ether. A white solid (0.26 g; 0.66 mmol) is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Product: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Oc1cc(Cl)cc(CC(=O)O)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).