Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([Cl:31])[C:23]=1[CH3:32]>>[Cl:31][C:24]1[C:23]([CH3:32])=[C:22]([NH:11][C:10]2[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: Cc1c(Cl)cc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])cc(Cl)c1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 1.0 g (3.98 mmol) of 1-bromo-3-chloro-2-methyl-5-nitrobenzene gave 670 mg (42% of theory) of the title compound. The starting material 1-bromo-3-chloro-2-methyl-5-nitrobenzene can be prepared from 2-chloro-1-methyl-4-nitrobenzene by a process described in U.S. Pat. No. 5,877,191 for the preparation of 3-bromo-5-fluoro-4-methyl-1-nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.C1(N2C3N=C(S(C)=[O:36])N=CC=3C(C)=C(I)C2=O)CCCC1>>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:36])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CSc1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Product: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1

Procedure:
Prepared from 6-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one following the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS (APCI) Calc'd for C13H14BrN3O2S: 357, 355.0. Found: 358 (M+1), 356. 1H NMR δ (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.63 (s, 1H), 5.91-5.86 (m, 1H), 2.89 (s, 3H), 2.15 (br s, 2H), 2.04 (br s, 2H), 1.87-1.79 (m, 2H), 1.61-1.58 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[CH3:9][N:10]([CH3:14])[C:11](=O)[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([C:22]2C=C([CH:26]=[CH:27][CH:28]=2)N)[CH:19]=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:12]=[C:11]([CH:26]=[CH:27][CH:28]=2)[N:10]([CH3:14])[CH3:9])[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cccc(-c2cncc(Br)c2)c1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN(C)c1cccc(-c2cncc(Br)c2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (83 mg) and methyl iodide (62 W) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 4 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of 3-(5-bromopyridin-3-yl)-N,N-dimethylaniline (7.1 mg) was thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[O:25]=[C:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:27]CC(Cl)=O>C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH2:16][CH2:27][C:26](=[O:25])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCC(=O)CCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC(=O)CCC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
A solution of 43.79 g acetic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester in 200 ml of THF was cooled to −70° C. A solution of 27.16 g potassium-tert-butoxide in 200 ml of THF was added at −70° C. during 20 min. and the resulting reaction mixture was stirred for 90 min. at the same temperature. Then a solution of 53.00 g 4-oxo-undecanoyl chloride in 200 ml of THF was dropped in and the reaction mixture was stirred for another 2.5 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was thin-layer distilled and purified by chromatography to yield 25.73 g of a yellow oil.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10](=O)[CH2:11][CH2:12][CH3:13].C[Si](C)(C)[O:17][C:18]1[CH2:21][CH2:20][C:19]=1[O:22][Si](C)(C)C.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([CH:10]1[C:19](=[O:22])[CH2:20][CH2:21][C:18]1=[O:17])[CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCC1C(=O)CCC1=O
Yield: 18.2 %

Procedure:
To a solution of BF3.OEt2 (1.30 g, 9.2 mmol) and butyraldehyde (0.40 g, 5.5 mmol) in DCM (5 ml) under N2 at −78° was added a solution of 1,2-bis trimethylsilyloxycyclobutene (1.4 g, 6.1 mmol) in DCM (3 ml) maintaining a temperature of less than −70°. After 2 h at −78° the solution was poured into saturated NaHCO3, extracted into EtOAc, washed (brine), dried (MgSO4) and the solution concentrated in vacuo to yield a clear liquid. To this liquid was added TFA (20 ml) and the solution heated at reflux for 24 h. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2, 50:50 EtOAc/hexane) to yield the title compound as an off-white solid (140 mg, 18%). δH (CD3OD) 2.46 (4H, s), 2.07 (2H, t, J 7.5 Hz), 1.40 (2H, m), 0.86 (3H, t, J 7.4 Hz). m/z (ESI, 70V) 141 (MH+).
Reaction SMILES: [H-].C(N([Al](N(CCCCCC)CCCCCC)N(CCCCCC)CCCCCC)CCCCCC)CCCCC.[Li+].N[C@H](C(O)=[O:53])CC1CCCCC1.[C:55]([C:57]([C:60]1[CH:67]=[CH:66][C:63]([C:64]#N)=[CH:62][CH:61]=1)([CH3:59])[CH3:58])#[N:56]>C1COCC1>[CH:64]([C:63]1[CH:66]=[CH:67][C:60]([C:57]([CH3:59])([CH3:58])[C:55]#[N:56])=[CH:61][CH:62]=1)=[O:53]
Reactant: CC(C)(C#N)c1ccc(C#N)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: CCCCCCN(CCCCCC)[Al](N(CCCCCC)CCCCCC)N(CCCCCC)CCCCCC
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(C=O)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
A suspension of lithium tris(dihexylamino)aluminum hydride, prepared according to Cha, J. S., et al; Org. Prep. Proc. Int. 1992, 24(3), 331-334, (21.2 g, 36 mmol) in THF (20 mL) was added via syringe to a solution of Example 35A (3.50 g, 20.6 mmol) in THF (50 mL) at 0° C. The reaction was allowed to proceed for 8 hr at 0° C., and then carefully quenched by addition of 3 N aq HCl(100 mL). The mixture was diluted with EtOAc, and the separated aqueous phase was extracted with EtOAc. The combined organic layer was washed with brine causing a white precipitate to form, which was filtered off. The filtrate was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting yellow solid was triturated with hexanes and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (Analogix® Intelliflash 280; 5% to 25% EtOAc/hexanes eluant; SF40-115 g column) to yield 2.24 g (63%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.00-7.93 (m, 2H), 7.80-7.74 (m, 2H), 1.73 (s, 6H). MS (DCI+) m/z 173 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.Cl.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22])[CH3:17].C1CCN2C(=NCCC2)CC1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([CH2:16][CH3:17])[CH:19]=2)=[N:4][N:3]=1
Reactant: CCc1cc(CN)ccc1OC
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCc1cc(CNc2nnc(Cl)c3ccc(C#N)cc23)ccc1OC

Procedure:
1,4-Dichlorophthalazine-6-carbonitrile and 3-ethyl-4-methoxybenzylamine hydrochloride were stirred at room temperature in 1-methyl-2-pyrrolidinone in the presence of DBU, whereby 1-chloro-4-[(3-ethyl-4-methoxybenzyl)amino]-6-phthalazine carbonitrile was obtained as a less polar compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 1.00 g of 4-(tert-butoxycarbonylamino)piperidine and 0.72 ml of triethylamine in 6 ml of dry N,N-dimethylformamide was stirred at an inner temperature of 50° C., and added dropwise with a solution of 0.79 g of n-butyl chloroacetate in 4 ml of dry N,N-dimethylformamide. Stirring was continued at the same temperature for 1 hour. Then, the reaction mixture was added with water, and the precipitated crystals were collected by filtration. The crystals were washed successively with water and n-heptane to obtain 1.46 g of colorless scales (mp: 115.5-116.5° C.).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10]OC(OC)N(C)C>>[N:1]12[CH:10]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCN1
Reactant: COC(OC)N(C)C
Product: C1CN2CCN3CCN1C23

Procedure:
In a manner similar to that of Example 1 (C), 4.55 g (35.5 mmol) of 1,4,7-triazacyclononane and 4.20 g of dimethylformamide dimethyl acetal were reacted to give 4.33 g (88%) clear, colorless liquid, bp 79°-80° (2.6mm).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:26][CH2:24][CH3:25])[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Reactant: CCN
Product: CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethyl-phenyl)cyclohexanone and ethylamine. Colourless oil. Rf value: 0.45 (alumina, petroleum ether/ethyl acetate=1:1, v:v).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OC(F)F)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OC(F)F)c(OCc2ccccc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
3-(Benzyloxy)-4-(difluoromethoxy)benzaldehyde described in Production Example 19-2 (3.94 g, 14.2 mmol) was dissolved in acetic acid (11 mL), then ammonium acetate (1.27 g, 16.4 mmol) and nitromethane (1.9 mL, 35.1 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to room temperature and then heated and stirred at 130° C. again for 1 hour. The precipitate was collected by filteration and washed with a liquid mixture of acetic acid and ethanol to obtain the title compound (2.36 g, 52%). The filtrate was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-4:1), and then the target fraction was concentrated under vacuum. The precipitate was washed with ethanol to obtain the title compound (406 mg, 8.9%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].C1(C)C=CC=CC=1>C(Cl)Cl.O>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg). 5-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (70 mg, 0.17 mmol) was dissolved in DCM (15 ml) and added TEA (0.2 ml, 1.4 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (42 mg, 0.34 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 168-171° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.68 (t, J 8.2, 1H), 7.64-7.58 (m, 3H), 7.54-7.50 (m, 1H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.2, 2H), 2.22-2.15 (m, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:38]=[C:39]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[C:40]([Cl:49])=[CH:41][C:42]=2[C:43]2[CH:48]=[CH:47][N:46]=[N:45][CH:44]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([N:18](CC2C=CC(OC)=CC=2OC)[C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1>CO>[Cl:8][C:9]1[C:10]([O:36][C:37]2[CH:38]=[C:39]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[C:40]([Cl:49])=[CH:41][C:42]=2[C:43]2[CH:48]=[CH:47][N:46]=[N:45][CH:44]=2)=[CH:11][C:12]([F:35])=[C:13]([S:15]([NH:18][C:19]2[S:20][CH:21]=[N:22][N:23]=2)(=[O:17])=[O:16])[CH:14]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(-c3ccccc3F)c(Cl)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Hydrogen chloride in dioxane (4M, 1.5 mL, 6.00 mmol) was added to a solution of 5-chloro-4-(6-chloro-2′-fluoro-4-(pyridazin-4-yl)biphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 92, 220 mg, 0.27 mmol) in methanol (1.5 mL) and the reaction stirred at room temperature for 18 hours. The mixture was evaporated to dryness and dissolved in dimethylsulfoxide (4.0 mL) and methanol (2.0 mL). The resulting precipitate was filtered, washed with methanol (2.0 mL) and the filtrate purified by preparative HPLC using a Phenomenex Luna C18 5 u 110 A 21.2×150 mm using acetonitrile:water as eluent to give the title compound (92 mg, 56%) as a beige coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:21][C:16]([C:17]([F:18])([F:19])[F:20])=[N:15][N:14]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)NNC(=O)C(F)(F)F)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cccc2oc(-c3nnc(C(F)(F)F)o3)cc12
Yield: 81.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 37 using N′-(4-methoxybenzo(b)furan-2-ylcarbonyl)trifluoroacetohydrazide (5.2 g), triethylamine (7.2 ml), triphenylphosphine (9.0 g) and diethyl azodicarboxylate (40% toluene solution, 6.2 ml), the title compound (4.0 g) was obtained as pale-yellow crystals.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N([O-])=O.[Na+].[I-:15].[K+].[OH-].[Na+]>Cl.O>[I:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1I
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-amino-3-nitro-pyridine (8 g, 57.5 mmol) in 60 mL of 6 N HCl cooled to 0° C. is added dropwise a solution of sodium nitrite (6.35 g, 92 mmol) in 40 mL of water. The mixture is stirred at 0° C. for 1.5 hours. Then a solution of potassium iodide (22.9 g, 138 mmol) in 40 mL of water is added dropwise to the yellow solution. The resulting red mixture is stirred at 0° C. for 30 minutes and then heated at 60° C. for 45 minutes. After cooling, the mixture is made basic by the careful addition of 3 N NaOH. The aqueous layer is extracted with CH2Cl2 (4×) and the combined organic layers are washed with 1 N HCl, dilute Na2SO3 and water. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product (2.72 g, 10.9 mmol) is used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18]C)=[O:17]>CO.C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:15]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(O)C(Oc1ccc(F)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2.80 g of p-fluorophenol and 1.19 g of sodium methoxide in 40 ml of methanol is added 50 mg of potassium iodide and 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed for 20 hours and the solvent removed under vacuum. To the residue is added water and the mixture is extracted with ether. The ether extracts are washed with 10% potassium carbonate and with water and dried (MgSO4). The solvent is removed under vacuum to given a tan oil. The oil is dissolved in 60 ml. of ethanol and 6 ml of water and 5 g of potassium hydroxide is added. The mixture is refluxed for 3.5 hours, acidified with concentrated hydrochloric acid, diluted with water and poured onto ice. The mixture is extracted with chloroform and the extracts washed with water and dried over magnesium sulfate. Concentration in vacuo gives an oil. The oil is dissolved in aqueous sodium bicarbonate and the mixture extracted with chloroform. The aqueous layer is acidified with concentrated hydrochloric acid, extracted with ether and the extracts dried (MgSO4). Removal of the solvent in vacuo gives the product as a tan oil. A small sample is crystallized, mp 106°-111° C.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[CH:20]([NH:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:20]([N:23]([C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)[NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)([CH3:22])[CH3:21]
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: Cc1cccc(C(=O)NNC(C)C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(C)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (100.0 mg, 0.39 mmol), N′-isopropyl-3-methylbenzohydrazide (113.4 mg, 0.59 mmol) and HATU (224.3 mg, 0.59 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.10 ml, 0.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that white (E)-N′-isopropyl-3-methyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (115.0 mg, 68.7%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.C(OCC)C>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[O:22][C:23]([CH:26]([OH:27])[CH2:1][CH3:2])=[CH:24][CH:25]=2)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 10° C., 1.1 ml (1.1 mmol) of a 1M solution of ethylmagnesium bromide in THF were added dropwise to 300 mg (0.99 mmol) of 1-benzyl-3-(5-formyl-2-furyl)indazole in 20 ml of diethyl ether. After 1 h at 10° C., the mixture was poured into ice-water and extracted with ethyl acetate, dried and concentrated. The crude product was purified by silica gel chromatography using dichloromethane/methanol (95:5). This gave 200 mg (61%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>CN(C=O)C>[CH2:18]([NH:21][C:22]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Product: CCCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C

Procedure:
The title compound was prepared in DMF using 3,5-di-tert-butyl-4-hydroxybenzaldehyde and n-propyl isocyanate according to the procedure described in Example H. The title compound was isolated in 100.0% yield as an off-white solid.