Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].[CH:29](OCC)(OCC)OCC.Cl>>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][CH:29]=[N:27][N:26]=1
Reactant: CCOC(OCC)OCC
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Agent: Cl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nncs1)OCO3
Yield: 77 %

Procedure:
A mixture of 0.57 g (1.43 mmol) of the starting material XVIII, 6 ml of triethyl orthoformate and a catalytic amount of hydrochloric acid was stirred at 80° C. for 1 h. After cooling the precipitated crystals were filtered off, washed with ethanol and dried to yield 0.45 g (77%) of the title compound; Mp.: 212-213° C.
Reaction SMILES: [Cl-].[Li+].[CH:3]([Mg]Cl)([CH3:5])[CH3:4].[C:8](Cl)(=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.[Cu]Cl>[CH3:4][CH:3]([CH3:5])[C:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)[Mg]Cl
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium chloride (27 mmol) and copper (I) chloride (13.46 mmol) are weighed into a flame dried 250 mL round-bottomed flask fitted with low temperature thermometer. Dry THF (50 mL) is added and the mixture stirred at RT for 1 h to give a cloudy yellow-green solution. This is cooled to −55° C. and isopropylmagnesium chloride (6.75 mL of a 2 M solution in THF, 13.5 mmol) is added. After 15 min hydrocinnamoyl chloride (13.46 mmol) is added quickly at −60° C. and the mixture allowed to warm slowly to RT overnight. The mixture is quenched with water (100 mL) and 35% ammonium hydroxide (20 mL) is added. The mixture is stirred at RT for 1 h and then extracted with diethyl ether (3×50 mL). The combined ether extracts are washed with saturated brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give 4-methyl-1-phenyl-pentan-3-one.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:82][CH2:83][CH2:84][CH2:85][NH:86]C(OC(C)(C)C)=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:62]([C:63]#[N:64])=[C:61]([S:65][CH2:66][C:67]3[N:68]=[C:69]([C:72]4[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=4)[O:70][CH:71]=3)[N:60]=[C:59]([NH2:79])[C:58]=2[C:80]#[N:81])=[CH:53][CH:52]=1)[CH2:19][O:20][C:21](=[O:48])[CH2:22][CH2:23][NH:24][C:25](=[O:47])[C@@H:26]([NH:39]C(OC(C)(C)C)=O)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97]>ClCCl>[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[NH2:39][C@@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:82][CH2:83][CH2:84][CH2:85][NH2:86])[CH2:49][O:50][C:51]1[CH:52]=[CH:53][C:54]([C:57]2[C:62]([C:63]#[N:64])=[C:61]([S:65][CH2:66][C:67]3[N:68]=[C:69]([C:72]4[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=4)[O:70][CH:71]=3)[N:60]=[C:59]([NH2:79])[C:58]=2[C:80]#[N:81])=[CH:55][CH:56]=1)=[O:48])=[O:47]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCNC(=O)[C@@H](N)CCCCN)OC(=O)CCNC(=O)[C@@H](N)CCCCN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 70 mg (0.058 mmol) of the compound from example 31A was introduced in 0.5 ml of dichloromethane, admixed with 0.045 ml (0.578 mmol) of trifluoroacetic acid and stirred at RT. After 3 hours, again, the same amount of trifluoroacetic acid was added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 45 mg (55% of theory) of the target compound.
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[C:11]([Br:18])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>O.O1CCOCC1>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:1])=[C:11]([Br:18])[CH:10]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1Br
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A solution of NaOH (7.8 g, 190 mmol) in water (60 mL) was cooled in an ice bath, and bromine (2.51 mL, 49 mmol) was slowly added. A solution of 1-(4-tert-butyl-2-bromophenyl)ethanone (3.1 g, 12 mmol) in dioxane (60 mL) was slowly added, and the cooling bath was removed. After being stirred at room temperature for 3 h the reaction was acidified with concentrated hydrochloric acid. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-tert-butyl-2-bromobenzoic acid (3.1 g, 100% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.3 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H), 7.41 (dd, J=8.3, 1.9 Hz, 1H), 1.34 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[ClH:13].OO.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.CN(C)C=O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: CNC(=O)c1cccc(C)c1N
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 10 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A mixture of 2-amino-N,3-dimethylbenzamide (i.e. the product of Step A) (16.6 g, 100 mmol) and N,N-dimethylformamide (15.0 g) was cooled to 10° C. and concentrated hydrochloric acid (70 g, 700 mmol) was slowly added. Then the mixture was heated to 30° C., and 30% aqueous hydrogen peroxide (18.5 g, 160 mmol) was added dropwise over 15 minutes at 30-35° C. After stirring at about 35° C. for 3 h, the mixture was cooled to about 10° C., and then water (200 mL) was added. Sodium sulfite (7.56 g, 60 mmol) was added, and then the pH was adjusted to 2.2 by slow addition of 50% aqueous sodium hydroxide (38.1 g). After stirring at 10° C. for 15 minutes, the mixture was filtered, and the solids were washed with water (2×50 mL), and dried in the vacuum oven to afford the title compound as pink solids, 14.61 g (72.7% yield). Quantitative HPLC of the solid product showed 99.1 wt % of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[O:7])=[CH:4][C:3]=1[O:17][CH3:18].CN(C)CCNC(=O)C1C=CC([N+]([O-])=O)=C(OC)C=1>>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:13][CH2:12][N:11]([CH3:14])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Agent: COc1cc(C(=O)NCCN(C)C)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)NCCCN(C)C)ccc1N

Procedure:
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3-methoxy-4-nitro-benzamide (Intermediate 197).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])(=[O:3])[NH2:2].[N+:14](=[CH2:16])=[N-:15]>C(OCC)C>[S:1]([C:5]1[CH:6]=[C:7]([C:8](=[O:9])[CH:16]=[N+:14]=[N-:15])[CH:11]=[CH:12][CH:13]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: C=[N+]=[N-]
Reactant: NS(=O)(=O)c1cccc(C(=O)Cl)c1
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1

Procedure:
11 g of 3-sulfamoylbenzoyl chloride were reacted as prescribed in Example 66b) with diazomethane in diethyl ether and the crystals were filtered off. Melting point: 142° C.
Reaction SMILES: Cl.[C:2]([S:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([CH3:17])[CH2:14][CH2:13][CH2:12]2)(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:27])=[C:24]([NH2:26])[CH:25]=1.N>Cl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:2]([S:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:16]=3[N:15]([CH3:17])[CH2:14][CH2:13][CH2:12]4)[NH:26][C:24]=2[CH:25]=1
Reactant: CN1CCCc2cccc(CSC(=O)O)c21
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: N
Product: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Yield: 14.7 %

Procedure:
8-Carboxythiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline hydrochloride (27.9 g) and 5-methoxy-o-phenylenediamine (13.8 g) in 4N hydrochloric acid (100 ml) were refluxed for 40 minutes. The reaction mixture was cooled, neutralized with aqueous ammonia and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (4:1)] to give 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][C@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@H:12]2/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][P:32]([O:37]CC)([O:34]CC)=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[Si](C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:15][C@H:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:13][C@H:12]2/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][P:32]([OH:37])([OH:34])=[O:33])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a solution of (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-diethoxyphosphoryl-1-pentenyl]pyrrolidine (146 mg) in dichloromethane (5.0 ml) was added bromotrimethylsilane (0.1 ml) and the mixture was stirred at room temperature for 3 hours. After the mixture was evaporated to dryness, the residue was dissolved in acetone (5 ml), and water (20 μl) was added thereto. The mixture was stirred at room temperature for 1 hour and the solvent was evaporated in vacuo. The residue was solidified with a mixture of chloroform and water to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-phosphono-1-pentenyl]pyrrolidine (70 mg) as a powder.
Reaction SMILES: [H-].[Na+].CS(O[C@@H:8]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=O)=O.CCOC(C)=O.CO>C1COCC1.CCCCCC>[Si:30]([O:29][CH2:28][C@H:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(C(F)(F)F)cc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 58.8 %

Procedure:
To a suspension of 4.0 g sodium hydride (60% dispersion in mineral oil) in 50 mL THF at 0° C. was added a solution (1R,2R)-1-((tert-butoxycarbonyl)amino)-3-(tert-butyldimethylsilyloxy)-1-(4-(trifluoromethyl)phenyl)-propan-2-yl methanesulfonate (13.5 g, 25.6 mmol) in 60 mL THF. The reaction progress was monitored by TLC (20% EtOAc in hexane). When no more starting material could be detected, 4 grams of MeOH was added to the mixture to remove the excess sodium hydride. The solvent was then removed at reduced pressure, and 200 mL of distilled water was added to the residue. The aqueous phase was extracted (3×150 mL) with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was then chromatographed eluting with 3% EtOAc in hexane. After removing the solvent, the product was obtained as a colorless oil (6.5 g, yield=58%). 1H NMR (400 MHz, CD3OD) o ppm 0.14-0.18 (m, 6 H) 0.95-0.98 (m, 9 H) 1.46 (s, 9 H) 2.78 (q, J=2.80 Hz, 1H) 3.64 (d, J=2.93 Hz, 1H) 4.11 (ddd, J=18.19, 11.93, 2.54 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.66 (d, J=8.02 Hz, 2H).
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([O:23]CC=C)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])=O.[NH4+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:6][CH:7]([O:9][C:10]([NH:12][CH2:13][C:14]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C[O-]
Solvent: C1COCCO1
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Yield: 78 %

Procedure:
To a stirred solution of compound (15) (1 g, 2.7 mmol) in dioxane (9 mL) was added ammonium formate (341 mg, 2.7 mmol) and palladium (II) acetate (12 mg) under a nitrogen atmosphere. The reaction mixture was heated to reflux for one hour and then concentrated in vacuo. The resulting oily residue was taken up in diethyl ether (50 mL), washed with 2N HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude compound was purified by column chromatography on silica gel, eluting with 30% ethyl acetate:hexane to give the desired product (11) as a colorless oil, which solidified on further standing at room temperature for 12 h (0.70 g, 78% yield), m.p. 62–64° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([CH2:14][CH2:15][O:16]C(=O)C)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1)[CH3:4].Cl>C(O)C>[CH2:3]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[O:13])=[CH:10][CH:11]=1)[CH2:14][CH2:15][OH:16])[CH3:4]
Reactant: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CCO)c1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A 150 ml of NaOH-solution (5 M in water) is added to a solution of 59.2 g (252 mmol) of 17 in 200 ml of ethanol and the mixture is stirred overnight at 40° C. The reaction mixture is cooled in an ice bath and neutralized with HCl (5 M) and extracted with dichloromethane. The organic layer is washed with a saturated NaHCO3-solution, with brine and dried over MgSO4. The solvents are evaporated under reduced pressure. The product is isolated as an oil and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:28]=[C:27]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]3[C:15]4[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:31])[N:26]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Oc3ccnc4ncc(=O)[nH]c34)c2)cc1

Procedure:
Method F2 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as a slightly yellow solid (9 mg, 13%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21](=[O:23])(=[O:22])[N:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19](=[O:28])[CH:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[O:36]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[C:24]([N:20]1[C:19](=[O:28])[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][S:49]([C:46]3[CH:45]=[CH:44][C:43]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:48][CH:47]=3)(=[O:51])=[O:50])=[CH:12][CH:13]=2)[S:21]1(=[O:23])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CCN)cc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[4-(2-Aminoethyl)phenyl]-2-tert-butylisothiazol-3(2H)-one 1,1-dioxide trifluoroacetate (36.7 mg, 0.0869 mmol) and triethylamine (36.3 μL, 0.260 mmol) were dissolved in N,N-dimethylformamide (0.15 mL). 4-Phenoxybenzenesulfonyl chloride (29.2 mg, 0.109 mmol) was added and the reaction was allowed to stir at room temperature for 30 minutes. The reaction was chromatographed on a 21.2 mm Luna C18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 15 minute period. The major fraction was evaporated to a clear glass (18 mg, 38%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.41 (t, J=8.1 Hz, 2H), 7.27 (d, J=7.8 Hz, 3H), 7.23 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 3.25 (t, J=6.8 Hz, 2H), 2.87 (t, J=7.1 Hz, 2H), 1.73 (s, 9H); LCMS found for C27H32N3O6S2 (M+NH4)+: m/z 558.2.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[Cl:21][C:19]1[N:18]=[CH:17][C:14]2[C:15]3[N:9]([CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1)[CH:8]=[C:7]([C:5]1[N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[N:2]=[CH:3][N:4]=1)[N:16]=3
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: NNc1ccccc1Cl
Agent: Cl
Product: Clc1cc2c(cn1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedures of Example 378, 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide was reacted with 2-chlorophenylhydrazine hydrochloride to give 8-chloro-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (MS(ESI+) 399.1/401.1) which was reacted with L-prolineamide to give 410. MS(ESI+) 477.1. 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.29 (br, 1H), 6.91 (br, 1H), 5.83 (s, 1H), 4.45-4.38 (m, 4H), 4.23 (d, J=7.7 Hz, 1H), 3.61-3.53 (s, 1H), 3.40-3.32 (m, 1H), 2.23-2.06 (m, 1H), 2.02-1.84 (m, 3H)
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[NH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:13][C:14]1[N:15]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ncc([N+](=O)[O-])n1-c1nccc2[nH]c(=O)ccc12
Yield: 66.7 %

Procedure:
A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 12.7 g of 2-methyl-5-nitro-1H-imidazole, 3.45 g of anhydrous potassium carbonate and 50 ml of N-methylpyrrolidinone was refluxed for 5.5 hours, cooled and concentrated in vacuo to remove most of the solvent. To the concentrate was added 100 ml of water and 10 ml of 35% aqueous sodium hydroxide; and, the mixture was treated with decolorizing charcoal and filtered. The filtrate was acidified with acetic acid and the precipitate was collected, washed with water, dried, recrystallized from dimethylformamide, and dried in a vacuum oven at 90°-95° C. to yield 4.5 g of 5-(2-methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2-(1H)-one, m.p. >300° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:17]=2[N:18]=1.[F:29][C:30]([F:47])([F:46])[C:31](=[O:45])[CH2:32][C:33]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[O:43][CH3:44])([CH3:35])[CH3:34]>C1COCC1>[F:47][C:30]([F:29])([F:46])[C:31]([CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:17]=2[N:18]=1)([OH:45])[CH2:32][C:33]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[O:43][CH3:44])([CH3:35])[CH3:34]
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1nc2cc(-c3ccccc3)ccc2o1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. 2-Methyl-5-phenyl benzoxazole (75 mg, 0.4 mmol) dissolved in anhydrous THF (2 mL) was added to this mixture dropwise. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 150 mg of the title compound as white crystals, m.p. 103° C.-104° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][OH:21].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][O:21][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 118 mg of 4,4-dimethyl-2-pentyn-1-ol, to which 43 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(4,4-dimethyl-2-pentynyloxy)-6-(2,3-difluorophenyl)pyrimidine (the present compound (119)).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C1CCCCN1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-ethoxycarbonylhexahydropyridine (5 g, 32 mmol) and triethylamine (3.2 g, 32 mmol) in 15 ml of benzene is added dropwise to phosgene, with ice-bath cooling. After the addition is complete, the mixture is allowed to warm to RT and is stirred for 2 hours. The reaction is diluted with benzene to about 150 ml, washed with water (3X), dried over sodium sulfate and stripped to give N-chlorocarbonyl-2-ethoxycarbonylhexahydropyridine.