Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:13])[C:9]([OH:12])=[CH:10][CH:11]=1)([O-:5])=[O:4].I[CH:15]([CH3:17])[CH3:16]>CS(C)=O>[CH:15]([O:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[OH:13])([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1O
Reaction time: 0.08 h
Yield: 25.7 %

Procedure:
To a stirred solution of sodium hydroxide (387 mg, 9.67 mmol) in anhydrous DMSO was added 4-nitrobenzene-1,2-diol (500 mg, 3.22 mmol) at 0° C. After stirring for 5 min, 2-iodo-propane (603 mg, 3.55 mmol) was added dropwise. The resulting dark mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water and then acidified with 1M HCl (pH=4) and then the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with sat. NaCl and then dried over MgSO4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography using a gradient of 0-20% EtOAc in hexanes to obtain 2-isopropoxy-5-nitro-phenol (163 mg, 51%)1H NMR (400.0 MHz, CDCl3) δ 7.86 (dd, J=2.5, 8.8 Hz, 1H), 7.76 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.73 (qn, J=6.1 Hz, 1H) and 1.43 (d, J=6.1 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[NH:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[NH:3]1
Reactant: CCOC(=O)c1noc(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
To a solution of crude ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g, 15.14 mmol) in MeOH (2 mL) is added aqueous 1M NaOH (4 mL, 4 mmol) at room temperature. After stirring for 5 hours at room temperature the reaction was quenched with 1N HCl (5 mL, 5 mmol), the crude is concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1C(O)=O.ClC1C=[C:18]([CH:22]=C(C(F)(F)F)N=1)[C:19](O)=O.C(N(CC)CC)C.ClC(OCC(C)C)=[O:38].C[Mg]Br.C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:7]([C:18]([OH:38])([CH3:19])[CH3:22])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=1
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CC(C)COC(=O)Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(O)c1cc(Cl)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (0.45 g, 2.0 mmol) and 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.55 g, 2.4 mmol) (as a mixture from Step A) in tetrahydrofuran (10 mL) cooled in an ice bath was added triethylamine (0.64 mL, 4.6 mmol) followed by isobutyl chloroformate (0.60 mL, 4.6 mmol, Aldrich). The reaction was stirred for 30 minutes, then was filtered through a pad of celite into a flask containing 3.0M methylmagnesium bromide in diethyl ether (4.0 mL, 12 mmol, Aldrich) in tetrahydrofuran (5 mL) also cooled in an ice bath. The celite pad was rinsed with an additional 10 mL of THF. After warming to room temperature, an additional portion of 3.0M methylmagnesium bromide in diethyl ether (4.0 mL, 12 mmol) was added to the reaction mixture. When the reaction was determined to be complete by LCMS, saturated ammonium chloride solution was added to the reaction. After stirring for 20 minutes, the mixture was transferred to a separatory funnel and was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded product (0.28 g, 58%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=1.4 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 1.60 (s, 6H); LCMS (M+H)+: 240.1, 242.1.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3]C.C1OC(O)(CO)COC1(O)CO.[S-:18][C:19]#[N:20].[K+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH2:22]([N:29]1[C:2]([CH2:1][OH:5])=[CH:3][N:20]=[C:19]1[SH:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: N#C[S-]
Reactant: CCCCO
Agent: OCC1(O)COC(O)(CO)CO1
Agent: [K+]
Solvent: CC(=O)O
Product: OCc1cnc(S)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
n-Butanol (50 ml), glacial acetic acid (25 g), dihydroxyacetone dimer (21.0 g), potassium thiocyanate (34.1 g) and benzylamine (28.0 g) are combined at room temperature. The mixture is stirred at room temperature for 50 hours and the product is filtered. A light brown product is obtained, 35.0 g (68.2%), m.p. 229°-231° C. The NMR spectrum shows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:52][C:53]([NH2:56])([CH3:55])[CH3:54]>CN(C=O)C.CO>[C:53]([NH:56][C:26]([C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1)=[O:27])([CH3:55])([CH3:54])[CH3:52]
Reactant: O=C(O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.113 mmol) of the compound from Example 15A was introduced in 1 ml of DMF and admixed with 18 mg (0.136 mmol) of 1-hydroxy-1H-benzotriazole hydrate and with 28 mg (0.147 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride. After 10 minutes of stirring at RT, 2-methylpropan-2-amine (13.1 μl, 0.124 mmol) was added and the mixture was stirred further at room temperature overnight. Subsequently the reaction solution was diluted with methanol and purified by preparative HPLC [Method 5]. This gave 13 mg (24% of theory) of the target compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][C@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: O[C@H]1CCCNC1
Product: CC(C)(C)c1nc(N2CCC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-piperidin-3-ol hydrochloride and isolated as light-yellow gum (13.3 mg, 70%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [N+:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH2:9][S:10]([O-:13])(=[O:12])=[O:11]>>[CH3:9][S:10]([O-:13])(=[O:12])=[O:11].[CH3:8][O:7][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(=O)(=O)[O-]
Reactant: [O-][n+]1ccccc1
Product: CO[n+]1ccccc1
Product: CS(=O)(=O)[O-]

Procedure:
N-methoxypyridinium methanesulfonate was prepared by mixing pyridine N-oxide and an equimolar amount of methylmethanesulfonate and heating the mixture at 95°C for 6 hours. The crude product obtained was recrystallized in a mixture of ethanol and ethyl acetate. By this procedure N-methoxypyridinium methanesulfonate having a melting point of 83° to 85.5°C were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:25]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:15][C:6]2[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=2)=[CH:24][CH:23]=3)=[O:26])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)O)cc4c3)c2cc1OC
Reactant: COc1cccc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(NC(=O)c2cc3cc(Oc4ccnc5cc(OC)c(OC)cc45)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid (0.1 g, 0.27 mmol, from step b), 3-methoxy-phenylamine (68 mg, 0.55 mmol) and DIEA (0.1 mL, 0.55 mmol) in 3 mL of DMF was added PyBOP (0.29, 0.55 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc, and the resulted solution was washed with 30 mL of satd. NaHCO3 followed by 30 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (50% to 100% EtOAc/hexane) to afford off-white solid as desired product. MS (ESI pos. ion) m/z: 470 (M+H). Calc'd Exact Mass for C27H23N3O5: 469.49.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:25])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[C:19]1([C:16]2[C:17](=[O:18])[NH:8][C:9](=[O:25])[N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Reaction time: 0.5 h

Procedure:
To a solution of 17.52 g (50 mmol) of 7-benzyl-9-phenyl-3,4-dihydro-2H,6H-pyrimido-[6,1-b][1,3]thiazine-6,8(7H)-dione in 500 ml of toluene, 25 g (100 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 100 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 4.21 g (32.4%, light white crystal) of the desired product.
Reaction SMILES: CN(P(=NP(=O)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C)C.C1(O)C=CC=CC=1.[CH2:43]([SH:53])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].[O:54]1[CH:60]2[CH:55]1[CH:56]1[CH2:61][CH:59]2[CH2:58][CH2:57]1>P(N(C)C)(N(C)C)N(C)C>[CH2:43]([S:53][CH:60]1[CH:55]([OH:54])[CH:56]2[CH2:61][CH:59]1[CH2:58][CH2:57]2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: C1CC2CC1C1OC21
Reactant: CCCCCCCCCCS
Agent: CN(C)P(=NP(=O)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: CN(C)P(N(C)C)N(C)C
Solvent: Oc1ccccc1
Product: CCCCCCCCCCSC1C2CCC(C2)C1O
Yield: 95 %

Procedure:
A reaction was conducted as described in Example 1 except that tris[tris(dimethylamino)phosphoranylidene-amino]phosphine oxide was replaced with the same molar amount of a partially hydrated tris[tris(dimethylamino)phosphoranylidene-amino]phosphine oxide, [(Me2N)3P=N]3P=O.0.29H2O, phenol was replaced with the same molar amount of decanethiol and PGE was replaced with 2,3-epoxynorbornane. Desired 2-decylthio-3-hydroxynorbornane was formed in an analytical yield of 95% and isolated in a yield of 90%.
Reaction SMILES: CC(CC(C)C)=O.[C:8]1([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>O>[C:8]1([C:14]2([NH:19][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1(c2ccccc2)CCCC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Into a 500 ml four-necked flask, there were charged methylisobutylketone (150 ml), 1-phenylcyclopentylamine (24.3 g) and triethylamine (16.0 g), and trimethylacetyl chloride (18.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, water (200 ml) was added thereto and the reaction mixture was gradually heated to remove methylisobutylketone, followed by cooling at room temperature. The precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to give N-(1-phenylcyclopentyl)trimethylacetamide (33.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[CH2:8]([N:10]([CH2:13]C)CC)C.Cl[PH:16][O:17][CH2:18]N(C)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([P:16]([N:10]([CH3:13])[CH3:8])[O:17][CH3:18])[NH:5][C:6]=1[Cl:7]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCN(CC)CC
Reactant: CN(C)COPCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COP(c1nc(Cl)c(Cl)[nH]1)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (3.44 g, 25.1 mmol) and triethylamine (14.0 mL, 10.16 g, 100.4 mmol) in THF (30 mL) was added dropwise Chloro(N,N-dimethylamino)methoxyphosphine (3.55 g, 25.1 mmol) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 2 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a yellow oil (2.81 g, 79%). 31P NMR (CDCl3) δ 129.3.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[N:48]O)[NH2:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:48]=[C:21]([C:20]3[CH:19]=[C:18]([C:16]4[CH:17]=[C:8]([C:2]([CH3:1])([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:3])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:26]=[CH:25][CH:24]=3)[O:23][N:47]=2)=[CH:42][CH:41]=1
Reactant: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: NC(=NO)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(c1cc(-c2cccc(-c3nc(-c4ccc(F)cc4)no3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of acid from step 2 in DMF (0.05M) was added CDI (2 eq) and 4-fluoro-N′-hydroxybenzenecarboximidamide (2 eq). The reaction mixture was stirred at rt for 15 min and 18 h at 120° C. The reaction mixture cooled to rt, diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 20:80) to afforded the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:24])[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH3:23])[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCCC(=O)O)ncc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.11 mmol), β-alanine (990 mg, 11 mmol) and NaOMe solution (16.6 mL, 8.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 1 with 1 M HCl, and the resulting precipitate was isolated by filtration and dried to give 14 mg of the title compound as a pale yellow solid. MS: (+) m/z 382.22 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]([O:29]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a cooled (0° C.) solution of 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.10 g, approx. 24.1 mmol) in methylene chloride (150 mL) was added a solution of 3-chloroperbenzoic acid (75%, 8.34 g, 36.2 mmol) in methylene chloride (120 ml) over 40 min. The mixture was warmed to rt and allowed to stir over night (16 h). The solution was washed twice with a half-saturated aqueous solution of sodium bisfulfite to destroy excess oxidant. The mixture was then twice washed with half-saturated aqueous potassium carbonate, and brine. The extracts were dried over magnesium sulfate, filtered and concentrated to afford a crude oil which was purified by silica gel chromatography (100% hexanes-80% hexanes/20% ethyl acetate gradient) to afford pure 6-(4-Chloro-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (5.34 g, 71%) as a clear, colorless oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([C:13]1[N:14]([S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)#[N:12].C(N(CC)CC)C.O>ClCCl>[C:11]([C:13]1[N:14]([S:20](=[O:24])(=[O:25])[N:21]([CH3:22])[CH3:23])[CH:15]=[C:16]([CH2:18][O:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1)#[N:12]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(C)S(=O)(=O)n1cc(CO)nc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(COC(=O)c2ccc(Cl)cc2)nc1C#N
Reaction time: 0.75 h

Procedure:
4-Chlorobenzoyl chloride (0.83 g) was added to a solution of 2-cyano-4-hydroxymethyl-1-(dimethylsulphamoyl)-imidazole (1.5 g) in dichloromethane (50 ml), containing triethylamine (1.0 ml) at 0°. The mixture was stirred for 45 minutes whilst the temperature was allowed to rise to room temperature. The mixture was added to water and the organic phase was separated, washed, dried and concentrated under reduced pressure. The residue was recrystallised from a mixture of diisopropyl ether and ethyl acetate to give 2-cyano-4-(4-chlorobenzoyloxy-methyl)-1-(dimethylsulphamoyl)imidazole, m.p. 94≥-96°. (Compound 1)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:7](=[O:23])[CH:6]=2.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[O:23]=[C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:32]#[C:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[CH:4]2)=[CH:9][N:8]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ncc3cc2=O)cc1

Procedure:
The coupling of 4-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzenesulfonamide (0.71 g, 1.81 mmol) with 3-phenyl-1-propyne (0.56 mL, 4.51 mmol) using triethylamine (0.50 mL, 3.61 mmol), CuI (0.025 g, 0.13 mmol), and Pd(Ph3P)4 (0.084 g, 0.07 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification is carried out on a silica gel column eluted with hexanes/ethyl acetate 3:1 to give the desired product.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([CH2:25][OH:26])=[CH:22][CH:21]=1.CN(C)C=O.N1C=CN=C1>CCOCC>[Si:1]([O:26][CH2:25][C:23]1[S:24][C:20]([Br:19])=[CH:21][CH:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(Br)s1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(Br)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyldiphenylsilyl chloride (7.8 mL, 30.1 mmol) was added to a solution of 5-bromo(thiophen-2-yl)methyl alcohol (4.9 g, 25.1 mmol) and 9.7 mL of dimethylformamide. The solution was treated with imidazole (4.29 g, 62.8 mmol) and stirred overnight at room temperature. The solution was diluted with ether and washed with 2% aqueous HCl. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine, and dried (MgSO4), and filtered, and the solvents were removed in vacuo. The residue was purified by silica gel chromatography (hexane) to produce the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:21][C:3]1[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cnc(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Then, 0.10 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) was dissolved in 0.62 ml of pyridine, to which 36 μl of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with 2N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 91 mg (yield, 73%) of 3-[4-chloro-2-fluoro-5-(methanesulfonylamino)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-37; m.p., 168.5° C.).