Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][N:10]([CH3:22])[C:11]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](N)=[CH:13][CH:12]=1)[CH2:4][CH2:3][CH2:2]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].[OH-].[Na+].[ClH:34]>O>[N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][N:10]([C:11]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([Cl:34])=[CH:13][CH:12]=1)[CH3:22])[CH2:4][CH2:3][CH2:2]2
Reactant: CN(CC12CCCN1CCC2)c1ccc(N)c2ccccc12
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(CC12CCCN1CCC2)c1ccc(Cl)c2ccccc12
Reaction time: 0.25 h
Yield: 14.1 %

Procedure:
To 6.31 g (21.4 mmol) of N-(1-azabicyclo[3.3.0]octan-5-yl)methyl-N-methyl-1,4-diaminonaphthalene, water (27.5 ml) and concentrated sulfuric acid (55 ml) were added to dissolve the compound therein. Sodium nitrite (1.40 g, 20.3 mmol) in water (8 ml) was added dropwise to the solution at a temperature of -5+ C. and then stirred for 15 minutes. Cuprous chloride (8.50 g, 85.9 mmol) suspended in concentric hydrochloric acid (18 ml) was added dropwise into the solution which was kept at 85° C. under stirring condition. After further stirring for 5 minutes, the reaction mixture was cooled by water with ice pieces. Several ice pieces were added to the reaction mixture which was made alkaline by adding 10% aqueous sodium hydroxide solution and extracted by chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, purified by column chromatography to afford the desired compound (950 mg, 14.1% ), as a colorless liquid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:12][CH2:13]3)[CH:18]=1)=[O:25])[CH2:31][CH2:30]2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(F)ccc21

Procedure:
100 mg (0.294 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 42 mg (0.31 mmol) 5-fluoro-2,3-dihydro-1H-indole, 100 mg (0.311 mmol) TBTU and 45 μL (0.320 mmol) triethylamine in 10 mL DMF were stirred overnight at RT. The reaction mixture was evaporated down using the rotary evaporator. The residue was dissolved in 3 mL DMF and purified by preparative HPLC-MS. The product fractions were combined and lyophilised.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:15][CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-N—BOC-3-pyrrolidinone (3.0 g) in methanol (30 ml) was added a solution of freshly prepared methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was stirred for 1 hour and then sodium borohydride (0.61 g) was added. After stirring for 4 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to give 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18 g).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=2)[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=2)=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Product: Cn1ccnc1-c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 29 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-pyrimidine-2,4-diamine (31.64 mg, 29% yield) as a beige foam. 1H-NMR (CDCl3) δ 10.68 (s, 1 h), 8.58 (d, J=8.68 Hz, 1H), 8.01 (s, 1H), 7.35 (m. 2H), 7.33 (s, 1H), 7.28 (m, 1H), 7.23 (m, 1H), 7.00 (m, 2H), 6.90 (s, 1H), 5.85 (m, 1H), 3.76 (s, 3H), 3.02 (t, J=9.4 Hz, 2H), 2.80 (m, 3H), 2.69 (m, 2H), 2.05 (m, 2H), 1.30 (m, 2H). LC/MS (ESI+)=523 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.[N+]([C:17]1[O:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=1)([O-])=O>CS(C)=O>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:17]2[O:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:11]([CH3:12])=[O:13]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(C)=O)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.1 g of an 80% dispersion in oil) was added, with vigorous stirring to a solution of (4-hydroxyphenyl)propan-2-one, ethylene ketal (6.8 g) in dimethylsulphoxide (50 ml). After 30 minutes, methyl 5 nitrofuran-2-carboxylate (5 g) was added and the resulting mixture was stirred and heated at 80°-90° C. for 10 hr. The cooled reaction mixture was poured into ice-water and extracted into diethylether. The organic layer was washed with 5% potassium hydroxide solution and water, dried (MgSO4) and evaporated to an oil which was chromatographed on silica gel. Elution with chloroform gave methyl 5-[4-acetonylphenoxy]-furan-2-carboxylate, ethylene ketal (3.3 g) which was taken up in a 1:1 mixture of methanol and 2N hydrochloric acid and stirred at ambient temperature for 4 hr. Evaporation of the methanol and extraction of the aqueous residue into dichloromethane gave an oil which was chromatographed on silica gel. Elution with chloroform gave methyl 5-[4-acetonylphenoxy]furan-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27])([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 73 μL (0.85 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 100 mg (70%) of a white solid; LC/MS: 503/505 (M+H)+, m.p.: 225-226° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].[K+].[Br-]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccc(N)cc1C
Reactant: N#Cc1cccnc1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2cccnc2)cc1C
Yield: 84 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.6 g, 83 mmol) and 3,4-dimetylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (15.6 g, yield 84%, mp 132-134 C, purity 99.7% by HPLC). 1H-NMR (CDCl3):δ 2.24-2.26 (d, 6H), 4.92 (bs, 2H, D2O exchangeable), 6.72-6.74 (d, 1H), 6.78 (s, 1H), 7.11-7.13 (d, 1H), 7.36-74 (m, 1H), 8.22-8.24 (d, 1H), 8.69-8.7 (d, 1H), 9.06 (d, 1H). IR (KBr) cm−1: 3313, 3142, 2997, 2958, 2918, 1651. MS m/z:226.1 (M+).
Reaction SMILES: [N+:1]1([O-])[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Si]([C:19]#[N:20])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:19]([C:6]1[N:1]=[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]=[CH:4][CH:5]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)c1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
A mixture of tert-butyl 2-pyridinecarboxylate N-oxide (12.4 g, 63 mmol), trimethylsilyl cyanide (9.6 g, 96 mmol), N,N-dimethylcarbamoyl chloride (10.3 g, 95 mmol) and nitroethane (80 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (3; 1, v/v) and recrystallized from tetrahydrofuran-hexane to give the titled compound (11.1 g, 85%).
Reaction SMILES: [N:1]1([C:9]([CH2:11][N:12]2[C:18]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([CH2:24][OH:25])=[N:15][CH:14]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:13]2=[O:37])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O.[O-2].[O-2].[Mn+4]>[N:1]1([C:9]([CH2:11][N:12]2[C:18]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([CH:24]=[O:25])=[N:15][CH:14]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:13]2=[O:37])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(NC(=O)NC2N=C(CO)c3cccc(C)c3N(CC(=O)N3CCCCCCC3)C2=O)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)NC2N=C(C=O)c3cccc(C)c3N(CC(=O)N3CCCCCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80320.2 %

Procedure:
A mixture of N-[(3RS)-1-(Azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-hydroxymethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (1.50 mg) and manganese dioxide (15.0 g) in acetone (40 ml) was stirred at ambient temperature for 5 hours. The undissolved substances were removed by filtration. The filtrate was evaporated in vacuo to afford a residue, which was triturated in diisopropyl ether and collected by filtration to give N-[(3RS)-1-(azacyclooctan-1-yl)carbonylmethyl-2,3-dihydro-5-formyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea as crystalline powder (1.20 g, 80.2% yield).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OP(=O)(Cl)Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a mixture of 225 g. phosphoryl chloride and 1.6 g. pyridine there is added 150 g. p-tert-butylphenol over a period of two hours at a temperature of 100°C. The temperature is then raised to 110°C. and held for two hours, stripped and cooled. Distillation of the reaction mixture affords 94.3 percent p-tert-butylphenyl phosphorodichloridate and 2.5 percent di-p-tert-butylphenyl phosphorochloridate.
Reaction SMILES: Br[C:2]1[C:3](OC(C)C)=[C:4]([CH:8]=[CH:9][C:10]=1OC)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Cl-].[Ca+2].C(N(CC)CC)C.[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1.Cl>C(#N)C>[NH:41]1[C:40]([NH:39][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=2)=[N:44][N:43]=[N:42]1
Reactant: COc1ccc(C(=O)O)c(OC(C)C)c1Br
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 1.28 g (4.43 mmol) 3-bromo-4-methoxy-2-(1-methylethoxy)benzoic acid (prepared in Step 3) and 0.83 g 5.12 g (5.12 mmol) of 1,1'-carbonyldiimidazole in 15 ml of acetonitrile is warmed at reflux under nitrogen atmosphere (or CaCl2 filled drying tube) for one hour. The reaction mixture is treated with 1.07 g (10.62 mmol) of triethylamine and 0.44 g (5.17 mmol) of anhydrous 5-aminotetrazole. The resulting mixture is warmed at reflux for 30 hours. The reaction mixture is then poured onto 180 g of ice water and acidified with aqueous 10% HCl and filtered to give 1.32 g (1.58 theor., 84%) of 3-bromo-4-methoxy-2- 1-methylethoxy)-N-1H-tetrazol-5-ylbenzamide as a white solid having melting point 255°-256° C.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][NH:11][C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)[CH:15]=[CH:14][C:13]=1[CH2:24][NH:25][C:26](=[O:38])[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([CH3:35])=[C:29]([O:36][CH3:37])[CH:28]=1)C1C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:37][O:36][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([O:33][CH3:34])[C:30]=1[CH3:35])[C:26]([NH:25][CH2:24][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[CH:17][C:12]=1[NH:11][CH2:10][C:9]([OH:39])=[O:8])=[O:38]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)OCc2ccccc2)cc(OC)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(=O)O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
To a solution of compound 14a (110 mg, 0.29 mmol) in a mixture of THF (3 mL) and methanol (3 drops) was added 10% LiOH (1 mL). The reaction mixture was stirred for 5 h at rt and acidified with 1 N HCl. The resulting solid was filtered, washed with water, and dried to give compound 47a (57 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].CI.[C:33](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:33]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), methyl iodide (0.14 mL, 0.23 mmol), and potassium carbonate (31 mg, 0.23 mmol) in acetone (4 mL) was stirred at room temperature for 4 h. Excess potassium carbonate was removed and the reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 30% EtOAc/hexanes to afford 74 mg of 5-(5-(3-fluoro-4-methoxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. LCMS [M+1]+ 451.4
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=O)[CH:10]=[O:11].C1(C)C=CC=CC=1>C(O)C>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=[CH:9][C:10]1=[O:11]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2ccccc2[nH]1
Temperature: 45 °C
Yield: 93 %

Procedure:
To a stirred suspension of o-phenylenediamine (50 g, 462.9 mmol) in ethanol (200 mL), at rt was added a solution of ethyl glyoxalate in toluene (50%; 113 mL, 555.48 mmol) over a period of 45 min. After heating to 45° C. for 10 h, the mixture was left at rt under stirring. The precipitate was filtered and the residue was washed with water and dried to give 1H-quinoxalin-2-one as an off-white powder (63 g, 93%): 1H-NMR (300 MHz, d6-DMSO): δ=12.44 (1H, s), 8.19 (1H, s), 7.78 (1H, d), 7.55 (1H, dd), 7.32 (2H, m) ppm.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>Cl.C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C@@H:5]1[CH2:4][N:3]([CH2:1][CH3:2])[CH2:7][C@H:6]1[OH:8]
Reactant: Sc1ccccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Sc2ccccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.1 mole) of crude 1-ethyl-3,4-epoxypyrrolidine, 14.4 g. (0.1 mole) of 2-chlorothiophenol and 1 drop concentrated hydrochloric acid on a steam bath overnight. The reaction mixture was dissolved in methylene chloride and the solution was washed with two 100-ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 23.8 g. of dark oil as residue which solidified when scratched with petroleum ether. The solid was collected by filtration and recrystallized from cyclohexane to yield 10 g. (39%) of tan solid, m.p. 90.5°-92.5°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:27]1)[CH:19]=[CH:18]2.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH2:25][N:26]1[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:27]1)[CH:19]=[CH:18]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4nc(-c5ccccc5)oc4C)ccc3c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(Cn3cc(CCC(=O)O)c(-c4ccccc4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.1 %

Procedure:
A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (243 mg, yield: 84%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 122–123° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Br)n1
Product: Cc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 51.1 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-6-methyl-3-nitropyridine (108 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as brown viscous oil (57 mg, 51%). 1H NMR (DMSO) δ 2.42 (s, 3 H), 3.31 (s, 3 H), 7.11 (d, J=8.0 Hz, 1 H), 7.51-7.63 (m, 5 H), 7.89 (d, J=8.0 Hz, 1 H); 13C NMR δ 14.6, 23.8, 118.0, 126.1, 127.7, 128.7, 129.4, 132.1, 134.8, 148.3, 150.9, 151.1. HRMS: cal for C14H14N3 [M+H+]: 224.1188; found: 224.1184.
Reaction SMILES: [Cu](C#N)C#N.[Br-].[Li+].[I-].[C:9]([C:11]1[CH:12]=[C:13]([Zn+])[CH:14]=[CH:15][CH:16]=1)#[N:10].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>O1CCCC1>[CH3:20][CH:19]([CH3:21])[C:18]([C:13]1[CH:12]=[C:11]([C:9]#[N:10])[CH:16]=[CH:15][CH:14]=1)=[O:22]
Reactant: N#Cc1cccc([Zn+])c1
Reactant: CC(C)C(=O)Cl
Agent: N#C[Cu]C#N
Agent: [Br-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a mixture prepared by adding copper cyanide (940 mg, 10.5 mmol) to a cooled solution of lithium bromide (1.82 g 21 mmol) in tetrahydrofurn at −25° C. under argon atmosphere was added a solution of 0.5M 3-cyanophenyl zinc iodide (20 ml, 10 mmol) in tetrahydrofuran. The reaction mixture was allowed to warm to 0° C. for 30 minutes then cooled down to −25° C. to which neat isobutyryl chloride (1.06 ml, 10.1 mmol) was added all at once. The reaction was kept at −25° C. for 30 minutes then quenched by adding 20 ml of a saturated solution of ammonium chloride. The mixture was extracted with 2×25 ml diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The crude oil was flushed through a silica plug using 10% ethyl acetate in hexane to give 3-(2-methylpropanoyl)benzenecarbonitrile (1.25 g, 72%) as a clear oil. H1NMR (CDCl3): 2.2-2.25 (d, H); 4.499-4.568 (m, H); 8.614-8.655 (m, 2H); 8.831-8.857 (m, H); 9.172-9.238 (m, H). ES-M (M+H+): 174.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:14]=1[NH:15][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 15.8 %

Procedure:
Using 5-methylsalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.