Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc2ccc(Br)cc2n1
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 100 °C
Yield: 93 %

Procedure:
To the suspension of 7-bromoquinoxalin-2-ol (2 g, 8.88 mmol) in neat phosphorus oxychloride (7 mL) was added DMF (2 drops). The mixture was heated to 100° C. for 3 h. Then it was cooled to room temperature. Phosphorus oxychloride was removed under vacuum, and the residue was dissolved into EtOAc and dropped into ice water with stirring. The mixture was extracted with EtOAc for three times, the combined organic layer was washed with saturated NaHCO3 solution. Then the organic layer was concentrated to afford 7-bromo-2-chloroquinoxaline as a solid in 93% yield (2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:17])C(=O)C1>ClCCl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1N
Solvent: ClCCl
Product: N#Cc1cc(Br)ccc1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
2-Aminobenzonitrile (5.0 g, 42.3 mmol) was taken into dichloromethane (60 mL). NBS (7.54 g, 42.3 mmol) was added and stirred at 0° C. for 3 h. The reaction mixture was diluted with dichloromethane and washed with brine, dried over MgSO4. The crude product was purified by column chromatography (hexane/ethyl acetate=10/1) to afford the titled compound (7.20 g, 87%). 1HNMR (400 MHz, DMSO-d6): δ 6.22 (s, 2H), 6.75 (d, J=9.2 Hz, 1H), 7.42 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.58 (s, 1H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[CH:6]=[CH:5][N:4]2[CH:15]=[N:2][N:1]=[C:3]2[CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1cc(-c2ccccn2)ccn1
Product: c1ccc(-c2ccn3cnnc3c2)nc1

Procedure:
A mixture of 2.0 g of 2'-hydrazino-2,4'-bipyridine and 50 ml of triethyl orthoformate was heated on a steam bath for 18 hours then chilled and filtered. The crystals were dissolved in methylene chloride, treated with activated carbon, filtered and the filtrate concentrated. Chilling and filtration gave 1.5 g of the desired product as cream colored crystals, mp 144-°145° C.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]([O:11]CC)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:20]([NH:2][C:3]2([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: Cl
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Yield: 33.4 %

Procedure:
The same reaction procedure as used in Reference Example 4 was repeated by using 4.36 g (21 mmol) of ethyl 1-aminocyclohexanecarboxylate hydrochloride and 3.15 g (21 mmol) of morpholine carbonyl chloride, whereby 1.8 g of the captioned 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 33%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: BrBr
Reactant: COc1cccc(-c2cn3ccnc(Cl)c3n2)c1
Solvent: CC(=O)O
Product: COc1cccc(-c2nc3c(Cl)nccn3c2Br)c1

Procedure:
To the product from example 170 in acetic acid (10 mL) was added a solution of bromine in acetic acid (0.25 mmol, 1 mL). Concentration of the reaction mixture afforded crude 3-bromo-8-chloro-2-(3-methoxy-phenyl)-imidazo[1,2-a]pyrazine. MH+ (LCMS) 338.0(m/z).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CC(N)C1)(OC(C)(C)C)=O>>[NH:48]1[CH2:43][CH:44]([NH:49][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:47]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N—Boc 3-amino azetidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.28 (m, 1 H) 1.33-1.46 (m, 2 H) 1.59-1.66 (m, 2 H) 1.75-1.87 (m, 4 H) 3.32 (s, 3 H) 3.67-3.80 (m, 4 H) 3.95 (s, 3 H) 4.07 (t, 2 H) 4.4-4.5 (m, 1 H) 4.65-4.83 (m, 1 H) 7.50 (d, J=8.3 Hz, 1 H) 7.54 (d, J=1.5 Hz, 1 H) 7.93 (s, 1 H) 8.21 (s, 1 H) 8.29 (d, J=8.1 Hz, 1 H) 8.81 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C25H31F2N7O3 516; found 516.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14](S(C)(=O)=O)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].CC[N:47](C(C)C)C(C)C>CO>[NH2:47][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:22]3[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)[CH:25]=[CH:26][C:27]=3[Cl:28])[C:8]([NH:7][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:43])=[N:21][C:12]=2[N:13]=1
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(S(C)(=O)=O)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of N—{3-[7-(3-tert-butyl-ureido)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-6-yl]-2,4-dichloro-phenyl}-3-trifluoromethyl-benzamide (80 mg, 0.12 mmol) in methanol (5 ml) is added ammonium (methanol solution, 20 ml, 0.14 mmol) and DIEA (41 μl, 0.24 mmol). The reaction is stirred at 80° C. for 4 hours. The methanol is removed by rotary evaporation and the crude product is purified by RP-HPLC to give the title compound as a white solid: 1H NMR 400 MHz (DMSO) δ 10.46 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 8.23 (d, 2H, J=8.0 Hz), 8.00 (s, 1H), 7.96 (d, 1H, J=8.4 Hz), 7.76 (m, 3H), 7.68 (d, 1H, J=8.8 Hz), 7.48 (s, 2H), 1.32 (s, 9H); MS m/z 592.2 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:34]3[CH2:35][CH2:40][CH2:39][CH2:38]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product.
Reaction SMILES: [C:1]([Si:5]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:6][CH:7]1[C:11]([CH2:14][OH:15])([CH2:12][OH:13])[O:10][CH:9]([N:16]2[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:17]2=[O:23])[CH:8]1[OH:24])([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(C1C=CC=CC=1)([C:46]1[CH:53]=[CH:52][C:49]([O:50][CH3:51])=[CH:48][CH:47]=1)[C:38]1[CH:45]=[CH:44][C:41]([O:42][CH3:43])=[CH:40][CH:39]=1.C(O[CH2:65][CH3:66])(=O)C>N1C=CC=CC=1>[CH3:51][O:50][C:49]1[CH:48]=[CH:47][C:46]([CH:37]([C:38]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[CH:44][CH:45]=2)[O:13][CH:12]([C:66]2[CH:65]=[CH:9][CH:8]=[CH:7][CH:11]=2)[C:11]2([CH2:14][OH:15])[O:10][CH:9]([N:16]3[CH:21]=[CH:20][C:19](=[O:22])[NH:18][C:17]3=[O:23])[CH:8]([OH:24])[CH:7]2[O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:53][CH:52]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](OC1C(O)C(n2ccc(=O)[nH]c2=O)OC1(CO)CO)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C2(CO)OC(n3ccc(=O)[nH]c3=O)C(O)C2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
Preferential protection with DMT at the α-hydroxymethyl position is performed following a published literature procedure (Nomura, M., et. al., J. Med. Chem. 1999, 42, 2901-2908). Generally, a solution of Compound 11 (1 eq.) in anhydrous pyridine is treated with DMTCl (1.3 eq.), then stirred at room temperature for several hours. Subsequently, the mixture is poured into ethyl acetate, washed with water, dried over anhydrous Na2SO4, filtered, and evaporated. Purification by silica gel chromatography will yield Compound 12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.C(NC(C)C)(C)C.[Cl:39][C:40]1[N:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>>[Cl:39][C:40]1[N:45]=[CH:44][C:43]([S:46]([N:17]2[CH2:16][CH2:15][C:14]3[C@:19]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[O:22])([CH2:20][C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[C:12]=4[CH:13]=3)[CH2:18]2)(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reaction time: 16 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 mL) (2.7 mL, ˜0.2 mmol) containing diisopropylamine (174 μL, 1 mmol) was added to 6-chloro-pyridine-3-sulfonyl chloride (53 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (85 mg). LCMS (Method B ESI): RT 3.92 min, m+H=550.0; 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=2.5 Hz, 1 H); 8.61 (d, J=4.7 Hz, 1 H); 7.85-7.86 (m, 3 H); 7.48-7.49 (m, 1 H); 7.42-7.43 (m, 2 H); 7.35 (d, J=8.4 Hz, 1 H); 7.27 (s, 1 H); 7.15-7.16 (m, 2 H); 6.50 (s, 1 H); 5.57 (d, J=12.4 Hz, 1 H); 4.23 (d, J=16.9 Hz, 1 H); 3.85-3.95 (m, 1H); 2.86-2.87 (m, 3 H); 2.66 (d, J=11.9 Hz, 1 H); 2.53 (d, J=15.1 Hz, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:7])C.[OH-].[Na+].C(OCC)C>C(O)C.O>[F:14][C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:15])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(C)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(CC(=O)O)c1cccc(F)c1
Yield: 92.6 %

Procedure:
A crude solution of 3-(3-fluorophenyl)butyric acid ethyl ester, 10.1 g, 48 mmol] in ethanol (50 mL) was treated with 10 M NaOH solution (50 mL, 857 mmol). The reaction mixture was refluxed overnight. The reaction mixture was dried under reduced pressure in order to get rid of the ethyl alcohol. The resulting residue was re-dissolved in 150 mL of water. The mixture was transferred to a separatory funnel using water (50 mL) and diethyl ether (200 mL). The mixture was equilibrated and the ether layer was removed. The aqueous layer was acidified by HCl solution (pH˜2) and extracted with diethyl ether (300 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This afforded 8.1 g of an orange viscous oil, 3-(3-fluorophenyl)butyric acid (92.6% yield). This material was determined to be 100% pure by GC/MS analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[K+].Cl[CH2:14][C:15](=[O:17])[CH3:16].C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:14][C:15]([CH3:16])=[O:17])=[O:6]
Reactant: O=C([O-])c1ccccc1CO
Reactant: CC(=O)CCl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)COC(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of potassium 2-hydroxymethylbenzoate (9.45 g) and chloroacetone (5 ml) in dry dimethylformamide (100 ml) was stirred for 3 hours at room temperature. Ethyl acetate and brine were then added and the organic layer, after further washing with water, was dried and evaporated to obtain acetonyl 2-hydroxymethylbenzoate (10 g) as a white powder. A solution of this material (1 g) in dimethylformamide (20 ml) was stirred for 3 hours in the presence of tert-butyldiphenylsilylchloride (2.32 ml) and imidazole (0.864 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([NH:13][CH3:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CN
Solvent: CCO
Product: CNc1cc(F)c(C#N)cc1F
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of 2,4,5-trifluorobenzonitrile (0.575 g, 3.7 mmol) in ethanol (20 ml) was added methylamine (30% aq, 4.2 ml, 37 mmol) and the mixture stirred for 3 h. The reaction mixture was then partitioned between diethyl ether (100 ml) and water (100 ml), and the aqueous layer re-extracted with diethyl ether (100 ml). The combined ether extract was washed with brine (200 ml), dried (MgSO4) and evaporated to give 2,5-difluoro-4-methylaminobenzonitrile (0.549 g, 89%), mp 160-163° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][N:7]=1
Reactant: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)c2ccc(F)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To methyl 6-fluoro-1oxo-1,2-dihydroisoquinoline-4-carboxylate (756 mg), phosphoryl chloride (5 ml) was added, and the mixture was stirred at 100° C. for one hour. The resulting solution was returned to room temperature, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, saturated sodium bicarbonate water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give methyl 1-chloro-6-fluoroisoquinoline-4-carboxylate (792 mg) as a brown solid.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11](=[O:37])[CH:12]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[C:29]([CH:30]=[O:31])=[C:28]([Cl:32])[N:27]=[C:26]3[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:19]=2)[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:40].C([N+](CCCC)(CCCC)CCCC)CCC>N1C=CC=CC=1>[C:1]1([CH3:38])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C:11](=[O:37])[CH:12]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[C:29]([C:30]([OH:40])=[O:31])=[C:28]([Cl:32])[N:27]=[C:26]3[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:19]=2)[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C2CCCC2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: c1ccncc1
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
250 mg (0.45 mmol) of the compound from Example III are dissolved in 2.5 ml (0.45 mmol) of pyridine and 162 mg of tetrabutylammonium permanganate, dissolved in 1.5 ml of pyridine, are added at 60° C., and the mixture is stirred at 60° C. for 2 h. The pyridine is evaporated, and the residue is taken up in water, acidified with dilute HCl and extracted with ethyl acetate. The organic phase is concentrated and the residue is chromatographed on silica gel 60 using CH2Cl2 /MeOH (10:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].[N:15]([O-])=O.[Na+].S(=O)(=O)(O)O>O.Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:7]([OH:11])=[O:13])=[N:15][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(F)ccc2C1=O
Reactant: O=N[O-]
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1n[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Fluoroisatin prepared according to the method of J. Org. Chem., 21, 169 (1956) is added to a solution of sodium hydroxide (7.4 g) in water (130 ml), and the mixture obtained is gently heated until it dissolves. After the solution is cooled to 0° C., a solution of sodium nitrite (13.8 g) in water (45 ml) is added dropwise to the reaction mixture, and this mixture is poured, in small portions with vigorous stirring, into the sulfuric acid (33.9 g) in water (430 ml) at 0° C. The mixture is stirred for 30 minutes at 0° C. A solution of stannous chloride (85.3 g) in hydrochloric acid (170 ml) is added dropwise to the reaction mixture at 0° C., and the mixture is stirred at 25° C. for 2 hours. The precipitates are collected and washed successively with water, acetone, and methanol, and dried to give the title compound (15.6 g), m.p. > 290° C. Mass spectrum: m/z 180.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:17]=[C:18]=[S:19])=[C:5]([C:20]([F:23])([F:22])[F:21])[N:4]=1.[CH3:25][O-:26].[Na+].[CH3:28]I>C1COCC1.CO>[F:24][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:17]=[C:18]([O:26][CH3:25])[S:19][CH3:28])=[C:5]([C:20]([F:23])([F:22])[F:21])[N:4]=1
Reactant: CI
Reactant: C[O-]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N=C=S)c1CC(C)C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(N=C(OC)SC)c1CC(C)C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 2.5 g (6.8 mmol) of methyl 2-(difluoromethyl)-5-isothiocyanato-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,129,943 example 41 step A) in 25 ml of anhydrous THF at room temperature was added 1.6 g (7.5 mmol) of 25% sodium methoxide in methanol. The reaction mixture was stirred for 30 min and was treated with 1.93 g (14 mmol) of methyl iodide. The reaction mixture was stirred for 3 h and concentrated in vacuo. The residue was partitioned with ether (75 ml) and 10% HCl (50 ml). The organic layer was washed with water (3×30 ml), dried (MgSO4), and concentrated in vacuo. The crude product was purified by chromatotron (20% EtOAc in hexane) to afford 2.32 g (82%) of a colorless oil, n25D 1.5982.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH:26]([Br:28])[Br:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][Br:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[O:16]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH:26]([Br:27])[Br:28])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[C:33]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)(=[O:32])[CH3:34].[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=[O:43])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: BrC(Br)c1cccc(Oc2ccccc2)c1
Agent: O=Cc1cccc(Oc2ccccc2)c1
Solvent: CO
Product: BrCc1cccc(Oc2ccccc2)c1
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The resulting m-phenoxybenzyl bromide can be easily esterified in a solvent such as acetic acid to produce m-phenoxybenzyl acetate. The product can be easily converted into m-phenoxybenzyl alcohol by a hydrolysis with a base in a solvent such as methanol. In accordance with the aforementioned treatment, m-phenoxybenzylidene dibromide is converted into m-phenoxybenzaldehyde. Thus, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde are produced by the treatment of the mixture of m-phenoxybenzyl bromide and m-phenoxybenzylidene dibromide, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde can be separated from the mixture by a distillation under a reduced pressure.
Reaction SMILES: O.[NH2:2][NH2:3].C(N(CC)CC)C.[CH2:11]([N:13]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]=O)=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]>O1CCCC1.O>[CH2:11]([N:13]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]=[N:2][NH2:3])=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(C=NN)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A quantity of 98% hydrazine monohydrate (50 ml, 1.4 mole, obtained from Aldrich, Milwaukee, Wis.) and 10 ml of triethylamine (obtained from Aldrich, Milwaukee, Wis.) were added to a 250 ml, 2-neck round bottom flask equipped with a mechanical stirrer and an addition funnel. The solution was stirred vigorously at room temperature for a period of 10-15 min. A solution of 9-ethyl-3-carbazolecarboxaldehyde (22.3 g, 0.1 mol, from Aldrich, Milwaukee, Wis.) in 30 ml of tetrahydrofuran (THF) was added slowly to the round bottom flask. After the addition of aldehyde was completed, the reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was diluted with 50 ml of water. A precipitate was collected by filtration and washed repeatedly with water to give crude, i.e. without further purification, 9-ethyl-3-carbazolecarboxaldehyde hydrazone, which was used immediately in the next step.