Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22](C2C=CC(NC3OC4C=CC(Cl)=CC=4N=3)=CC=2)[O:21]1>>[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:21]1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: CC1(C)OB(c2ccc(Nc3nc4cc(Cl)ccc4o3)cc2)OC1(C)C
Product: Cc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (1.5 g, 4.95 mmol) using the method described for the preparation of N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-chloro-1,3-benzoxazol-2-amine. The product was formed as white floculent solid (0.79 g, 46%); RP-HPLC Rt 17.382 min, 98% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 1.29 (12H, s), 2.38 (3H, s), 6.94 (1H, d, J 8.1 Hz), 7.30 (1H, s), 7.36 (1H, d, J 8.1 Hz), 7.67 (2H, d, J 8.5 Hz), 7.75 (2H, d, J 8.5 Hz), and 10.74 (1H, s).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.Cl.[CH3:15][N:16]([CH3:18])[OH:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([O:17][C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4])=[O:8])[CH3:18]
Reactant: CN(C)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)OC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6.00 Grams of acetylsalicylic acid chloride was dissolved in 70 ml of methylene chloride, and 7.37 g of N,N-dimethylhydroxylamine hydrochloride was added. Then, 9.16 of triethylamine was added dropwise thereto with stirring at room temperature. After completion of addition, stirring was carried out at room temperature for further 6 hours. The reaction mixture was washed with a 0.5N hydrochloric acid and then twice with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 3.10 g of 2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:59]=[N:60][C:61]([NH:64][C:65]3[CH:66]=[C:67]([NH2:72])[C:68]([CH3:71])=[N:69][CH:70]=3)=[N:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:72][C:67]1[C:68]([CH3:71])=[N:69][CH:70]=[C:65]([NH:64][C:61]2[N:60]=[CH:59][C:58]([C:55]3[CH:54]=[CH:53][C:52]([O:51][CH3:50])=[CH:57][CH:56]=3)=[CH:63][N:62]=2)[CH:66]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(N)c3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.04 mmol) in DMF (1 mL) is added HATU (0.05 mmol) and DIEA (20.12 mmol). The resulting mixture is stirred for 2 min at rt and then N5-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-2-methyl-pyridine-3,5-diamine 12 (0.032 mmol) is added. The reaction mixture is stirred at 45° C. for 12 h. The mixture is cooled down and directly purified by preparative LCMS to afford 2-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-ylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester 20. MS (m/z) (M+1)+: 519.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:5]=2[N:6]([CH2:14][CH2:15]3)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.C(O)C.[BH4-].[Na+]>O>[CH3:2][CH:3]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]2[CH2:14][CH2:15][C:16]3=[CH:17][CH:18]=[CH:19][C:4]1=[C:5]23
Reactant: CC1=Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 2 h

Procedure:
A stirred mixture, under N2, of 24.3 g (0.09 mole) of 1,2-dihydro-6-methylindolo[1,7-ab][1,5]benzodiazepine hydrochloride and 200 ml of absolute ethanol is cooled to 0° C. Then sodium borohydride is added in small portions and at such a rate as to minimize foaming and to maintain the reaction below 10° C. A total of 4.0 g of NaBH4 is added, 3.4 g to discharge the initial purple color, 0.6 g more to insure completeness of reduction. After 2 hours more at ambient temperature, water is added in portions to decompose excess reagent and to maximize precipitation of product. The solid is collected, washed repeatedly with water, and dried to yield product with m.p. 127°-134° C. Recrystallization from 75 ml of benzene (charcoal) afforded 6-methyl-1,2,6,7-tetrahydroindolo-[1,7-ab][1,5]benzodiazepine, m.p. 134°-136° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(O)(=O)C.[CH:18](N)=[NH:19]>C(O)(=O)C>[CH3:10][N:8]([C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:18][NH:19][C:11](=[O:13])[C:3]=2[CH:4]=1)[CH3:9]
Reactant: CN(C)c1cc(C(=O)O)c(N)cn1
Reactant: N=CN
Solvent: CC(=O)O
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Yield: 44.1 %

Procedure:
5-Amino-2-(N,N-dimethylamino)-pyridine-4-carboxylic acid (0.54 g) was treated with formamidine acetate (3.12 g) in glacial acetic acid (20 ml) and heated at reflux for 16 hours. The mixture was cooled, evaporated to dryness in vacuo and partitioned between ethyl acetate and water. The organic phase was separated, dried over magnesium sulphate and concentrated in vacuo to give, after chromatography on silica, the title compound (0.25 g); δH CDCl3 9.10(1H,d), 8.80(1H,s), 8.31(1H,s), 7.07(1H,s), 3.20(6H,s); m/z (M+1+) 191.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CCCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=[C:2]([NH:30][C:27]3[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H](C)c3ccc(F)cc3)n2)n[nH]1
Temperature: 115 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 30, 1.08 g, 3.7 mmol), 5-isopropoxy-1H-pyrazol-3-amine (0.57 g, 4.0 mmol), and DIEA (0.80 ml, 4.6 mmol) in n-BuOH (10 ml) was heated in a sealed tube at 115° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.32 g, 22%). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:20]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:22]=[N:21]1>>[CH2:17]([C:16]1[C:11]2=[N:10][CH:9]=[C:3]([C:1]3[NH:2][N:22]=[N:21][N:20]=3)[C:4](=[O:5])[N:12]2[CH:13]=[CH:14][CH:15]=1)[CH2:18][CH3:19]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCCc1cccnc1NC=C(C#N)C(=O)OCC
Product: CCCc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Yield: 27.6 %

Procedure:
The title compound (m.p. 269°-272° with decomposition, 27.6% yield) was prepared from ethyl 2-cyano-3-(3-n-propyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2 of U.S. Pat. No. 4,122,274.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C)C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: COC(=O)C1(C(C)=O)CCOCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C1CCOCC1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Combine methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (23.06 g, 123.84 mmol) with isopropyl alcohol (124 mL) and water (124 mL). Add sulfuric acid (33.00 mL, 5.0 eq). Heat the reaction mixture to 100° C. over two nights. Cool and add the reaction mixture slowly to a mixture of sodium bicarbonate (136 g) in water (1 L). Extract with dichloromethane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 25% ethyl acetate in hexanes to 50% ethyl acetate in hexanes, to give the title compound (7.39 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ 3.79 (m, 2H), 3.27 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.66 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].CI.[C:17]([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.CCOC(C)=O>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([F:1])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
6.0 g (30.0 mmol) of 3,5-difluoro-2-nitro-benzoic acid was dissolved in DMF, treated with 8.5 g (60.0 mmol) of MeI and 9.5 g (90.0 mmol) of Na2CO3, and heated at 80° C. for 2 h. Water was added to the reaction mixture, and extraction with EtOAc produced 3,5-difluoro-2-nitro-benzoic acid methyl ester. LCMS: 218 (M+1)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(S([C:19]1[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=1[C:24]#[N:25])=O)C>C(#N)C>[C:1]1([S:7][C:19]2[S:20][C:21]([C:26]#[N:27])=[CH:22][C:23]=2[C:24]#[N:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CCS(=O)c1sc(C#N)cc1C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cc(C#N)c(Sc2ccccc2)s1
Reaction time: 8 h

Procedure:
4.4 ml of thiophenol and 5.0 ml of triethylamine are added, while stirring, to a solution of 8.9 g of 2-ethylsulphinyl-3,5-dicyanothiophene, obtained according to Example I, in 100 ml of acetonitrile. After leaving to stand overnight, the reaction mixture is refluxed for 8 hours. After evaporating the solvent, the residue is taken up in methylene chloride and chromatographed over a 1 l dry silica gel column. The desired product is obtained in a yield of 9.07 g; melting-point 68°-71° C. Optionally, any 2-alkylsulphinyl compound may be used as the starting substance.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([NH:19][S:20]([C:23]2[S:24][C:25]([CH2:29][CH2:30][O:31][CH3:32])=[C:26]([CH3:28])[CH:27]=2)(=[O:22])=[O:21])=[O:18])[CH:13]=[C:12]([S:33][CH3:34])[CH:11]=1)(C)(C)C.Cl>CO>[OH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][C:17]([NH:19][S:20]([C:23]2[S:24][C:25]([CH2:29][CH2:30][O:31][CH3:32])=[C:26]([CH3:28])[CH:27]=2)(=[O:22])=[O:21])=[O:18])[CH:13]=[C:12]([S:33][CH3:34])[CH:11]=1
Reactant: COCCc1sc(S(=O)(=O)NC(=O)Nc2cc(SC)cc(NCCO[Si](C)(C)C(C)(C)C)n2)cc1C
Agent: Cl
Solvent: CO
Product: COCCc1sc(S(=O)(=O)NC(=O)Nc2cc(SC)cc(NCCO)n2)cc1C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
The below prepared N-({6-[(2-(tert-butyl-dimethyl-silanyloxy)-ethyl)amino]-4-(methylthio)pyridin-2-yl}carbamoyl)-5-(2-methoxyethyl)-4-methylthiophene-2-sulfonamide (0.160 g, 0.278 mmol) was dissolved in 5 mL of MeOH and treated with aq. HCl (1.0 mL 1 N). After 2 h at ambient temperature, the reaction mixture was poured onto icewater, twofold extracted with AcOEt, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt gave 0.081 g of the title compound as off-white crystals.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:11][C:10]1[C:5]2[C:4](=[CH:3][CH:2]=[C:1]([CH3:13])[CH:6]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCc1ccc(C)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccc(C)cc21

Procedure:
In close analogy to the procedure described above, N-(2-p-tolyl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Reactant: Clc1ccnc2ncccc12
Product: Oc1ccc(Sc2ccc(OCc3cccc(F)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 22 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (75 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.16 (s, 2H) 6.31 (d, J=7.36 Hz, 1 H) 6.64 (d, J=8.82 Hz, 2 H) 7.09-7.28 (m, 6 H) 7.29 (2, 1H) 7.44 (m, J=6.61 Hz, 1 H) 7.93 (dd, J=4.41 Hz, 1 H) 8.47 (d, J=6.98 Hz, 1 H) 9.14 (dd, J=1.47 Hz, J=8.46 Hz, 1 H) 9.18 (dd, J=1.47 Hz, J=4.41 Hz, 1 H) 9.79 (s, 1 H) 11.16 (br s,1 H) 14.52 (br s,1 H); MS (ESI+) m/z, 470 (M+H−TFA)+; (ESI−) m/z, 468 (M−H−TFA)−.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[O:20]>C(Cl)Cl>[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19](=[NH:21])[O:20][CH3:6]
Reactant: C[O+](C)C
Reactant: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A solution containing trimethyloxonium tetrafluoroborate (100 g; 0.68 mol) and methylene chloride (2 liters) is prepared. It is stirred and 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzamide (220 g; 0.61 mol) is then added in portions at ambient temperature. The stirring is continued for 24 hours at ambient temperature. The solution is then washed with a 10% aqueous solution of sodium carbonate (cooled beforehand) and dried over sodium sulphate. The methylene chloride is removed by evaporation to leave a yellow solid of methyl 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzimidate (217 g; yield 95%) melting at 46° C. and having the formula: ##STR20##
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:45][S:46]([NH:49][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)=[CH:11][CH:12]=1)(=[O:48])=[O:47]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC(=O)c1ccc(Nc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.2 %

Procedure:
To a solution of 4-(3-(trifluoromethyl)phenylamino)benzoic acid (150 mg, 0.533 mmol) in DMF (4 mL) were added HATU (243 mg, 0.640 mmol), methanesulfonamide (152 mg, 1.60 mmol) and DIPEA (0.296 mL) and the reaction stirred at room temperature for 16 hours. Methanesulfonamide (152 mg, 1.60 mmol) was added and the reaction stirred at room temperature for 72 hours. After this time the reaction was quenched by the addition of potassium hydrogen sulfate (20 mL) and the aqueous extracted with dichlormethane (3×20 mL). The combined organics were washed with brine (40 mL), filtered through a phase separation cartridge and then the solvent was removed under reduced pressure to give an oil (325 mg). The crude was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1](Br)[CH:2]=CC1C=CC=CC=1.[Cl-].[Mg].C(Br)=C.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[CH:1]=[CH2:2])=[CH:20][CH:19]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: C=CBr
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OC)cc1

Procedure:
Instead of the cinnamyl bromide, the chloride may also be used. Illustrative of its preparation is the following procedure: To the Grignard reagent, prepared from 2.25 g of magnesium, 9.75 g of vinyl bromide and 50 ml of tetrahydrofuran, the solution of 10.2 g of 4-methoxybenzaldehyde in 75 ml of diethyl ether is added dropwise while stirring under nitrogen and cooling with ice. The mixture is stirred for 2 hours at room temperature, again cooled, and 12 ml of saturated aqueous ammonium chloride are added dropwise. The resulting suspension is filtered, the filtrate dried and evaporated, to yield the 4-methoxy-α-vinylbenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[C:8]([F:28])[CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[C:8]([F:28])[CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3cc(F)ccc3C2C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccc(F)cc2-c2ccc(F)cc2N1S(=O)(=O)c1cccc(O)c1

Procedure:
The title compound was prepared from 3,9-difluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (150 mg, 0.37 mmol), cyclohexene (757 μL, 7.5 mmol), and 1.0 M solution of boron tribromide in dichloromethane (2.24 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane, to afford the product (98 mg, 78%) as a solid, m.p. 167.2-173° C.;
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.C(O)(=O)C>O>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc2nccc(O)c2c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2ncc(Cl)c(O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of methyl 4-hydroxyquinoline-6-carboxylate (2.07 g), N-chlorosuccinimide (1.36 g), and acetic acid (56 mL) was stirred at room temperature for one day. The reaction mixture was diluted with water, and then, the precipitate was collected by filtration to obtain methyl 3-chloro-4-hydroxyquinoline-6-carboxylate (2.13 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].CI.[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:14][C:2]([F:1])([F:13])[C:3]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH3:17])=[O:4]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc(I)cc1
Temperature: 80 °C

Procedure:
Intermediate 32 (1.0 g, 3.175 mmol) in 20 mL of acetone was combined with CH3I (6.350 mmol, 0.901 g, 0.395 mL) and K2CO3 (6.350 mmol, 0.876 g) then refluxed at 80° C. for 2 hours. The reaction was worked up quenching the reaction with 1× saturated NaHCO3, extracted 4×25 mL EtOAc then washed 1× water, 1× saturated NaCl, dried over Na2SO4, then concentrated. The product was carried through without purification. ES/MS calcd. for C9H7F3INO 328.95. Found m/z=330 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:11][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1cnc(O)c(I)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(O)c(I)c1
Temperature: 25 °C

Procedure:
A suspension of 4.6 g (17.36 mmol) of 5-iodo-6-hydroxynicotinic acid and 7.0 mL of concentrated sulfuric acid in 40 mL of ethanol was refluxed for 16 h. The reaction mixture was cooled to rt and filtered to afford 3.0 g of a white solid as the title compound: 1H NMR (500 MHz, DMSO) δ 1.25 (t, J=6.9, 3H), 4.21 (q, J=6.6, 2H), 8.05 (d, J=1.4, 1H), 8.33 (d, J=1.3, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18]C(S(C)(=O)=O)=[N:20][N:21]=3)[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1.[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=O)OC(C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[S:18][C:41]([NH:40][CH2:39][CH2:38][CH2:37][NH2:36])=[N:20][N:21]=3)[CH:15]=2)[NH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Solvent: C1COCCO1
Product: NCCCNc1nnc(-c2ccc3[nH]cc(-c4ccccc4F)c3c2)s1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 2-(3-(2-fluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.053 g, 0.10 mmol) in p-dioxane (1 mL) was added tert-butyl 3-aminopropylcarbamate (88 mg, 0.50 mmol, Aldrich), and the reaction was heated at 90° C. for 8 h. The residue was then purified with RP-HPLC. The purified material was dissolved in dioxane (1 mL) and aq. NaOH (1M, 0.1 mL) was added. The solution was heated in a microwave at 120° C. for 10 min. The solution was concentrated under reduced pressure and the resulting oil was stirred with 4M HCl/dioxane for 30 min, then evaporated under reduced pressure. The residue was purified by preparative HPLC to give N-(5-(3-(2-fluorophenyl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)-1,3-propanediamine (32 mg, 61.4%). MS (ESI, pos. ion) m/z: 368 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.10 (1H, s), 7.66-7.72 (1H, m), 7.62-7.66 (1H, m), 7.59 (1H, d, J=1.6 Hz), 7.53-7.57 (1H, m), 7.17-7.35 (3H, m), 3.57 (2H, t, J=6.7 Hz), 3.03-3.10 (2H, m), 2.04-2.11 (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:63])[CH2:36][CH:37]1[CH2:46][C:45]2[C:40](=[CH:41][C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])=[CH:43][CH:44]=2)[N:39]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:38]1=[O:62]>>[CH2:55]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])[CH:41]=2)[CH2:46][CH:37]([CH2:36][C:35]([OH:63])=[O:34])[C:38]1=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNC(=N)N)cc2N(Cc2ccccc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1ccc2c(c1)N(Cc1ccccc1)C(=O)C(CC(=O)O)C2

Procedure:
The title compound was prepared according to the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate was replaced with [1-benzyl-7-(3-guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester.