Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>[OH-].[Na+]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Br)cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-bromobenzenesulphonyl chloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous ethanol, had a melting point of 115°-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH3:22])[C:9]([NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:9]1[S:33][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12][N:11]=1)[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A solution of (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.0 g, 2.93 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (1.18 g, 2.93 mmol, 1.0 equiv) in THF (29 mL) was heated at reflux for 2 hours. The reaction wash then cooled to room temperature and filtered through a pad of celite, using THF to wash through. The filtrate was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 30%) provided (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (0.600 g, light green solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 5.23 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 1.48 (s, 9H). MS m/z 340.1 (M+H)+; Rt-0.99 min.
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH2:3]([S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cc(N[C@H](C)CO[Si](C)(C)C(C)(C)C)nc(SCc3ccccc3)n2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(NS(=O)(=O)c2ccc(C(=O)O)o2)nc(SCc2ccccc2)n1

Procedure:
Lithium hydroxide (33 mg) was added to a solution of the subtitle product of step i) (0.23 g) in THF/H2O (1 ml/1 ml) and stirring maintained for 1 h. The THF was removed in vacuo and the residue neutralised with AcOH before extracting with EtOAc. The organics were then washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as an off-white solid. Yield: 0.14 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:32])[NH:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[F:36][C:34]1[CH:33]=[C:4]([CH:3]=[C:2]([F:1])[CH:35]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:9][C:8](=[O:32])[NH:7]1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(C)[Si](Oc1cccc2c1CN[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)[Si](Oc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-8-(triisopropylsilyloxy)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one Step F (12), 120 mg, 0.23 mmol) in acetonitrile (2 mL) were added potassium carbonate (64 mg, 0.46 mmol) and bromodiphenylmethane (91 mg, 0.37 mmol). This mixture was put on microwave at 75° C. for 2 h and 15 min. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 120 mg of the title compound (75% yield): 1H NMR (CDCl3, 500 MHz) δ 0.90 (18H, m), 1.06 (3H, m), 2.47 (1H, m), 2.76 (1H, d, J=20 Hz), 3.16-3.23 (2H, m), 3.69 (1H, d, J=20 Hz), 3.75 (1H, m), 4.02 (1H, m), 4.18 (1H, d, J=20 Hz), 4.72 (1H, m), 4.80 (1H, s), 4.92 (1H, s), 6.61 (1H, d, J=10 Hz), 6.76-6.80 (4H, m), 7.03-7.06 (1H, m), 7.17-7.30 (6H, m), 7.39 (4H, t, J=5 Hz). MS (ESI) (M+H)+ 683.31.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:3].[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35]2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=[C:31]([NH2:38])[C:30]=2[N:29]=[CH:28]1>>[NH2:38][C:31]1[C:30]2[N:29]=[CH:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][NH:22][S:18]([C:15]3[CH:16]=[CH:17][C:12](/[N:11]=[N:10]/[C:7]4[CH:8]=[CH:9][C:4]([N:2]([CH3:3])[CH3:1])=[CH:5][CH:6]=4)=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:35]=2[C:34]([CH3:36])=[C:33]([CH3:37])[N:32]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Product: Cc1nc(N)c2ncn(CCCCNS(=O)(=O)c3ccc(/N=N/c4ccc(N(C)C)cc4)cc3)c2c1C

Procedure:
Using the method of Examples 15-29 4-dimethylaminoazobenzene-4′-sulfonyl chloride was reached with of 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 521.2452.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[C:24](Cl)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH2:17]([NH:16][C:14]([C:4]1[S:3][C:2]([NH:1][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:6][C:5]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of 2-amino-N,4-dibenzylthiazole-5-carboxamide (0.053 g, 0.16 mmol) in tetrahydrofuran (5 mL) at 0° C. was added hydrocinnamoyl chloride (0.03 mL, 0.20 mmol), DMAP (cat.) and triethylamine (0.3 mL, 2.10 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound in 49% yield (0.036 g); 1H NMR (CDCl3, 400 MHz) δ 7.35-7.15 (m, 15H), 4.56 (d, J=5.6 Hz, 2H), 4.37 (s, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.74 (t, J=7.6 Hz, 2H); MS (ES+) m/z 456 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:15])=[O:14])[CH:9]=[CH:8][C:7]=1[OH:16].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Cl)=[CH:22][CH:21]=1)([O-:19])=[O:18].[I-].[Na+]>CN(C)C=O>[OH:12][C:11]1[C:6]([CH2:5][CH2:4][CH3:3])=[C:7]([O:16][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[C:13](=[O:14])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Temperature: 100 °C

Procedure:
To sodium hydride (6.1 g, 50% dispersion) in dry dimethylformamide (200 ml) was added 2,4-dihydroxy-3-propylacetophenone (24.6 g) in dimethylformamide (20 ml), dropwise with stirring under nitrogen. The resulting solution was heated to 100° C. and 4-nitro-1-(3-chloropropoxy)benzene (27.3 g) and sodium iodide (19.0 g) were added rapidly. The reaction mixture was left to stir over night at 100° C., cooled and evaporated under reduced pressure to a brown oil. The oil was taken up in water, extracted with dichloromethane (×2), washed with aqueous sodium hydroxide (2N), then aqueous sodium thiosulphate, dried over magnesium sulphate, filtered and evaporated under reduced pressure to a dark brown solid. The solid was recrystallised from methanol, with charcoaling, to give pale yellow needles of product, m.p. 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:23][S:24]([CH2:27][C:28](O)=[O:29])(=[O:26])=[O:25].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: C[C@@H]1Nc2ccc(Br)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (130 mg, 351 μmol) and 2-(methylsulfonyl)acetic acid (53.4 mg, 386 μmol) in pyridine (3.51 ml) was added phosphoryl chloride (64.3 μl, 702 μmol). The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-bromo-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (161 mg, 94%) as a white solid. MS m/z 512/514 (MNa)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH3:26])[C:14]1([CH2:24][OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH3:12][N:13]([CH3:26])[C:14]1([CH2:24][OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:9])[CH2:16][CH2:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)C1(CO)CCSc2ccccc21
Solvent: ClCCl
Product: CN(C)C1(CO)CCS(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
248 mg of 70% m-chloroperbenzoic acid was added to a 20 ml of methylene chloride solution containing 222 mg of 4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran dissolved therein, and stirred at room temperature for 30 minutes. The reaction solution was washed with 5% aqueous sodium thiosulfate solution, saturated sodium bicarbonate solution and brine in this order, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crystals were recrystallized from a solvent mixture of ethyl acetate and isopropyl ether. 53 mg of the title compound was obtained as colorless crystals. ##STR33## Melting point: 132°-133° C. IR(KBr)cm-1 : 3245, 1070, 1000
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].CN1CCCC1=O.[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:21]([N:24]([CH2:25][CH:26]=[CH2:27])[C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:22]=[CH2:23]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.9 %

Procedure:
A mixture of 2,4-dinitrofluorobenzene (9.3 g, 50 mmol), 1-methylpyrrolidinone (50 mL), diallylamine (5.82 g, 60 mmol) and potassium carbonate (6.9 g, 50 mmol) was stirred at ambient temperature for 1 h. The mixture was poured into water (250 mL) and extracted with ethyl ether. The ether extract was washed with 0.5 N hydrochloric acid, water, and saturated brine solution, and dried over magnesium sulfate. Concentration of the extract gave N,N-diallyl-2,4-dinitrobenzeneamine as a yellow oil (14.6 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([NH2:27])[C:22]([NH2:26])=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[K+].[K+]>>[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]2[NH:26][C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:27][C:21]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Temperature: 140 °C
Yield: 69.3 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (10.0 g, 41 mmol) and 4,5-difluoro-benzene-1,2-diamine (5.95 g, 41 mmol) in polyphosphoric acid (140 g) was heated at 140° C. for 7 h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether, ethyl acetate and pentane to afford the title compound as a light brown solid (7.14 g, 69%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].CO[C:12](=[O:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:17]([C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc(C(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a 2 l four-necked flask equipped with a mechanical stirrer, dropping funnel, thermometer, reflux condenser, and a nitrogen-inlet tube, 32 gm (0.8 mol) of 60% sodium hydride, 79 gm (0.79 mol) of pinacolone, and 700 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream. To this solution, 70 gm (0.36 mol) of dimethylterephthalate in 300 ml of tetrahydrofuran was added dropwise over one hour. After the addition, the reaction mixture was refluxed with heating for 6 hours, and was cooled to room temperature. After addition of 180 ml of 2N aqueous hydrochloric acid, the reaction mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give a crude product. The crude product was recrystallized using hexane to obtain 78 gm of the target compound as colorless scales (yield: 66%).
Reaction SMILES: [F:1][C:2]([C:5]1[NH:9][N:8]=[N:7][N:6]=1)([F:4])[F:3].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25]Cl>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24](=[O:27])[CH2:25][N:6]1[C:5]([C:2]([F:4])([F:3])[F:1])=[N:9][N:8]=[N:7]1
Reactant: FC(F)(F)c1nnn[nH]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1C(F)(F)F)c1ccc(Cl)cc1Cl

Procedure:
Trifluoromethyl tetrazole was made according to the procedure published in Tetrahedron Letters 38(7):1257-1260. A mixture of tetrachlorosilane (5 mmol) and sodium azide (15 mmol) in dry acetonitrile (10 ml) and trifluoromethyl acetamide (5 mmol) was refluxed and stirred with the exclusion of moisture. The reaction mixture was poured into ice cold sodium carbonate solution and extracted with chloroform (3×20ml). The solvent was distilled off under reduced pressure to yield trifluoromethyl tetrazole (MS: MH—=136.7) which was used without further purification. Trifluromethyl tetrazole (1 mmol), Cs2CO3 (1.3 mmol) and 1-(2,4-dichlorophenyl)-2-chloroethan-1-one (1 mmol) were refluxed in DMF(2 ml) overnight. The reaction mixture was cooled and concentrated in vacuo, and then extracted into ethyl acetate and dried over sodium sulfate. The extract was further purified by column chromatography on silica gel to yield 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one. 1 mmol of 1-(2,4-dichlorophenyl)-2-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]ethan-1-one was heated to 80° C. in neat DMF-DMA for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether. 1 mmol of the above enaminone, 1 mmol of amino {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 were dissolved in DMF and heated to 90° C. for fourteen hours. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the residue after solvent evaporation was purified by column chromatography eluting with 5-10% methanol in methylene chloride to yield {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}{4-(2,4-dichlorophenyl)-5-[5-(trifluoromethyl)(1,2,3,4-tetraazolyl)]pyrimidin-2-yl}amine as a yellow powder after lyophilization.
Reaction SMILES: [F:1][C:2]([S:5]([NH2:8])(=[O:7])=[O:6])([F:4])[F:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([NH:8][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)=[O:23])(=[O:7])=[O:6]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of trifiuoromethylsulphonamide (2.1 g, 14.1 mmol) in anhydrous dichloromethane (50 ml), cooled to 0° C. was treated with triethylamine (2.0 ml, 14.1 mmol) followed by a solution of 3-nitrobenzoyl chloride (2.5 g, 13.4 mmol) in anhydrous dichloromethane (50ml) dropwise. After stirring at 0° C. for 1h, the mixture was stirred at ambient temperature for 2 h. The mixture was extracted using 1M NaOH (100 ml), and the aqueous phase was acidified using 5M HCl. The aqueous phase was then extracted using dichloromethane (4×100 ml), followed by ethyl acetate (2×100 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to leave a yellow solid. This was recrystallised from diethyl ether:hexane (1:1) to afford the title compound (1.5 g, 36%) as a pale yellow solid. mp 80°-83° C. 1H NMR (360 MHz, D6 -DMSO) δ 7.73 (1H, dd, J=8.0 and 8.0 Hz), 8.35 (2H, m), 8.56 (1H, brs), 8.68 (1H, m).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[NH:7][C:8](=[O:10])[CH3:9])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][CH2+:36]1SC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][C:36]1=[N:14][C:13]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1cc(NC(C)=O)ccc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 3′-ethylamino-4′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.45–7.53 (3H, m), 7.27–7.37 (4H, m), 7.17 (1H, m), 7.03–7.09 (2H, m), 6.91 (1H, d), 6.83 (1H, br d), 6.75 (1H, brs), 5.18 (2H, s), 3.78 (3H, s), 2.99 (2H, m), 2.15 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[NH:4][C:3]1=[O:13].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:12])[C:9]=2[Cl:11])[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2)C(=O)Nc2ccc(Cl)c(Cl)c21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3c2ccc(Cl)c3Cl)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.4 g of 3-amino-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.4 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.46 g. M.p.=161°-163° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([C:30]#[N:31])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:34])C>[OH-].[K+]>[CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:8]([C:30]([NH2:31])=[O:34])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1ncc(C#N)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Agent: [K+]
Agent: [OH-]
Product: CCCCc1ncc(C(N)=O)c(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1

Procedure:
2-Butyl-4-{N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carbonitrile, the product of Example 14, is heated in dilute aqueous potassium hydroxide. Neutralization with acetic acid affords the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28-3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3 H).