Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH2:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.CN(C)C=O>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[CH3:1])[C:9]([NH2:12])=[N:8][CH:7]=[CH:6]3)[CH2:15][CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc2c(N)nccc2cc1OC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A couple of drops of glacial acetic acid was added to a solution of 7-methyl-6-(piperidin-4-yloxy)isoquinolin-1-ylamine (30 mg, 0.117 mmol) in N, N-dimethylformamide (1 ml), followed by addition of benzaldehyde (50 μL). The mixture was then treated with sodium triacetoxyborohydride (100 mg) and stirred for 2 h. Water (1 ml) was added, the mixture was stirred for 30 min and then purified by prep-HPLC to give 6-(1-benzyl-piperidin-4-yloxy)-7-methylisoquinolin-1-ylamine (24 mg), El-MS: m/z=348.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([NH2:32])=O)[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)([C:25]2[O:29][N:28]=[C:27]([C:30]#[N:32])[N:26]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(c1ccc(Cl)cc1)(c1nc(C(N)=O)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCC(c1ccc(Cl)cc1)(c1nc(C#N)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 37 step F above (6.8 mg, 0.014 mmol) in pyridine (1.0 mL) was added POCl3 (32.8 mg, 0.28 mmol) at 0° C. After stirring at RT overnight, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=457.1[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a stirring solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (16 mg, 0.05 mmol) in DMF (0.25 mL) at room temperature under argon was added K2CO3 (14 mg, 0.1 mmol), followed by 1-(chloromethyl)-4-(methylsulfonyl)benzene (11 mg, 0.0547 mmol). The reaction mixture was stirred at 70° C. for 10 min. After the reaction mixture was cooled to room temperature, water (2 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to obtain crude product. This was purified by reverse phase preparative HPLC (without TFA) to isolate 14.5 mg of the title compound as a pale yellow solid. HPLC/MS: retention time=2.27 min, [M+H]+=491.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37](Cl)[N:36]=[C:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9].O>C1COCC1>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:46])[C@@H:20]([NH:30][C:31]([C:33]2[CH:38]=[C:37]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[N:36]=[C:35]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:34]=2)=[O:32])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-n3ccnc3)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Imidazole (3 mg) was added to a suspension of NaH (1.7 mg) in anhydrous THF (0.2 ml) at RT. After 30 min stirring at RT, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (25 mg) dissolved in THF (0.2 ml) was added. The mixture was allowed to stir at RT overnight. Water was added and the resulting mixture was extracted with DCM. The org. phases were dried (Na2SO4) and evaporated off.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>Cl>[CH:15](=[N:9][NH:8][C:5]1[N:6]=[N:7][C:2]([Cl:1])=[C:3]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1nnc(NN=Cc2ccccc2)cc1N1CCCC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-5-(pyrrolidin-1-yl)pyridazin-3-ylhydrazine (14 g, 0.063 mol) in 0.1 N hydrochloric acid (600 ml) was added benzaldehyde (6.4 ml, 0.063 mol) dropwise at room temperature. The mixture was stirred at 60° C. for 15 min, yielding a thick slurry. The pH of the solvent was adjusted to ˜11 with 4 N aqueous sodium hydroxide solution, and the precipitate filtered off. The residue was washed with water, ethanol and diethyl ether, yielding the title compound as a white solid (14 g, 73%). 1H NMR (360 MHz, DMSO) δ1.93 (4H, m), 3.58 (4H, m), 6.57 (1H, s), 7.35 (1H, m), 7.39 (2H, m), 7.66 (2H, d, J=7.1 Hz), 8.06 (1H, s), 11.16 (1H, s). MS (ES+) m/e 302 [MH]+, 304 [MH]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:18])=[CH:19][CH:20]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=C(O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) (0.16 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (0.16 mmol), and N′N-diisopropylethylamine (0.48 mmol) is stirred at room temperature for 20 min. under N2. Morpholine (0.48 mmol) is added and the mixture is stirred at room temperature for 16 hr. Water (10 mL) is added and the mixture extracted with ethyl acetate (2×70 mL). The extracts are subsequently washed with water (2×30 mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is triturated with diethyl ether to give [4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone (8) as a cream solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[SH:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[O:5]=[C:3]([CH3:4])[CH2:2][S:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([OH:15])=[O:14]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CSc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.2 %

Procedure:
To a solution of chloroacetone (5.18 g, 55.99 mmol) in DMF (25 ml) were added thiosalicylic acid (8.63 g, 55.99 mmol) and potassium carbonate (7.74 g, 55.99 mmol), and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added water and ethyl acetate and the mixture was separated by a separating funnel. The aqueous layer was acidified with 1N diluted hydrochloric acid (about pH 4) and extracted with ethyl acetate. Further the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration the solvent was removed in vacuo to give the subject compound (7.44 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9]S(O)(=O)=O.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>CCOCC>[Cl:16][CH2:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)CSc1ccccc1Br
Agent: [Na]
Solvent: CCOCC
Product: ClCSc1ccccc1Br
Temperature: 0 °C
Yield: 86.2 %

Procedure:
A mixture of 60.4 g of [(o-bromophenyl)thio]methanesulfonic acid, sodium salt and 98.0 g of phosphorus pentachloride is blended until liquified, diluted with 600 ml of ether, and then poured on 1.2 kg of crushed ice. The ether layer is separated, washed, dried, and concentrated to give about 43.7 g of the named compound, bp about 86° (0.6 mm), mp about 28°-30°.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[N:12][C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9](=[O:23])[N:8]3[N:24]=[CH:25][N:26]=[C:7]3[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:27][C@@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:27][C@H:28]1[CH2:29][N:30]([CH:1]([C:4]2[CH:13]=[N:12][C:11]3[N:10]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:9](=[O:23])[N:8]4[N:24]=[CH:25][N:26]=[C:7]4[C:6]=3[CH:5]=2)[CH3:2])[CH2:31][C@@H:32]([CH3:34])[O:33]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)N4C[C@@H](C)O[C@@H](C)C4)cnc32)cc1
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (67 mg, 0.19 mmol), (2S,6R)-2,6-dimethylmorpholine (0.060 ml, 0.49 mmol), acetonitrile (1 ml) and acetic acid (0.020 mL, 0.35 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 3 days at 50° C. The mixture was filtered and purified by preparative HPLC to afford 26 mg (23%) of 266 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])=[CH:8][C:9](=[O:22])[N:10]2[CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)CN.[C:36]([BH3-])#[N:37].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:26]([O:25][CH3:24])[CH:27]=[CH:28][C:31]=1[CH2:36][NH:37][CH:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([CH3:23])=[CH:8][C:9]2=[O:22])[CH2:16][CH2:17]1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC(=O)CC3)c2c1
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CNC2CCC(CCn3c(=O)cc(C)c4ccc(OC)cc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To 3 mL of methanol solution containing 30 mg of 7-methoxy-4-methyl-1-(2-(4-oxocyclohexyl)ethyl)quinolin-2(1H)-one, 16 mg of 3,5-dimethoxybenzylamine, 8 μL of acetic acid and 9 mg of sodium cyanoborohydride were added, and the mixture was allowed to stand overnight after stirred at room temperature for 1 hour. To the reaction mixture, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [gradient elution of chloroform:methanol=90:10-80:20], to give 22 mg of 1-(2-(4-((2,4-dimethoxybenzyl)amino)cyclohexyl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[Cl:12][CH:13](C(=O)C)[C:14](=[O:16])[CH3:15]>>[Cl:12][C:13](=[N:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14](=[O:16])[CH3:15]
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: [Na+]
Product: CC(=O)C(Cl)=NNc1ccccc1
Yield: 40.3 %

Procedure:
The reaction of 10.55 g (0.113 mol)of aminobenzene with 13.2 g of sodium nitrite and 20 g of 3-chloro-2,4-pentanedione as in Example 1 yielded 8.95 g of 1-chloro-1-[(phenyl)hydrazono]-2-propanone, mp 132°-134° C.
Reaction SMILES: [CH3:1]NC1C=CC=CC=1.[C:9]([C:14]1[N:15]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[C:16]2[C:21]([C:22]=1S(Cl)(=O)=O)=[CH:20][C:19]([Cl:27])=[CH:18][CH:17]=2)([O:11][CH2:12][CH3:13])=[O:10]>>[C:9]([C:14]1[N:15]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:30])[C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:27])=[CH:18][CH:17]=2)([O:11][CH2:12][CH3:13])=[O:10].[CH3:1][C:35]1[CH:36]=[C:31]([S:28]([NH2:15])(=[O:29])=[O:30])[CH:32]=[CH:33][CH:34]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: Cc1cccc(S(N)(=O)=O)c1

Procedure:
In the manner outlined in Example 68, Step B, N-methylaniline was added to 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-sulfonylchloride to give, after flash column chromatography on silica (dry loaded, eluting with an ethyl acetate/hexanes gradient, 10-30% ethyl acetate) the title compound as colorless crystals (from dichloromethane/hexanes);
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][NH2:24].[C:25]([O:28][CH2:29]C)(=O)[CH3:26]>CC(O)C.O>[CH2:25]([O:28][CH2:29][N:24]([CH3:23])[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:26]
Reactant: CN
Reactant: CCOC(C)=O
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCOCN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 100 °C
Yield: 72 %

Procedure:
To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (0.50 g, 1.50 mmol) in 10 mL of 2-propanol was added 2.0 M solution of methylamine (3.0 mL). The mixture was heated at 100° C. overnight with stirring. The solution was diluted with 20 mL of water and 50 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting material was dissolved in 8 mL of ethanol and then 0.22 mL of formaldehyde (37% in water), a few drops of 5% sodium hydroxide solution were added. The mixture was heated at 90° C. for 1 d with stirring, and then diluted with 10 mL of water and 30 mL of ethyl acetate. The organic layer was washed with water, then dried and concentrated. The resulting crude material was purified by silica gel column chromatography to give the title compound (0.38 mg, 72%). 1H NMR (CDCl3, 400 MHz) δ 7.22 (d, 1H, J=8.4 Hz), 7.18 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=8.4 Hz), 6.67 (t, 1H, J=6.8 Hz), 5.30 (s, 2H), 3.90 (s, 3H), 3.57 (q, 2H, J=6.8 Hz), 3.49 (s, 3H), 3.22 (s, 3H), 1.17 (t, 3H, J=6.8 Hz); ESI-MS m/z 353 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-nitrophenyl)butyryl chloride (5.4 g, 23.7 mmol) and 4-fluorobenzene (2.6 mL, 26.2 mmol) dissolved in carbon disulfide (25 mL) was treated in portions with aluminum chloride (4.1 g, 30.75 mmol) under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated to 60-70° C. for about 12 hours. The resulting mixture was cooled in an ice bath, treated with concentrated hydrochloride acid (12 mL), and stirred for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide, water, and brine, dried and evaporated in vacuo. Purification by silica gel chromatography, eluting with 5% ethyl acetate/hexane gave the title compound as a white solid (3.81 g, 56%). The product was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=2)[CH:4]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 130 °C
Yield: 36 %

Procedure:
A mixture of 2-amino-5-bromopyridine (2.00 g, 11.6 mmol), copper (I) bromide (160 mg, 1.09 mmol), 1,10-phenanthroline monohydrate (225 mg, 1.12 mmol) and benzonitrile (25 mL) was heated in a 50-mL 3-necked flask to 130° C. During 24 h a gentle flow of (O2/N2 5:95) was bubbled through the reaction mixture (>97% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 6-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.14 g, 36%) as a light brown solid with 99.7% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1O[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH3:2].FC(F)(F)C([O-])=O.[CH3:33][NH3+:34].CN>>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:34]([CH3:33])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH3:2]
Reactant: CCCCCc1ccc(-c2nnc(-c3ccccc3SCC)o2)cc1
Reactant: C[NH3+]
Agent: CN
Agent: O=C([O-])C(F)(F)F
Product: CCCCCc1ccc(-c2nnc(-c3ccccc3SCC)n2C)cc1

Procedure:
2-[2-(Ethylthio)phenyl]-5-(4-pentylphenyl)-1,3,4-oxadiazole (1-E) (100 mg, 0.28 mmol), methylammonium trifluoroacetate (1.64 g, 11.34 mmol, prepared by combining equal amounts of methylamine and trifluoroacetic acid in ether followed by evaporation in vacuo) and methylamine (2M/MeOH, 5.68 mL, 11.34 mmol) were stirred together in a glass bomb at 150° C. for 2.5 d. The mixture was evaporated in vacuo and the residue partitioned between methylene chloride and water. The organic phase was washed with water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, ethyl acetate:hexane, 7:3) to provide 3-[2-(ethylthio)phenyl]-4-methyl-5-(4-pentylphenyl)-4H-1,2,4-triazole (1-F). MS m/z 366 (M+1). 1H NMR (500 MHz, CDCl3): δ 0.96 (t, 3H); 1.29 (t, 3H); 1.40 (m, 4H); 1.73, (m, 2H); 2.73, (t, 2H); 2.90 (q, 2H); 3.58 (s, 3H); 7.37 (m, 3H); 7.55 (m, 3H); 7.72, (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>N1C=CC=CC=1>[CH3:36][C:29]1[CH:30]=[C:31]([O:35][S:45]([CH3:44])(=[O:47])=[O:46])[CH:32]=[C:33]([CH3:34])[C:28]=1[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=2)[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To an ice-cooled solution of ethyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (600 mg, 0.989 mmol) in pyridine (10 mL) was added dropwise methanesulfonyl chloride (227 mg, 1.98 mmol). The mixture was stirred at room temperature for 16 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (670 mg, yield 98%) as a colorless oil.