Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]([O:23]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:46]([N:14]1[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:12][C:11](=[O:23])[N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:8])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(COc2nc(OCc3ccccc3)nc(OCc3ccccc3)n2)cc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: O=c1nc(OCc2ccccc2)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Yield: 21 %

Procedure:
Furthermore, a synthesis method of the hydroxy group-protecting agent 5 will be explained. To a 10 mL eggplant flask, 599.2 mg (1.50 m mol) of 2,4,6-tribenzyloxy-1,3,5-triazine, 5.00 mL of toluene and 38.8 mg (030 m mol) of iodine were added, heat-perfused, and reacted for 31 hours. After the reaction, 5 mL of an aqueous solution of saturated sodium thiosulfate was added, which was washed with 5 mL of 1 N sodium bicarbonate water, 5 mL of 1 N hydrochloric acid, 5 mL of water and 5 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which the solvent was distilled away, and the residue was isolated and purified by silica-gel chromatography to obtain 126.2 mg of 1,3-dibenzyl-6-(benzyloxy)-1,3,5-triazine-2,4(1H,3H)-dione (yield: 21%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][Cl:19].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>CS(C)=O>[ClH:19].[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Reactant: CN(C)CCN
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCN(C)C)c2n1
Product: Cl
Temperature: 0 °C

Procedure:
The product of step (ii) (16 g), DMSO (16 ml) and N,N-dimethylethylenediamine (120 ml) was heated at 80° C. for 4 h then evaporated under reduced pressure. The residue was azeotroped with acetonitrile then heated under reflux in acetonitrile (250 ml) for 30 min then cooled to 0° C. for 1 h. The solid was filtered off and dried. Yield 15.32 g.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccn2)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccn2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[4-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxylate (2.00 g, 2.31 mmol) in pyridine (15.9 mL) cooled in an ice bath was slowly added thionyl chloride (0.84 mL, 12 mmol). The mixture was allowed to warm to room temperature and stirred overnight (17 h). The brown reaction mixture was quenched with ice water and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-10% B over 25 min. Bottle A =hexanes, Bottle B=EtOAc) to give 404 mg (53%) of desired product as light brown oil. LC-MS calculated for C16Hl9F3N2O2: (M+H) 329; found 273.1 (M-tBu+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C=C(C)C=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:34](=[O:41])[NH:35][CH:36]([CH:38]2[CH2:40][CH2:39]2)[CH3:37])[CH:3]=1.C(O)(=O)C.[BrH:46].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:46])[CH2:12]2)=[O:10])=[C:4]([C:34](=[O:41])[NH:35][CH:36]([CH:38]2[CH2:40][CH2:39]2)[CH3:37])[CH:3]=1
Reactant: Br
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 2.5 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl4-methylbenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 2.5 hours. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 260 mg of the desired product in a paste form.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH2:46][CH2:45][C:44]=3[CH:48]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH2:46][CH2:45][C:44]=3[CH:48]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.85 g), sodium hydrogen carbonate (2.68 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.40 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.56 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.89 g, 60%).
Reaction SMILES: [Li]CCCC.[CH2:6]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[CH3:7].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>CCCCCC.C1COCC1>[CH2:6]([NH:8][C:9]([C:11]1[S:12][C:13]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:14][C:15]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])=[O:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCNC(=O)c1sc([Si](C)(C)C)cc1[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
A solution of 2.5M n-BuLi in hexane (18 mL) was added dropwise to a solution of N-ethyl-2-thiophenecarboxamide (3.1 g, 20 mmol) in 50 mL THF at below -65° C. under a positive nitrogen atmosphere and the resulting solution was stirred at -70° C. for 45 min. After that, TMSCl (9 mL) was added slowly at below -60° C. and stirring was continued at below -60° C. for min. The solution was allowed to warm to 0° C., then poured into water and extracted with CH2Cl2. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 5% ethyl acetate-hexane yielded 3.1 g of Example 248 as a white solid, m.p. 81-84° C., and 1.1 g of Example 249 as a colorless oil. nD24 1.5228.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]C6CCCCO6)[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:42])C(=O)C1.O1CCOCC1>C(Cl)Cl.Cl>[Br:42][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1ccc2ncc(Br)n2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (obtained by analogy of Stage 185.1 by replacing (rac)-6-chloro-3-[1-(3-methyl-3H-benzoimidazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine with (rac)-6-chloro-3-(1-imidazo[1,2-a]pyridin-6-yl-ethyl)-imidazo[1,2-b]pyridazine (Example 292), 150 mg, 0.328 mmol) was dissolved in DCM (3.3 mL) and NBS (64.2 mg, 0.984 mmol) was added. It was stirred at rt for 3 h then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated and dissolved in DCM (1 mL) with 4 N HCl in dioxane (0.246 mL, 0.984 mmol). The RM was stirred at rt for 2 min. The solvent was removed and the residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=452, 1H-NMR in DMSO-d6: 8.46 (s, 1H); 8.40 (s, 1H); 8.04 (m, 2H); 7.78 (s, 1H); 7.67 (s, 1H); 7.52 (m, 2H); 7.33 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.75 (q, 2H); 1.80 (d, 3H)).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.[CH3:30][O:31][C:32](Cl)=[O:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[N:22]1[CH:21]=[C:20]([C:18]([NH:17][C:15]2[CH:16]=[C:11]([C:8]3[N:7]=[C:6]([CH:4]4[CH2:3][N:2]([C:32]([O:31][CH3:30])=[O:33])[CH2:5]4)[O:10][N:9]=3)[CH:12]=[CH:13][C:14]=2[CH3:29])=[O:19])[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=12
Reactant: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (21) (25 mg, 0.0667 mmol) in anhydrous pyridine (1 mL) was added methylchloroformate (5 μL, 0.667 mmol). The reaction was stirred to room temperature for 10 minutes. The pH was adjusted to neutral with 10% citric acid. The crude was purified by reverse phase HPLC to afford methyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F15) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s 1H), 9.52 (d, J=7.2 Hz, 1H), 8.71 (s, 1H), 8.10 (s, 1H), 7.82-7.91 (m, 2H), 7.69 (t, J=8.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31 (td, J=7.2, 0.8 Hz, 1H), 4.15-4.44 (m, 5H) 3.59 (s, 3H), 2.37 (s, 3H). MS m/z 433.3 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][N:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].[Br-:12].[Br-:13].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[OH2:33]>CC(O)(C)C>[Br:12][C:5]1([Br:13])[C:4]2[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[N:9][C:8]=2[NH:7][C:6]1=[O:33]
Reactant: N#Cc1ccnc2[nH]ccc12
Reactant: [Br-]
Reactant: O
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Product: N#Cc1ccnc2c1C(Br)(Br)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-cyano-7-azaindole (1 g, 6.0 mmol) in t-BuOH (60 mL) was added pyridinium tribromide (6.5 g, 20.19 mmol) by small portions. The solution was stirred at RT for 2 h and water was added. Solvent was evaporated, a solid precipitated which was filtered, rinsed quickly with IPOH and dried to give 3,3-dibromo-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1)[CH:2]=[CH2:3].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:14].[CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[CH:11][CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[C:5]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: C=CCn1c(N2CCNCC2)c(C(=O)O)c(=O)c2cc(F)ccc21
Product: Cl
Yield: 26.1 %

Procedure:
A mixture of 1-allyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.94 g, piperazine 2.9 g and 2 ml of pyridine was refluxed for 8 hours by heating. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in an aqueous solution of acetic acid and the insoluble matters were removed by filtration. The filtrate was neutralized with an aqueous solution of NaOH. The precipitated crystals were collected by filtration, washed with water and dried. Recrystallizing the crystals from a mixed solvent of concentrated hydrochloric acid and ethanol, 0.32 g (26%) of 1-allyl-6-fluoro-1,4-dihydro-4-oxo-(1-piperazinyl)-quinoline-3-carboxylic acid hydrochloride was obtained. Colorless powders.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(C#N)cc3)CCC2)cc1
Yield: 86.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 540 mg (3.7 mmol) of 4-cyanophenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (19:1) gave 480 mg (89%) of 1-[2-(4-cyanophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) δ2.07 (m, J=7 Hz, 2H), 2.42 (s, 3H), 2.89 (t, J=7 Hz, 4H), 7.05 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([NH:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1)=[O:17]>C(O)C>[CH:16]([NH:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: O=CNNc1ccc(N=C=S)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Dibenzylamine (0.20 g, 0.001 mole) and 4-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were mixed in ethanol (25 ml) and the resulting mixture was heated to reflux for 20 minutes. The reaction mixture was cooled to room temperature, then was chilled in ice. After scratching the flask walls, a white crystalline solid was separated out of solution. The solid was filtered off, washed thoroughly with ether, and allowed to dry. This gave 0.31 g (80 percent) of product as a white crystalline powder, m.p. 174°-176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:26][CH:23]2[CH2:25][CH2:24]2)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Product: COCCCOc1cc(CNC2CC2)ccc1OCc1ccccc1

Procedure:
4-(Benzyloxy)-3-(3-methoxypropoxy)benzaldehyde (945 mg) and cyclopropylamine (0.44 ml) were treated in the same manner as Reference Example 1 to give N-[4-(benzyloxy)-3-(3-methoxypropoxy)benzyl]cyclopropanamine (947 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>O>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(CC(=O)O)OCC
Temperature: 110 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 3,3-diethoxypropanoate (20 g, 105 mmol) in water (80 ml) was added sodium hydroxide (5 g, 125 mmol, 1.2 eq). The resulting solution was stirred for 1 hour at 110° C. in an oil bath and then adjusted to pH 5 with aqueous hydrogen chloride (3N). The crude product was then extracted with tetrahydrofuran (3×80 ml) and the organic layers were combined, dried over anhydrous sodium sulfate, and filtered before being concentrated under vacuum. The crude residue was purified by silica gel chromatography using 3-50% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 3,3-diethoxypropanoic acid as light yellow oil (12 g, 70%); 1H NMR (300 MHz, DMSO): δ 4.80-4.82 (t, J=5.7 Hz, 1H), 3.41-3.61 (m, 4H), 2.49 (d, J=5.7 Hz, 2H), 1.06-1.24 (m, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16](O)=[O:17]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16]([Cl:3])=[O:17]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of thionyl chloride (7.25 mL, 99.5 mmol) and N,N-dimethylformamide is added to a mixture of 5-chloro-2-nitrobenzoic acid in toluene. The reaction mixture is heated to and held at 80° C. for 16 hours, cooled to room temperature, concentrated in vacuo, diluted with toluene, concentrated in vacuo and diluted with toluene to obtain the title product as a 1 molar solution in toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:28][OH:29]>C(O)C.O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:28][OH:29])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66.7 %

Procedure:
To a stirred suspension of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid (0.718 g, 0.00215 mol) and potassium carbonate (0.167 g, 0.00121 mol) in absolute ethanol (15 mL) was added a solution of hydroxylamine hydrochloride (0.180 g, 0.00259 mol) in water (3 mL), and the mixture stirred at room temperature for 6 days. The mixture was rotary evaporated. The residue was dissolved in methanol, silica gel (10 g) was added, and the mixture rotary evaporated to dryness. The powder was purified by chromatography on silica gel, eluting with dichloromethane-methanol (20:1) to give 0.499 g of 4-(4′-bromo-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 175-176° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]1[C:39](B(O)O)=[CH:38][CH:37]=[N:36]1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:14]3)=[C:2]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:7]=1
Reactant: Cn1nccc1B(O)O
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 6 %

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (80 mg, 0.166 mmol), potassium carbonate (115 mg, 0.832 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (84 mg, 0.666 mmol), tetrakis(triphenylphosphine)palladium(0) (19.23 mg, 0.017 mmol), dioxane (1109 μl) and water (555 μl). The reaction was heated in a microwave at 100° C. for 30 min. The resulting mixture was concentrated and purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were dried under a vacuum to provide a white solid 5-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (5 mg, 0.01 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.48 (s, 3H) 7.01 (s, 1H) 7.05 (d, J=1.82 Hz, 1H) 7.11 (s, 1H) 7.21 (s, 1H) 7.43 (d, J=6.41 Hz, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.53-7.64 (m, 3H) 7.64-7.75 (m, 3H) 8.11 (d, J=8.23 Hz, 1H) 8.34 (s, 1H) 8.43 (d, J=1.60 Hz, 1H); m/z (ESI) 482.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H](C3C=CC=CC=3)C)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:22]C(OC(Cl)C)=O>ClCCCl>[ClH:22].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Brc1ccc([C@H]2CNCCO2)cc1
Product: Cl
Yield: 93.7 %

Procedure:
To a solution of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (intermediate 13, 50.0 g, 144 mmol) in 1,2-dichloroethane (240 ml) was added 1-chloroethyl chloroformate (103 g, 722 mmol) at room temperature. The mixture was refluxed for 8 hours. The mixture was concentrated under reduced pressure and methanol (120 ml) was added. The mixture was refluxed for 3 hours, and was concentrated under reduced pressure to afford the crude product. This crude product was washed with acetone, dried under reduced pressure to afford (2S)-2-(4-bromophenyl)morpholine hydrochloride (intermediate 14, 37.6 g, 93%).