Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: NC1CCCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cnc(NC2CCCCC2)c2nccn12
Temperature: 90 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
(5,8-Dibromoimidazo[1,2-a]pyrazine, 200 mg, 0.72 mmol), cyclohexylamine (86 mg, 0.86 mmol) and di-isopropylethylamine (140 mg, 0.74 mmol) are suspended in iso-propanol (5 ml). The mixture is stirred at 90° C. for 18 h. The solvent is evaporated in vacuo and the residue dissolved in dichloromethane (5 mL). The organic layer is washed with saturated NaHCO3(aq) (10 ml), H2O (10 ml) and brine (10 mL). The organic layer is dried (MgSO4) and evaporated in vacuo. The oily residue is purified by column chromatography, eluting with 5:1 hexane:ethyl acetate to give a brown oil (147 mg, 69%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 3.83 min (99.8%), m/z (APCI) 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CCNCC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CC(=O)CC(C)=O
Product: CC1(C)C2COC(=O)C21
Yield: 73.9 %

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (41.3 mmole, 6.36 g) in dioxane (20 ml) was added dropwise to a refluxing solution of cupric acetylacetonate (1.03 mmole, 0.27 g) in dioxane (400 ml) over a period of 7 hours under an argon atmosphere. After completion of the addition, the reaction mixture was heated under reflux for 1 hour. The crude reaction mixture was distilled to afford (±)-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (3.85 g, 75% yield); bp 110°, 16 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:11]=[C:12]([C:19](O)=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14](O)=[O:15]>C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([N:1]2[C:19](=[O:20])[C:12]3=[CH:11][C:10]([OH:9])=[CH:18][CH:17]=[C:13]3[C:14]2=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2C(=O)N1c1cccc(O)c1
Yield: 80.5 %

Procedure:
m-Aminophenol(13.23 g, 0.12 mol) and 4-hydroxyphthalic acid (16.98 g, 0.09 mol) are allowed to react in refluxing acetic acid as described above. The product (21.6 g, 91%), collected as a tan solid, is recrystallized from methanol to give 18.5 g of pale yellow powder [mp 270° C. differential scanning calorimetry] having the following structure: ##STR7##
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:29]=[C:28]([CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:18]=3)[S:13][C:6]=12)[NH2:30]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)cn4)sc23)c(F)c1
Temperature: 25 °C
Yield: 1.1 %

Procedure:
To a solution of nitro compound 169 (400 mg, 0.88 mmol) in EtOH/H2O (8 mL/4 mL) at 100° C. (bath) was added iron powder (420 mg, 7.48 mmol) and NH4Cl (41 mg, 0.76 mmol) and the reaction mixture was stirred vigorously at reflux temperature for an hour. The mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was collected and concentrated to give the title compound 170 (4.20 mg, 88% purity) as a yellow solid. MS (m/z): 424.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.O>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1c(N2CCCCC2)nc2ccccc2n1-c1ccc(Cl)cc1

Procedure:
A solution of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (7.5 g), piperidine (2.4 g), and triethylamine (2.9 g) in ethanol (50 ml) was stirred at 20° C. for 2 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent and recrystallisation from ethanol gave the title compound mp 184°-185° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][O:27][CH:28]=1)CCC>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3[O:24][CH2:25][CH2:26][O:27][CH:28]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCO1

Procedure:
Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane. Light brown solid. MS (m/e): 294.4 ([M+H]+, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:17][C:16]2[NH:15][C:14]3[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10](=[O:20])[C:9]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:7]=2[C:6](=[O:30])[CH2:5]1.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.CN(C)C=O>[CH3:19][C:12]1([CH3:18])[CH2:13][C:14]2[N:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]3[CH2:17][C:4]([CH3:31])([CH3:3])[CH2:5][C:6](=[O:30])[C:7]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:9]=2[C:10](=[O:20])[CH2:11]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)N1C2=C(C(=O)CC(C)(C)C2)C(c2ccc([N+](=O)[O-])cc2)C2=C1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 17 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of anhydrous tetrahydrofuran was stirred at room temperature under an atmosphere of dry nitrogen and treated dropwise with a solution of 200 mg of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8(2H,5H)-acridinedione in 5 ml of dimethylformamide. The mixture was then heated at reflux for 15 minutes, cooled to room temperature, treated with 44 ml of methyl chloroformate and stirred at room temperature under an atmosphere of dry nitrogen for 18 hours. The solvents were removed under reduced pressure and the resulting waxy residue was taken up in diethyl ether and the insoluble material was filtered off. The filtrate was then purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 80:20 to 50:50) as the eluent to give methyl 2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1H-acridine-10-carboxylate as a white crystalline solid of melting point 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[C:27]([O:35][C:36]([F:39])([F:38])[F:37])[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[O:35][C:36]([F:37])([F:38])[F:39])(=[O:33])=[O:32])[C:6](=[O:11])[C:5]2([OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
Under nitrogen atmosphere, to a solution of 5.00 g of 5-chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one, which is the compound described in Preparation 1.1A of brochure Publication No. WO01/5513,0 in DMF (50 ml) was added 760 mg of NaH under ice cooling, then, the reaction mixture was warmed to room temperature and stirred for 30 minutes. To the stirred solution, under cooling at −20° C., was added dropwise a solution of 5.52 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride in DMF (10 ml) over 3 minutes, then, the solution was stirred at the same temperature for 5 hours. After warming to 0° C., to the reaction solution was added CHCl3 and an aqueous solution of 5% K2CO3, and the solution was stirred at room temperature for 30 minutes. The liquid separation of the stirred solution was performed, then the aqueous layer was extracted with CHCl3, the combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and was solvent under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1; v/v) to obtain 4.55 g of the title compound (orange color solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:32][CH2:33][CH2:34][NH2:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:35][CH2:34][CH2:33][NH:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(NCCN)cc1OC
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Product: COc1ccc(NCCNCCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and 2-(3,4-dimethoxyphenylamino)-ethylamine analogously to Example 6.
Reaction SMILES: [NH3:1].CO.Br[CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1>C1COCC1>[NH2:1][CH2:5][C:6]1[C:7]([F:23])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:17]#[N:18])[C:9]([F:12])=[CH:10][CH:11]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2F)c1
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A 7M solution of ammonia in MeOH (45.8 mL, 321 mmol) was added to a solution of 3-{[3-(bromomethyl)-2,6-difluorophenyl]oxy}-5-chlorobenzonitrile (2.3 g, 6.41 mmol) in THF (30 mL) at RT. The reaction was capped and stirred for 16 h at RT then concentrated to dryness under vacuum. Ethyl acetate (200 mL) and saturated aqueous NaHCO3 solution (300 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (2×200 mL), water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated to give a white solid. The crude product was purified on silica gel (10% MeOH/DCM) to give the title compound (1.63 g, 86%) as a white solid (N4011-13-100). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.82 (s, 1H), 7.40-7.66 (m, 3H), 7.31 (t, 1H), 3.75 (s, 2H), 1.86 (br. s., 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=O)[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:39][C:40]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:41]=1[CH2:42][C:43]1[CH:44]=[C:45]2[NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[C:46]2=[N:47][CH:48]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:51]2[C:45]3[C:46](=[N:47][CH:48]=[C:43]([CH2:42][C:41]4[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:40]=4[F:39])[CH:44]=3)[C:49]([CH3:53])([CH3:52])[CH2:50]2)=[O:25])[CH2:10][C@H:9]1[CH3:26])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3F)cnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3F)cc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 51.3 %

Procedure:
A mixture of (2R,5S)-4-carboxymethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.32 mmol), 1,1′-carbonyldiimidazole (0.057 g, 0.35 mmol) and DCM (5 mL) was stirred at 20° C. for 24 h. 6-(2,4-Difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.32 mmol) was added and the mixture heated at 35° C. for 24 h. Solvent was evaporated and the residue dissolved in 1,2-dichloroethane and the mixture was heated to 60° C. for 24 h. Mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (3×20 mL) and combined organic extracts were dried and evaporated to give an oil. Chromatography (SiO2, gradient elution, 0-100% EtoAc in petrol 40-60) gave the title compound (0.103 g) as an oil. MS: [M+H]+=628.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:11][S:10](=[O:21])(=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:22])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][S:10](=[O:21])(=[O:20])[NH:9]2)=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)NS(=O)(=O)N=C1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2ccc(Cl)cc2)NS(=O)(=O)NC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
To a solution of 3,4-bis-(4-chloro-phenyl)-3-methyl-2,3-dihydro-[1,2,5]thiadiazole 1,1-dioxide (5.38 g, 15.1 mmol) in 91 mL of in ethanol cooled to 0° C. was added sodium borohydride (0.30 g, 61 mmol) portionwise over 7 min. After stirring at 0° C. for another 45 min, the mixture was allowed to warm to room temperature and stirred for 3.5 h. The reaction was then cooled to 0° C. and quenched by dropwise addition of 1 M hydrochloric acid (38 mL). The reaction mixture was taken up in 500 mL of ethyl acetate then washed with water (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with 3:1 heptane-ethyl acetate) to give rac-(3R*,4S*)-3,4-bis(4-chlorophenyl)-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide (4.3 g).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])([S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:20][C:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a solution of 15.3 g (47 mmol) of 2-methyl-2-(4-trifluoromethyl-benzenesulfonyl)-propionic acid ethyl ester in THF/water (4/1, 160 mL) were added 3.95 g (94 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (60 mL) and then washed with DCM (2×40 mL). The basic aqueous layer was cooled in an ice bath and then acidified with 1N aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with DCM (3×60 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 11.6 g of 2-methyl-2-(4-trifluoromethyl-benzenesulfonyl)-propionic acid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#CC(N)c1ccccc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1
Reaction time: 12 h

Procedure:
2-Amino-2-phenyl-acetonitrile (0.04 mole) and benzoyl acetone (0.04 mole) are refluxed for four hours in 30 ml. of anhydrous benzene in the presence of 100 mg. of p-toluenesulfonic acid. After cooling the reaction mixture is filtered and the solvent is evaporated off to give an oily residue which is dissolved in an ethanol solution containing sodium ethoxide (0.041 mole) and the mixture is allowed to stand for 12 hours at the room temperature. The solid precipitate which forms is recovered by filtration.
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)C.BrC1C=C[C:30]([N:33]2CCC(N(C)C)C[CH2:34]2)=CC=1>>[CH3:30][N:33]([CH3:34])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN(C)C1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 120 °C
Yield: 23 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 1-(4-bromophenyl)-N,N-dimethylpiperidin-4-amine (139 mg, 0.49 mmol) and the reaction was heated to 120° C. for 4 h. Crude product was purified by flash chromatography using EtOAc/Et3N as eluent (1:0 to 98:2) to give the title compound as a yellow solid (37 mg, 23%). 1H NMR (400 MHz, MeOD) δ 7.61 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 3.89-3.86 (m, 2H), 2.75-2.69 (m, 2H), 2.36-2.30 (m, 1H), 2.30 (s, 6H), 1.96-1.64 (m, 2H), 1.65-1.48 (m, 2H), 1.32 (s, 12H); MS ESI 331.1 [M+H]+, calcd for [C19H31BN2O2+H]+ 331.25.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([NH:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15].NN.[ClH:27]>CO>[ClH:27].[NH2:3][O:12][CH2:13][C:14]([NH:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: O=C(CON1C(=O)c2ccccc2C1=O)NOCc1ccccc1
Agent: Cl
Agent: NN
Solvent: CO
Product: NOCC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5.0 g of [(1.3-dihydro-1,3-dioxo-2H-isoindole-2-yl)oxy]-N-(phenylmethoxy) acetamide is suspended in 100 ml anhydrous methanol. While stirring and maintaining the temperature at 0° C., 0.54 g hydrazine in 10 ml. methanol is added. Stirring is continued at 0° C. for 12 hours. After this time an equivalent amount of hydrochloric acid in methanol is added, the insoluble precipitate is filtered off and the mother liquor evaporated in vacuo. The residue is dissolved in a small amount of methanol, filtered and evaporated. The only residue is now treated with 100 ml of diethyl ether. 3.4 g of 2-(Aminooxy)-N-(phenylmethoxy)acetamide, hydrochloride having a melting point of 173° C. to 175° C. is filtered off.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([N+:23]([O-])=O)[CH:12]=[CH:13][C:14]=2[C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Sn]Cl.Cl>C1COCC1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([NH2:23])[CH:12]=[CH:13][C:14]=2[C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C#Cc2ccccc2)c(C#Cc2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccccc2)c(C#Cc2ccccc2)c1
Yield: 75.3 %

Procedure:
A solution of 3,4-bis(phenylethynyl)nitrobenzene (2.5 g, 7.7 mmol), SnCl2 (7.3 g, 39 mmol, 5 eq.), and HCl (5 mL, 10 eq.) in THF (20 mL) was stirred at room temperature for 5 h. After neutralization with NaOH (1.0N solution), product was extracted with dichloromethane. Solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform as the eluent to yield 1.7 g (75%) of 3,4-bis(phenylethynyl)phenylamine as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.67-7.61 (m, 4H), 7.42-7.35 (m, 7H), 6.85 (d, J=2.4 Hz, 1H), 6.62-6.58 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 3.85 (broad, 1H). 13C NMR (68 MHz, CDCl3) δ 146.3, 132.9, 131.5, 131.2, 131.8, 128.3, 128.2, 127.7, 126.5, 123.7, 123.1, 117.3, 117.2, 115.1, 114.9, 92.8, 91.2, 88.9, 88.5. m/z (high res. ESI) 294.1283 (Calc. C22H16N 294.1283).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC(C)C(N1CC2C(=CC=C(C3C=CC([N+]([O-])=O)=CC=3)C=2)C1)C(OC)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11](=[CH:10][CH:9]=2)[CH2:12][N:13]([CH:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:14]3)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1
Yield: 55 %

Procedure:
The compound of example 673 was prepared analogous to the compound of example 6 by reduction of the compound of example 672.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].O>CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)c1cccnc1Cl
Reaction time: 0.5 h

Procedure:
Into a suspension of 2-chloro-3-pyridinecarboxylic acid (23.7 g) in 500 ml of acetone, triethylamine (30.7 ml) is added. After 30 minutes of stirring, pivaloyloxymethyl chloride (22.5 ml) is poured into the reaction mixture, and the resulting mixture heated to reflux for 2 hours. The mixture is then cooled to a temperature of 15°-20° C., and then poured into 1000 ml of cooled water. The resulting mixture is then extracted with methylene chloride (2×100 ml), and the water layer discarded. To the remaining organic extract, 10 g of anhydrous magnesium sulfate is added and then separated by filtration. The organic extract is distilled at normal pressures to separate methylene chloride. When all methylene chloride is distilled off, the distillation is continued under vacuum (0.17 mm Hg) to separate the desired product compound. The distilled product fraction separates at 131°-133° C., and is pivaloyloxymethyl 2-chloro-3-pyridine-carboxylate. Yield: 21.8 g (53.5% of theory).