Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[O:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[C:53]([NH:55][NH2:56])=[O:54]>CN(C)C1C=CN=CC=1.ClCCl>[O:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[C:53]([NH:55][NH:56][C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1)=[O:54]
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: NNC(=O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1ccco1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-furanhydrazide (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 7.5 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was then washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure. The solid thus obtained was recrystallized from dichloromethane-hexane to give the title compound (58 mg, 0.11 mmol, 58%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:34])[CH2:22][CH2:21]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:20]2[CH2:25][CH2:24][C:23]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[CH2:22][CH2:21]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ncnc(N2CCC3(CC2)C(=O)Nc2ccccc23)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (1.0 g, 5.3 mmol) in methanol (20 mL) was added triethylamine (2.0 mL, 14.3 mmol) and spiro[indoline-3,4′-piperidin]-2-one (1072.5 mg, 5.3 mmol). The mixture was stirred at ambient temperature for 2 h and then 10 wt % Pd on C (wet) was added. The resulting mixture was stirred under hydrogen for 18 hours, diluted with methanol, and was filtered through Celite. The filtrate was concentrated, and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the mixture was filtered and dried under reduced pressure. The resulting compound was submitted to next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.86 (s, 1H), 7.45 (d, 1H), 7.20 (td, 1H), 6.98 (t, 1H), 6.87 (d, 1H), 6.30 (q, 1H), 4.15 (s, 2H), 3.45 (dd, 2H), 3.26-3.18 (m, 2H), 2.86 (d, 3H), 1.97-1.88 (m, 2H), 1.82 (dd, 2H). MS (EI) for C14H20N6O: 325.6 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:22][N:23](C)C=O.S(Cl)(Cl)=O.CN>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH:23][CH3:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2nc3ccc(Cl)nc3n2CC(=O)O)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CNC(=O)Cn1c(-c2ccc(C)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of methylamine in tetrahydrofuran (21.5 ml of a 2.59M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with isopropyl ether. Upon cooling, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 70° C. to give 1.86 g (64% yield) of title compound, mp>250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][C:18]([CH:21]=[O:22])([CH3:20])[CH3:19]>C1COCC1>[CH3:17][C:18]([CH3:20])([CH3:19])[CH:21]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1)[OH:22]
Reactant: CCCSc1ccc(Br)cc1
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCSc1ccc(C(O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-bromo-4-(propylthio)benzene (500 mg, 2.16 mmol) in THF (10 ml) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.91 ml, 2.27 mmol). The resulting yellow solution was stirred at −78° C. for 15 minutes then pivaldehyde (0.29 ml, 2.59 mmol) was added. The mixture was allowed to warm to room temperature, during which time the solution turned colourless. The mixture was partitioned between ethyl acetate (60 ml) and water (30 ml). The organic phase was separated, washed with brine (30 ml), dried over MgSO4 filtered and evaporated to give a colourless oil. The crude product was chromatographed on silica eluting with 5% ethyl acetate in hexanes to give the title product as a pale yellow oil (468 mg). 1H NMR δ (CDCl3) 7.28-7.20 (4H, m), 4.36 (1H, s), 2.89 (2H, t, J=7.3 Hz), 1.84 (1H, s), 1.71-1.63 (2H, m), 1.02 (3H, t, J=7.3 Hz), 0.91 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:37]I>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:31]([F:33])([F:32])[F:34])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH3:37])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)Cc1ccccn1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
In a solution of 0.35 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-234) synthesized similarly to Synthetic Example 5 in 20 ml of N,N-dimethylformamide, 0.04 g of 55% oily sodium hydride was added under cooling with ice with stirring, and stirred at the same temperature for 30 minutes. Then, 0.12 g of methyl iodide was added and thereafter the temperature was raised to room temperature, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was diluted with 80 ml of ethyl acetate, washed with water (50 ml×2), dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with high performance liquid chromatography that was eluated with acetonitrile-water (85:15) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.I[C:40]1[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cn1ccc(I)cc1=O
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(-c4ccn(C)c(=O)c4)cc3)C(=O)O2)o1
Yield: 41.8 %

Procedure:
To a solution of (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.12 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (33 mg, 0.14 mmol) in dry 1,4-dioxane (15 mL) were added Cs2CO3 (2M, 1 mL) and Pd(PPh3)Cl2 (7.7 mg, 0.01 mmol). The mixture was heated at reflux for 2 h under N2 atmosphere, the solid was filtered off, and the mixture was diluted with water (30 mL) and EtOAc (30 mL). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep TLC to afford (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, yield: 41.8%). LC-MS Method 2 tR=0.984 min, m/z=499.1; 1H NMR (CDCl3): δ1.48-1.50 (m, 3H), 2.16-2.20 (m, 1H), 2.23-2.26 (m, 1H), 2.27-2.32 (m, 2H), 2.39 (s, 3H), 2.40-2.47 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.90 (m, 1H), 2.98-3.01 (m, 1H), 3.58 (s, 3H), 5.62-5.64 (m, 1H), 6.45-6.48 (m, 1H), 6.87 (s, 1H), 6.92-6.94 (d, 2H), 7.20-7.24 (m, 4H), 7.25-7.35 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[CH3:28]>C(O)C>[CH2:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30]1)[CH3:28]
Reactant: CCN1CCCC(N)C1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCCC(NCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
7.2 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one, 2.8 gm of sodium carbonate and 3.8 gm of 1-ethyl-3-amino-piperidine were refluxed in 100 ml of ethanol for 5 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was purified on a silica gel column. The evaporation residue of the eluate was recrystallized from ethyl acetate.
Reaction SMILES: C(O)C.[F:4][C:5]([F:18])([F:17])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:9]=2[CH:10]=1.[BH4-].[Na+]>C(O)(=O)C>[F:18][C:5]([F:4])([F:17])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1
Reactant: O=Cc1ccc2oc(C(F)(F)F)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: OCc1ccc2oc(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To an ethanol solution (2.0 mL) of 2-(trifluoromethyl)benzofuran-5-carbaldehyde (220 mg, 1.03 mmol) synthesized in Reference Synthesis Example 95, sodium borohydride (115 mg, 3.05 mmol) was added and the resultant solution was stirred at 70° C. for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature and acetic acid was added to the cooled solution, followed by concentrating the resultant mixture under reduced pressure. To the obtained residue, water was added and extraction with dichloromethane from the resultant mixture was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (219 mg, yield 99%).
Reaction SMILES: CO[C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=3[CH3:24])[N:10]=2)=[CH:5][CH:4]=1.F[C:28](F)(F)C(O)=O>>[CH2:7]([S:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[N:10]=1)[CH2:6][CH2:25][CH2:26][CH2:3][CH2:4][CH2:5][CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CSc2nc(Cl)cc(Nc3cccc(C)c3C)n2)cc1
Product: CCCCCCCCSc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
To a suspension of 2-p-methoxybenzylthio-4-chloro-6-(2,3-xylidino)-pyrimidine (8 g; see example 5) in trifluoroacetic acid (80 ml) anisole (2,7 ml) is added and the mixture is refluxed for 50'. After cooling, the trifluoroacetic acid is evaporated. The residue is dissolved in ethyl ether and the separated solid is filtered, washed with ethyl ether, then with water to neutrality, with cool acetone and again with ethyl ether. 5 G of the desired product (III, 33) are obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].Cl>O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:22](=[O:24])[CH3:23])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])=[CH:14][CH:15]=1
Reactant: CCCc1c(OCc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(N)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-[2-hydroxy-4-(4-nitro-benzyloxy)-3-propyl-phenyl]-ethanone (1.0 g, 3.0 mmol) in tetrahydrofuran (13 mL) is added concentrated hydrochloric acid (2.7 mL) and stannous chloride dihydrate (2.2 g, 9.9 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture is quenched into saturated aqueous NH4Cl (100 mL). The resulting emulsion is filtered and the filtrate extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with brine, dried over sodium sulfatesodium sulfate, and concentrated to provide the title compound in crude form (980 mg,). LC-MS (m/z): 298 (M−1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:40][C:41](=O)[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C)C=O>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:41](=[O:40])[CH2:42][NH:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
14.2 g (42 mmoles) of glycine benzyl ester p-toluenesulfonate are dissolved in 100 ml of dimethyl formamide, 4.6 ml (42 mmoles) of N-methylmorpholine and 14.2 g (40 mmoles) of tert.-butoxycarbonyl-glycine 2,4,5-trichlorophenyl ester are added, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated, and the residue is dissolved in a mixture of 150 ml of ethyl acetate and 50 ml of water. The ethyl acetate phase is washed twice with 30 ml of ice-cooled 1 n aqueous hydrochloric acid, each, and then with water, dried over sodium sulfate and evaporated. The residue is triturated with a 1:1 mixture of diisopropyl ether and petroleum ether, filtered, the solid is washed with the same solvent mixture and dried in a desiccator. 11.0 g (82.8%) of tert.-butoxycarbonyl-glycyl-glycine benzyl ester are obtained; m.p.: 83° C., Rf14 =0.1-0.2.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])=[N+:2]=[N-:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: Nc1ccc(Cl)cc1
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
2-Azido-4-fluoro-benzoic acid (3.01 g, 17 mmol; Barral, Karine; Moorhouse, Adam D.; Moses, John E. Organic Letters (2007), 9(9), 1809-1811) was dissolved at ambient temperature in thionyl chloride (27.3 ml) under an argon atmosphere. The reaction mixture was heated to 80° C. for 1.5 h and brought to dryness under reduced pressure to give 2-azido-4-fluoro-benzoyl chloride as orange oil. 2-Azido-4-fluoro-benzoyl chloride was dissolved at ambient temperature in CH2Cl2 (23 ml) under an argon atmosphere. 4-Chloro-phenylamine (2.12 g, 17 mmol; [106-47-8]) was added and the reaction mixture was stirred at ambient temperature for 14 h. Saturated aqueous NaHCO3 solution was added until a pH of 8 was adjusted, the layers were separated and the aqueous layer was extracted two more times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from heptane/CH2Cl2 to give the title compound (3.08 g, 11 mmol; 64%) as off-white crystals. MS: m/e=291.0 [M+H+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[S:6].[CH3:7]OS(=O)(=O)OC.[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[Na+]>>[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[CH3:7][S:6][C:2]1[S:3][CH:4]=[CH:5][S+:1]=1
Reactant: COS(=O)(=O)OC
Reactant: S=c1sccs1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CSc1scc[s+]1
Reaction time: 0.5 h

Procedure:
A mixture comprising 26.8g (0.2 mole) of 1,3-dithiol-2-thion and 25.2g (0.2 mole) of dimethylsulfuric acid was reacted at 60° C for 30 minutes and then at 90° C for 30 minutes. After cooling, the reaction product was poured into 150 ml of a saturated aqueous sodium perchlorate solution to deposit crystals. The crystals were recovered by filtration, washed with ether, dried and then recrystallized from methanol to obtain 42.5g of yellow crystals, m.p. 42°-46° C, yield 85.8%.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH:16]=[N:15]2)[CH2:10][C@H:9]1[CH3:33])=[O:7])[CH3:4].CCO>[Pd].CCOC(C)=O>[CH2:3]([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:18]([C:19]([F:20])([F:21])[F:22])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]2)[CH2:10][C@H:9]1[CH3:33])=[O:7])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)C[C@H]1C
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A pressurized vial was charged with palladium 10 wt. % (dry basis) on activated carbon, wet (1.367 g, 1.284 mmol) while under a stream of N2 (gas). Then a solution of benzyl 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.631 g, 12.84 mmol) in a 1:1 mixture of EtOH (32.1 ml)/EtOAc (32.1 ml) was added into the vial. The reaction mixture atmosphere was purged with hydrogen gas (3×). The reaction was stirred vigorously under hydrogenation (35 psi) conditions for 2.5 h. The progress of the reaction was monitored by LC/MS, which suggested reaction completion LCMS (ESI) m/z 371.2 (M+Na)+. The mixture was filtered through a plug of celite and the filtrate was concentrated in-vacuo. The residue was diluted with hexane and agitated. The precipitate was collected by filtration and the solids were rinsed with hexane. This gave 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (3.810 g, 10.94 mmol, 85% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-8.21 (m, 1H), 4.47-4.69 (m, 1H), 4.01-4.16 (m, 2H), 2.56-2.70 (m, 1H), 2.12 (dt, J=4.21, 12.37 Hz, 1H), 1.93-2.06 (m, 2H), 1.71-1.90 (m, 3H), 1.19 (t, J=7.04 Hz, 3H), 0.92 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 371.2 (M+Na)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:34]=O)[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][CH:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=CC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and cyclobutanecarboaldehyde (0.5 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47 g) as yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]1(=[O:25])[NH:23][C:22](=[O:24])[CH:21]=[CH:20]1>CO>[CH:5]1[C:4]2[CH2:3][C:2]3[CH:10]4[CH:18]([C:17]5[C:12]([NH:11]4)=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:21]4[C:22](=[O:24])[NH:23][C:19](=[O:25])[CH:20]4[C:1]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1C=CC(=O)N1
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Solvent: CO
Product: O=C1NC(=O)C2C1C1=C(Cc3ccccc31)C1Nc3ccccc3C12
Yield: 62.3 %

Procedure:
A mixture of 2-(2-indenyl)indole (1.0 g, 4.3 mmol) and maleimide (525 mg, 5.41 mmol) in a 10 cm sealed reaction vial was heated at 180°-190° C. for 30 min. After cooling the reaction to ambient temperature, MeOH (5 mL) was added. The product was collected to give 880 mg (62%) of a white solid product with a m.p. of 254°-255° C. (MeOH). The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ3.1-3.4 (m, 2H), 3.8 (m, 2H), 3.95 (t, 1H), 4.35 (d, 1H), 6.9-7.4 (m, 7H), 7.75 (d, 1H), 11.05 (s, 1H), 11.25 (s, 1H).