Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.39 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as a light brown solid (0.054 g, 11%). MS (ISP) 476.0 [(M+H)+]; mp 238° C.
Reaction SMILES: [OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.F[C:14]1[C:23]([N+:24]([O-])=O)=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1>>[CH3:6][C@:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:5])[NH:24][C:23]2[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([C:27]([F:30])([F:28])[F:29])=[CH:15][C:14]=2[O:1]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Product: COC(=O)c1cc2c(cc1C(F)(F)F)O[C@@](C)(c1ccccc1)C(=O)N2

Procedure:
Using (2S)-2-hydroxy-2-phenylpropanoic acid and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)-benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.1 g, 5.08 mmol) (from Example 10a supra), triphenylphosphine (3.2 g, 12.20 mmol) (Aldrich) and phthalimide (1.8 g, 12.20 mmol) (Aldrich) in anhydrous tetrahydrofuran (45 mL) was cooled to 0° C. To this was added dropwise diethyl azodicarboxylate (2.1 mL, 2.3 g, 12.20 mmol) (Aldrich) and the resulting solution was allowed to slowly warm to room temperature. After stirring overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated and the residue was purified by chromatography on a silica gel column using a 0–35% ethyl acetate in hexanes gradient to give (±)-cis-2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-isoindole-1,3-dione as a white solid. (Yield 1.52 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2cc(NCc3ccccc3)nc(N)n2)cc1
Temperature: 130 °C

Procedure:
0.30 g (0.001 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide and 11 ml (0.1 mol) of benzylamine were dissolved in 15 ml of ethanol and stirred in an autoclave at 130° C. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C(#N)C>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])=[O:32]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(Cl)CCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCCCCl)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (U.S. Pat. No. 3,534,019) and 19.6 parts of acetonitrile is added 0.298 part of sodium bicarbonate followed by 0.6 part of 5-chloropentanoyl chloride. The solution is stirred for 48 hours at room temperature, after which time the solvent is removed under reduced pressure and the resulting residue is purified by recrystallization from ethyl acetate-cyclohexane to afford 1-(5-chloropentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine, which has a melting point at about 148°-149° and is structurally represented by the following formula ##STR9## 14.8 Parts of the above chloride is reacted with 7.94 g of sodium iodide in 145 parts by volume of acetone containing a catalytic amount of sodium thiosulfate. The reaction mixture is stirred in the dark and refluxed for 5 hours and allowed to stand at room temperature. The solvent is removed and the residue taken up in benzene containing 1% sodium thiosulfate. The benzene is washed with aqueous sodium chloride and dried over sodium sulfate to provide an approximately 50--50 mixture of 1-(5-iodopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine and the (5-chloropentanoyl) derivative. 8 Parts of this mixture is reacted with 1.65 parts of morpholine in 80 parts by volume of acetone for 48 hours. The acetone is removed and 10% hydrochloric acid and benzene is added to the benzene layer. The benzene layer is separated and the aqueous acid layer is made basic with 5% potassium hydroxide and then extracted wtih benzene. The benzene layer is washed with sodium chloride solution and dried over sodium sulfate. The solvent is removed and the residue is crystallized from ethyl acetatecyclohexane to provide 1-(5-morpholinopentanoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine melting at 107°-114° C. and having the following structural formula ##STR10##
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH2:28][CH2:29][CH2:30][C:31]1[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl>[I:1][CH2:28][CH2:29][CH2:30][C:31]1[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(CCCO)s1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCI)s1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Iodine (187 mg, 0.74 mmol) was added to a solution of triphenylphosphine (194 mg, 0.74 mmol) and imidazole (49 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) at 23° C. After 0.5 h a solution of methyl 5-(3-hydroxypropyl)thiophene-2-carboxylate 7 (123 mg, 0.62 mmol) in CH2Cl2 (0.5 mL) was added. After stirring for 2 h the reaction was concentrated in vacuo and the residue was purified by FCC (silica gel, 7:3 hex/EtOAc) to provide 170 mg (89%) of the iodide 108.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:30]([Cl:31])=[CH:29][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21][C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH:17]=[CH:16][C:15]=3[Cl:28])[NH:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[C:24]([C:22]([NH:21][CH2:20][C:18]1[CH:17]=[CH:16][C:15]([Cl:28])=[C:14]([NH:13][C:11]2[NH:12][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:30]([Cl:31])=[CH:29][C:9]=3[N:10]=2)[CH:19]=1)=[O:23])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cc2[nH]c(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)nc2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(C(=O)O)cc3[nH]2)c1

Procedure:
A mixture of Ethyl-2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-carboxylate (0.91 g, 1.9 mmol) in 20 ml EtOH was treated with 1 N NaOH (3.9 ml+0.98 ml+0.98 ml) for 4 h at rt, for 5 h at 50° C. and for 3 d at rt. The mixture was concentrated, diluted with H2O, acidified with 1 N HCl and cooled in an ice bath. The precipitate was filtered, washed with ice water and dried to give the sub-title compound. Yield 0.81 g (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.Cl.[N:11]([O-])=O.[Na+]>O>[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)=[N+:9]=[N-:11]
Reactant: NNc1cccc(Cl)n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(Cl)n1
Temperature: 0 °C

Procedure:
2-Chloro-6-hydrazinopyridine (3.00 g, 20.90 mmol) was suspended in water (20 mL) and cooled to 0° C. Concentrated HCl (3.00 mL, 36.5 mmol) was added to dissolve the starting material and attain a pH of ˜1. Sodium nitrite (1.73 g, 25.07 mmol) in water (10 mL) was added dropwise. The thick suspension was allowed to warm to room temperature and extracted with CH2Cl2 (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The crude residue was purified by flash chromatography (0-10% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [Li+].[I-].Cl[C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](COC3C=CC4C(=O)N(C5CCCC5)SC=4C=3)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([O:12]C)=[O:11].O>N1C=CC=CC=1>[C:6]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 110.4 %

Procedure:
LiI (0.042 g, 0.32 mmol) was added to a solution of methyl 3-chloro-3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylate (0.158 g, 0.32 mmol) in pyridine (5 mL). The reaction mixture was refluxed for 12 h, and then cooled to room temperature. Excess solvent was removed under vacuum. The product was purified by HPLC using isopropanol:water as the solvent system to afford 3-chloro-3′-(2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid as a colorless solid (70 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.80 (d, 1H, J=8.6 Hz), 7.71-7.76 (m, 4H), 7.49-7.47 (m, 2H), 7.05 (d, 1H, J=8.5 Hz), 5.23 (s, 2H), 4.83-4.81 (m, 1H), 2.02-1.99 (m, 21-1), 1.62-1.60 (m, 6H). LC-MS (ESI) Calcd for C26H22ClNO4S [M+H]+: 480.09. Found: 479.95. HRMS (ESI) calcd for C26H22ClNO4S [M+H]+: 480.1031. Found: 480.1031.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=[O:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:40])[CH2:25][CH:26]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:33][C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:12])([CH3:11])[CH3:10]>O1CCCC1.C(OCC)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[CH2:4][O:22]2)=[CH:15][C:14]=1[NH:23][C:24](=[O:40])[CH2:25][CH:26]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:33][C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(CCC=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC2CO2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A suspension of 690 mg (15.8 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil, which had previously been washed with hexane) in 10 ml of dimethyl sulfoxide was stirred for 30 minutes, after which 2.66 g (12.1 mmol) of trimethylsulfoxonium iodide were added. The resulting mixture was stirred for 1 hour at 40° C., and then a solution of 4.50 g (10.5 mmol) of N-[2-t-butyl-5-(3-oxopropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 19) in 25 ml of tetrahydrofuran was added dropwise over a period of 5 minutes. The reaction mixture was then stirred for 1 hour, after which the reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The diluted mixture was washed several times with water and once with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 250 g of silica gel, using a 9:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 3.00 g (yield 65%) of the title compound as crystals, melting at 156°-157° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:16][CH3:17].CC(OC([NH:25][C@H:26]([CH2:30][CH3:31])[C:27](O)=[O:28])=O)(C)C.CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[NH2:25][C@H:26]([CH2:30][CH3:31])[C:27]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:16][CH3:17])[CH:4]=2)=[CH:10][CH:11]=1)=[O:28]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(Oc2ccc(N)cn2)ccc1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Yield: 119.3 %

Procedure:
6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine (Intermediate 50, 500 g), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (530 g) and Et3N (905 mL) are mixed together in ethyl acetate (2 L) and stirred at 0° C. until complete dissolution. ®T3P (2.15 L) was added dropwise in 30 minutes maintaining the temperature at ˜0° C. Ethyl acetate (500 mL) was added for washing the line. Work-up: 10% w/w sodium carbonate aqueous solution (2.5 L) was added and the mixture was stirred for 20 minutes. Then water (1.5 L) and ethyl acetate (1 L) were added and the two phases separated. The organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L), stirring the mixture for 10 minutes before separation of phases, then with 28% malic acid aqueous solution (2.5 L) and finally with 20% NaCl aqueous solution (2.5 L). The organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L) was added, the solution was concentrated to the lowest volume (<2 L) and acetonitrile was added up to 12.5 L (it is a solution of Intermediate 64 in acetonitrile). To this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C. and the resulting reaction mixture was stirred at 45° C. for 1.5 hours. The obtained suspension was cooled to 20° C., stirred for 1 hour and then filtered. The collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L), then dried under vacuum at 40° C., until constant weight, obtaining the title compound (817 g).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[O:19])[CH3:18])[N:16]=2)[N:7]=1
Reactant: CC(=O)c1csc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1csc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazol-4-yl)ethanone (343 mg, 1.35 mmol), iron powder (229 mg, 4.06 mmol) and NH4Cl (366 mg, 6.77 mmol) in a mixture of EtOH (6.0 mL) and water (3.0 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by water (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.62 min; [M+H]+=224.36.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][C:28]1[CH:29]=[N:30][NH:31][C:32]=1[NH:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[CH3:27][C:28]1[CH:29]=[N:30][N:31]2[C:22]([CH2:23][CH2:24][CH3:25])=[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)[C:17](=[O:18])[N:33]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:32]=12
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1cn[nH]c1NC1CCOCC1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g), 4-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (0.4 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and 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 a colorless solid (0.63 g, 61%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]1C[O:29][CH2:28][CH2:27]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:29]=[CH:28][CH2:27][CH2:26][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[N:19]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCCc2ccc(Cl)nc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCCCc2ccc(CCC=O)nc21
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1,1-dimethylethyl 2-chloro-5,6,7,8-tetrahydro-9H-pyrido[2,3-b]azepine-9-carboxylate (3.32 kg), potassium carbonate (3.25 kg), palladium acetate (132 g) and 1,1′-bis(diphenylphosphanyl)ferrocene (dppf) ((326 g) in THF (16.5 L) was degassed and put under an atmosphere of nitrogen. The THF solution of the hydroborated acrolein acetal was then added. The reaction mixture was degassed, purged with nitrogen and then heated at reflux for 26 hours. The reaction mixture was then cooled to 20° C., water (66 L) was added and the mixture was stirred for 30 minutes. The two layers were allowed to settle and the lower aqueous phase was discarded. IPAc (10 L) was then added and, after stirring for 5 minutes and allowing the mixture to settle, the lower aqueous phase was again discarded. The resulting organic layer was concentrated by distillation under reduced pressure to minimum volume (55 L of distillate removed) and a second portion of IPAc (33 L) was then charged. The two layers were again separated, the aqueous phase was discarded and the remaining organic layer was concentrated to minimum volume (10 L) under reduced pressure. IPAc (23 L) was added and the mixture held overnight at ambient temperature. The solution was cooled to 0° C. and treated with pre-cooled (0° C.) 2M hydrochloric acid (23.0 L), while keeping the temperature below 10° C. The resulting two phase mixture was stirred at 0° C. for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: OC1CCc2cc(Cl)cnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ol (570 mg, 3.36 mmol) in dimethylsulphoxide (17.7 ml) was treated at room temperature with triethylamine (2.81 ml, 20.2 mmol) followed by sulphur trioxide-pyridine complex (1.6 g, 10.1 mmol). The solution was stirred at room temperature for 1 hour. After completion, the reaction mixture was treated with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, then evaporated leaving a dark red liquid. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=70:30 to 30:70 as the eluent. The 3-chloro-5,6-dihydro-[1]pyrindin-7-one was obtained as a pink solid (472 mg, 84%); (calculated) C8H6ClNO [167.60]; (found) [M+H]+=168.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:44]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C(OCC)(=O)CC(C)=O.C(O)(=O)C(O)=O.NN.[CH:18]1([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][C:22]=2[CH:29]=[O:30])CC1>>[CH:26]1([N:25]2[C:21]([CH3:18])=[C:22]([CH:29]=[O:30])[CH:23]=[N:24]2)[CH2:27][CH2:28]1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: NN
Agent: O=C(O)C(=O)O
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C1CC1

Procedure:
1-Cyclopropyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl acetoacetate and cylclopropyl hydrazine oxalate (Gever, G. and Hayes, K. J. Org. Chem, 1949, 14, 813-818) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).