Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[C:19]([O:21]C)=[O:20])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+:24]>CO.O>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH:7]2[C:19]([O-:21])=[O:20])=[O:5])[CH2:3][CH2:2]1.[Na+:24]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)C(C(=O)[O-])C1
Reaction time: 24 h
Yield: 106.9 %

Procedure:
To a solution of 11.5 g (36.8 mmol) of 1-tert-butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in 127.5 ml of methanol are added 1.77 g of sodium hydroxide dissolved in 22.5 ml of water. The mixture is stirred for 24 hours and the reaction medium is then concentrated under reduced pressure and the residue co-evaporated with toluene, to give 12.6 g of sodium 1-tert-butyl 4-cyclopropane-carbonylpiperazine-1,3-dicarboxylate in the form of a white powder after drying, and is used as obtained in the rest of the synthesis.
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=[O:20])C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:39]2[CH:40]=[C:41]([N+:44]([O-:46])=[O:45])[CH:42]=[CH:43][C:38]=2[NH:37][C:36](=[O:47])[C:35]([CH3:49])([CH3:48])[N:34]=1>C(Cl)Cl.CCCCCC>[NH2:34][C:35]([CH3:49])([CH3:48])[C:36]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:39]=1[C:33](=[O:20])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[Cl:26])=[O:47]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(N)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
From 76 g (0.21 mol) of 2-amino-2'-(o-chlorobenzoyl)-2-methyl-4'-nitro-propionanilide there is obtained, in analogy to the details in paragraph (b) of Example 1, 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 242° (methylene chloride/n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:19][CH:20]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]#[C:14][C:15]1[CH:20]=[N:19][C:18]([NH:21][C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:17][CH:16]=1
Reactant: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3N)nc2)c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 5-((2,6-dichloro-3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.33 mmol), Iron (147 mg, 2.64 mmol) and ammonium chloride (214 mg, 3.96 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (58 mg, 35%). MS (ES+) C21H18Cl2N4O2 requires: 429, 431. Found: 430, 432 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.55-8.44 (br, 2H), 6.97 (s, 1H), 6.89-6.86 (m, 1H), 6.57 (d, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.6 Hz), 4.75 (s, 2H), 3.94 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH3:15].CO>CO>[C:9]1([C:1]2[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=2)[CH2:7][NH2:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: N
Solvent: CO
Product: NCc1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-biphenylcarboxaldehyde (0.011 eq.) in 30 mL of methanol was added 10 eq. of 7N NH3/MeOH and NaCNBH4 (2 eq.). A yellow gum precipitated from solution. The solution was then heated at 60° C. until gum dissolved and the solution was stirred at room temperature overnight. The reaction mixture was then concentrated and the resulting residue diluted with ice water and ethyl acetate. The organic layer was then washed with brine and extracted with 5N HCl. The pH of the aqueous layer was then adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-(phenyl)benzyl amine as an oil.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>O>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:29][CH2:28][CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: NCCc1ccccn1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(NCCc4ccccn4)nc23)cc1
Temperature: 200 °C

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-pyridin-2-yl-ethyl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (250 mg, 0.81 mmol) and 2-pyridin-2-yl-ethylamine (0.97 mL, 8.1 mmol) combined in a microwave vial and heated to 200° C. for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was dried, filtered, and concentrated. The residue was purified via reverse phase chromatography (Phenomenex Gemini-NX C18 AXIA column acetonitrile in water with trifluoroacetic acid modifier). Fractions containing product were neutralized by combining in saturated sodium bicarbonate and extracting with 3 portions of dichloromethane. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield a light yellow powder (195 mg, 61%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.70 (d, J=6.7 Hz, 1H), 8.49 (s, 1H), 8.42-8.35 (m, 3H), 8.04 (d, J=7.9 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.31 (m, 1H), 7.04 (t, J=14.6, 7.4 Hz, 1H), 6.93 (m, 1H), 3.51 (m, 2H), 3.28 (s, 3H), 2.93 (t, J=14.1, 7.0 Hz, 2H). MS=394 (MH)+.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:19])[C:10]([NH:12][C:13]([NH:15][C:16]([NH2:18])=[O:17])=[O:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)(=O)C>O>[CH2:1]([O:8][CH:9]([C:10]1[NH:12][C:13](=[O:14])[NH:15][C:16](=[O:17])[N:18]=1)[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OCc1ccccc1)C(=O)NC(=O)NC(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(OCc1ccccc1)c1nc(=O)[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To an ice-cold suspension of 2-benzyloxy-N-ureidocarbonyl-propionamide (9.4 mmol, 2.5 g) in water (15 mL) was added KOH (28 mmol, 1.6 g) in water (10 mL). The reaction temperature was slowly raised to room temperature, and the reaction was allowed to stir for 1 h. Sufficient acetic acid was added to adjust the pH of the reaction to 5, and the resulting cloudy solution was extracted with chloroform (3×20 mL). The chloroform layer was collected, dried, filtered and the filtrate was concentrated to obtain a residue, which was triturated with isopropyl ether to obtain 6-(1-benzyloxy-ethyl)-1H-[1,3,5]triazine-2,4-dione (74%, 1.72 g); NMR 1.4 (d, 3H), 4.2 (t, 1H), 4.6 (dd, 2H), 7.4 (m, 5H), 11.2 (s, 1H), 12.1 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][CH2:7][O:8][C:9](=O)[CH3:10])(=O)[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17]C(O)=C[CH:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClC1C=CC=CC=1Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:1]([O:4][CH2:5][O:6][CH2:7][O:8][C:9]2[CH:10]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)=[CH:2][CH:14]=1
Reactant: CC(=O)OCOCOC(C)=O
Reactant: Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(OCOCOc2ccc(Cl)cc2)cc1
Yield: 63.5 %

Procedure:
A solution of 16.2 g (0.1 mole) of bis(acetoxymethyl) ether and 39 g (0.30 mole) of p-chlorophenol in 80 ml of o-dichlorobenzene were treated with 1.0 g of neutral aluminum oxide (80-240 mesh) and heated to reflux (pot temp. 180°-185° C.). Distillate was removed at about 10 ml/hr over a 4 hour period. The reaction mixture was filtered hot, stripped in vacuo, and triturated with light petroleum ether to furnish 19.0 g (61% yield) of product, mp 53.5°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2c1cnn2C1CCCCO1
Temperature: 45 °C
Yield: 94.6 %

Procedure:
To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated in vacuo to yield 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 110.2 g (95%) as an orange solid. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([F:11])([F:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[BH4-].[Na+].Cl.[CH3:16]O>O>[CH3:16][O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]([F:11])([F:10])[CH2:3][OH:2]
Reactant: CO
Reactant: COC(=O)C(F)(F)CCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC(F)(F)CO
Reaction time: 2 h

Procedure:
To a solution of 2 g of 2,2-difluoroglutaric acid 1-methyl ester in 20 ml of methanol is added at 25° 250 mg of sodium borohydride and the mixture allowed to remain at 25° for 2 hrs. The solution is diluted with water and acidified to pH 1 with 1 N HCl and the methanol removed in vacuo. The residual suspension is extracted with methylene chloride and the extract dried with sodium sulfate and evaporated to dryness in vacuo. The residual oil is treated with ethereal diazomethane until the yellow color persists and the ether is removed in vacuo. There remains behind the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
A solution of (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.7 mmol), diethylamine (51 mg, 0.7 mmol) and acetic acid (0.06 mL) in THF (mL) was stirred for 30 min at ambient temperature. After addition of sodium triacetoxyborohydride (368 mg, 1.7 mmol) the reaction was stirred overnight, quenched by addition of saturated aqueous NaHCO3 and extracted with EtOAc. The solvent was removed in vacuo and the residue was purified by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give the title compound. MS (LC-MS): 345.0 [M]+; tR (HPLC conditions c): 4.09 min.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.N(OC(C)(C)C)=O>C1COCC1>[C:19]([C:4]1[C:3]([CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1C=CCCCC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1C=CCCCC1
Temperature: 67.5 °C
Yield: 40 %

Procedure:
To 5-amino-3-cyano-4-(cyclohept-2-enyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (208 mg, 0.5 mmol, Example 10) in dry THF (8 ml) heated at 65° C. was added dropwise tert-butyl nitrite (160 mg, 1.5 mmol) in dry THF (2 ml) over 30 min. The solution was heated for a further 2 hr at 65-70° C. The solvent was removed in vacuo and the resulting brown oil purified by silica chromatography (eluting with hexane, hexane/diethyl ether 19/1, hexane/diethyl ether 9/1, hexane/diethyl ether 4/1, hexaneldiethyl ether 1/1, finally diethyl ether). The resulting orange solid was recrystallised from hexane to yield 80 mg of the title compound as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH2:22][CH3:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1
Reactant: [H][H]
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Yield: 93 %

Procedure:
A solution of 0.255 (0.79 mmol) of the product of Example 7, Step G in 10 mL ethanol was placed in a small Parr hydrogenation flask and 50 mg of a 10% palladium on carbon catalyst was added. The reaction mixture was then shaken in a Parr apparatus under a 45 psig hydrogen atmosphere for 1 hour at room temperature. The reaction mixture was then removed from the flask, filtered, evaporated and dried in vacuo to afford 0.239g (93%) of the title compound which was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19](O)=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:18]=1[C:19]([NH:9][CH2:8][CH:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20]
Reactant: NCC(c1ccccn1)N1CCOCC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)c(C(=O)NCC(c2ccccn2)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3 mmol), 2-chloro-5-methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room temperature overnight. The mixture was purified by preparative HPLC to yield the title compound (100 mg, yield: 90%). LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.89
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1.[CH3:22][O-:23].[Na+]>>[CH3:22][O:23][C:2]1[CH:9]=[C:8]2[N:4]([C:5]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][S:11][C:6]=3[C:7]2=[O:10])[CH:3]=1
Reactant: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2csc3c2-n2cc(OC)cc2C3=O)cc1

Procedure:
1 equivalent of the compound obtained in Example 12 is stirred, at ambient temperature, into a solution of sodium methanolate. After 12 hours' reaction, the reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane; the organic phase is then washed with a saturated NaCl solution, dried over sodium sulphate and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:39])=[O:40]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-Methoxy-4-methylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (7.8 mg). MS m/z 373 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:19][CH2:20][N:21]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](N1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
The example 13 was prepared form the reaction of piperazino derivative 2 and 4-(trifluoromethyl)benzoyl chloride by following the similar procedure described for the example 12.
Reaction SMILES: CC(C)=O.CN.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27]([N:29](CC)CC)C>O>[CH3:27][NH:29][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CN
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)NC
Temperature: 0 °C

Procedure:
To 500 cc of acetone was added 15.5 g of methylamine to form a mixture. 60.0 g of stearoyl chloride was drop-wise added to the mixture, while the mixture was stirred and cooled using ice water. The addition was conducted at a temperature of not higher than 20° C. Further, 20.2 g of triethylamine was dropwise added to the mixture at a temperature of not higher than 20° C. After the addition was complete, the mixture was allowed to react for 3 hours. The reaction mixture was then poured into water and the aqueous mixture was filtered to collect produced crystals, and the crystals were recrystallized from a mixed solvent of ethyl acetate and methanol to give a white crystalline product of N-methylstearic amide (Amide compound No. 1 mentioned above).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[Na].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][CH2:19][CH3:20])=[C:13](Cl)[C:12]=2[CH:22]=1>C(O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:12]=2[CH:22]=1
Reactant: CCCCS
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Agent: [Na]
Solvent: CCO
Product: CCCCSc1c(CCC)c(=O)oc2ccc(Br)cc12
Reaction time: 0.5 h

Procedure:
1-Butanethiol (0.39 ml) was added dropwise to a solution of sodium (0.08 g) in ethanol (3 ml). The solution was stirred for 1/2 hour and then added slowly to a refluxing solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (1 g) in ethanol (4 ml). The mixture was heated under reflux for 41/2 hours, filtered hot through kieselguhr and the filtrate allowed to cool. The precipitate was purified by silica gel column chromatography to give 6-bromo-4-butylthio-3-propyl-2H-1-benzopyran-2-one, m.p. 62-4° (compound 15)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][NH:17]4)[N:9]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[CH3:26][CH:27]([NH2:29])[CH3:28]>C1COCC1>[NH:17]1[C:18]2[C:14](=[C:13]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:29][CH:27]([CH3:28])[CH3:26])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=4)[O:12][N:11]=3)[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Fc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F
Temperature: 52.5 °C
Reaction time: 40 h

Procedure:
To a solution of 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (300 mg) in THF (1.5 ml) was added, propane-2-amine (0.75 ml), and after sealing the tube, the solution was stirred at 50 to 55° C. for 40 hours. It was concentrated under reduced pressure, and then purified by silica gel chromatography (n-hexane:EtOAc). The obtained solid was dissolved in acetone under heating, and added with n-hexane, and the precipitate was filtered to obtain 4-[3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl]-N-isopropyl-2-(trifluoromethyl)aniline (295 mg).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:11][OH:12])(=[O:10])[CH3:9].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:12][NH:11][C:8](=[O:10])[CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
60% sodium hydride (11.68 g, 0.292 mol) was added to a dimethylformamide solution (200 ml) of acetohydroxamic acid (21.9 g, 0.292 mol) with cooling in an ice bath. After stirring for 1 hour at room temperature, benzylbromide (50 g, 0.292 mol) was added thereto and allowed to react for 24 hours at room temperature. The reaction solution was poured into 500 ml of water, and extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 31.3 g of N-benzyloxyacetamide (yield: 65%). The proton NMR spectrum of the compound is 1.85 s (3H); 4.89 bs (2H); 7.37 s (5 H); 8.30 bs, 8.81 bs (1H) (solvent: CDCl3).