Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13].[C:24](=[O:26])=[O:25]>O1CCCC1>[F:9][C:10]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][C:19]=1[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: COC(=O)c1c(F)cccc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropyl amide in dry tetrahydrofuran (prepared from diisopropylarnine (17.0 ml) and n-butylithium (48.4 ml) in dry tetrahydrofuran)was added to a solution of methyl 2-fluoro-6-trifluoromethylbenzoate (22.39 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3 hours. The solution was poured onto solid carbon dioxide pellets and stirred until it had warmed to room temperature. The mixture was evaporated and treated with hydrochloric acid (2 M). It was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-fluoro-3-methoxycarbonyl-4-trifluoromethylbenzoic acid (24.43 g) as an off-white solid, NMR (CDCl3) 3.95(s,3H), 7.55(d,1H), 8.15(t,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].C1C(=O)N([Br:32])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.CCCCC>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:32])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCC
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.42 g, 1.0 mmol) in 1,2-dichloroethane (9 mL) were added NBS (0.20 g, 1.1 mmol) and AIBN (30 mg, 0.2 mmol) and the reaction mixture was heated under reflux for 45 minutes. The reaction mixture was allowed to cool to ambient temperature and was diluted with pentane (4.0 mL), the solid was removed by filtration and the liquors were then concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g cartridge, Si-SPE, 30-100% DCM in pentane) to afford the title compound as a white solid (0.46 g, 90%). LCMS (Method B): RT=4.55 min, M+H+=489.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[C:10]1([CH3:20])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=O.C1(C)C=CC=CC=1>O>[CH3:20][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=[N:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: NCc1ccc(Cl)nc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Yield: 99.1 %

Procedure:
A mixture of 5-aminomethyl-2-chloropyridine (14.25 g), mesitaldehyde (14.8 g) and toluene (100 ml) was heated under reflux for 3 hours. The water which was formed during the reaction was trapped by Dean and Stark constant water separator. The toluene was distilled off from the mixture under reduced pressure, so as to obtain N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (27 g). m.p. 47°-48° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:21]2\[C:22](=[O:31])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[NH:16][C:15]=1[CH3:32])=[O:13])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:18]([CH3:19])=[C:17](/[CH:20]=[C:21]2\[C:22](=[O:31])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[NH:16][C:15]=1[CH3:32])=[O:13]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
[3-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-propyl]-carbamic acid tert-butyl ester was suspended in methanol. 2 ml of HCl (4N) in dioxane was added and the reaction stirred at room temperature overnight. The solvent was removed to yield the desired compound (0.098 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ 13.8 (s, 1H); 11.00 (s, 1H); 7.90-7.70 (m, 5H); 6.9 (m, 2H); 3.30 (q, 2H); 2.80 (q, 2H); 2.50 (dd, 6H) 1.80 (m, 2H). LCMS: inconclusive due to fluorescence.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>C1COCC1.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:21][O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CC#N
Product: COC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of (2S,4R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (15.5 mmol; 5.0 g) in THF (135 mL) is added 1 M THF solution of borane THF complex (31 mmol; 31 mL) at 0° C. under nitrogen. The solution is stirred for 1 hour at room temperature, quenched by dropwise addition of 15 ml of MeOH. After concentrating, the mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude product. To a solution of crude material in MeCN (20 mL) were added Ag2O (46.5 mmol; 8.9 g) and MeI (155 mmol; 21.8 g) at room temperature, heated and stirred under reflux condition for 3 hours. After filtration and concentration, the resulting mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude (2S,4R)-4-benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O1CCCC1>[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:37][CH:36]=1
Reactant: CN(C)CCOc1ccc(CN)cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NCc1ccc(OCCN(C)C)cc1

Procedure:
To a cooled suspension of 14.3 g of 2-methoxy-5-sulfamoylbenzoic acid in 60 ml of tetrahydrofuran were successively added dropwise 6.25 g of triethylamine and 7.45 g of pivaloyl chloride with stirring. The mixture was stirred at the same temperature for 1 hour and then a solution of 10.0 g of 4-[2-(dimethylamino)ethoxy]-benzylamine in 40 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 14 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate to give a precipitate, which was washed with water and ethyl acetate, of 16.6 g of colorless crystals. Recrystallization of the crystals from ethanol gave the title compound as colorless needles, m.p. 154°-155° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C1COCC1>[S:26]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.08 h
Yield: 97.6 %

Procedure:
In a 1-liter three-neck flask, 8.65 cm3 of freshly distilled pyrrole (125 mmoles) was introduced together with 100 cm3 of THF and 1 cm3 of a 40% aqueous solution of tetrabutylammonium hydroxide. 125 cm3 of a 50% aqueous NaOH solution was added and the mixture was then vigorously stirred. After 5 minutes, a solution of 38 g of tosylchloride (200 mmoles) in 100 cm3 of THF was dropwise added. The obtained adduct was maintained under stirring until the temperature reached a maximum and then again during some 30 minutes more. After decantation, the aqueous layer was extracted with ethyl acetate, and the combine organic layer was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and evaporated. 27 g of a white solid compound was obtained (1) (M=221, yield: 97.6%). Recrystallization in methanol. F (° C)=92. Elemental analysis: calc.: C 59.73; H 4.98; N 6.33; found: C 59.59; H 4.67; N 6.32. NMR: (CDCl3) ppm 7.7 d J(Hz) 8 2H; 7.2 4H; 6.25 2H; 2.33 s 3H.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19])([O-:11])=[O:10]>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH:7][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N+:9]([O-:11])=[O:10])(=[O:19])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN(CCN)CCN
Solvent: ClCCl
Product: CN(CCN)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of N1-(2-aminoethyl)-N1-methylethane-1,2-diamine (10.58 g, 90 mmoles) in DCM (350 mL) was added slowly a solution of 2-nitrobenzene-1-sulfonyl chloride dissolved in DCM (50 mL). After 2 h at RT, the reaction mixture (RM) was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel with a gradient of methanol in DCM (0 to 10%), yielding to 6.9 g of N-(2-((2-aminoethyl)(methyl)-amino)ethyl)-2-nitrobenzenesulfonamide 6a and 3.9 g of N,N′-(2,2′-(methylazanediyl)-bis(ethane-2,1-diyl))bis(2-nitrobenzenesulfonamide) 6b; m/z (6a)=303 (M+H)+, m/z (6b)=488 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 124, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-3-trifluoromethyl-benzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:9][CH2:8][CH2:7]2.[F:22][C:23]1([CH:43]=[CH:42][CH:41]=[CH:40][CH2:39]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:22][C:23]1([CH:39]=[CH:40][CH:41]=[CH:42][CH2:43]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:13]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)NCC2
Reactant: O=C(CBr)N(CC1(F)C=CC=CC1)C1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(CC(=O)N(CC1(F)C=CC=CC1)C1Cc3ccccc3C1)(c1ccccc1)NCC2
Temperature: 80 °C
Yield: 77.8 %

Procedure:
A mixture of 6, 7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (160, 153 mg, 0.5 mmol), N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol) and potassium carbonate (500 mg) in acetonitrile is heated at 80° C. overnight. After cooling, the mixture is filtered and concentrated. The resulting residue is purified by column chromatography eluting with 5% methanol in chloroform to provide the title product (162) as a thick oil (215 mg, 78%). 1H NMR (CDCl3) 6.8-7.3 (m, 14H), 6.60(s, 1H), 6.05 (s, 1H),
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH:3]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[OH:4].C(N(C(C)C)CC)(C)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:10][C@H:2]1[C@H:3]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)[O:4][C:21](=[O:23])[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)C(O)c1nccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1NC(=O)O[C@H]1c1nccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diastereoisomers of 2-amino-1-thiazol-2-yl-propan-1-ol (4.20 g, 18.2 mmol) was dissolved in 160 mL of CH2Cl2. Diisopropylethylamine (11.1 mL, 63.6 mmol) was added at 0° C., followed by triphosgene (2.70 g, 9.09 mmol) dissolved in 40 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 2 hours and then diluted with CH2Cl2. The organic solvents were separated, washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (80 g SiO2) using EtOAc in hexane from 0% to 100 in order to give the title compound as a single enantiomer (2.16 g, 64%). LC-MS: [M+H] 185.3; Rt 0.45 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-d): 7.75 (d, 1H), 7.35 (d, 1H), 5.60 (br s, 1H), 5.32 (d, 1H), 4.18-4.09 (m, 1H), 1.45 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[CH:16][CH:17]=1
Reactant: O=C(O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
A suspension of 15 g. finely powdered 4-nitrobenzoyl-β-alanine in 200 ml. ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g. of palladium-charcoal (5%), while cooling gently. When the absorption of hydrogen had ceased, the reaction mixture was filtered and the filtrate concentrated to a small volume. Upon adding diethyl ether and cooling, 4-aminobenzoyl-β-alanine was obtained. The yield was 11.5 g.; m.p. 156°-158° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:14]2[N:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH:17]=[CH:16][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)n1
Agent: Cl
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A methanolic solution of the product prepared in Step A was diluted to 100 ml and 12.4 ml of concentrated HCl was added. The solution was stirred at ambient temperature for 18 hours, concentrated, and the residue was dissolve in 80 ml of water and extracted twice with CH2Cl2. The aqueous layer was concentrated, treated with n-propanol and concentrated under high vacuum to give the title compound as a foam.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([O:23][CH3:24])[N:17]=2)=[CH:9][CH:8]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:22][C:20]1[N:19]=[C:18]([O:23][CH3:24])[N:17]=[C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]3[O:25][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:12][CH:11]=2)[CH:21]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(=O)NNC(C)=O)cc2)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1nc(Cl)cc(NCCc2ccc(-c3nnc(C)o3)cc2)n1
Reaction time: 0.08 h
Yield: 84.1 %

Procedure:
A mixture of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (0.2 g, 0.55 mmol), and Burgess reagent (0.39 g, 1.65 mmol) in THF (6 mL) is placed in a microwave reactor. After 5 min at 130° C., the mixture is concentrated in a rotavap, and subjected to a chromatography eluting with 10% MeOH in CH2Cl2 to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-amine (160 mg). LCMS: RT=2.29 minutes; MS: 346 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>CC(O)=O.O>[Br:12][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: BrBr
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
The title compound was prepared by dissolving 4-Methyl-2-nitro-phenylamine (20.0 g, 131 mmol) in 200 mL of HOAc. The reaction mixture was then heated to 100° C. until reaction mixture was homogeneous. At this point the reaction mixture was cooled to room temperature and Br2 (25.21 g, 157 mmol) was added drop wise over the course of 10 minutes. An orange solid formed, and upon completion of the addition the reaction mixture was diluted with water and the title compound collected by filtration (29 g, 96%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=CO
Reactant: O=C(NCCNO)c1cc(Cl)cc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCNC(=O)c1cc(Cl)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 28 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.5 mL) was added to a solution of 2,3,5-trichloro-N-(2-hydroxyamino-ethyl)-benzamide (0.27 g, 1.0 mmol) in pyridine (10 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h at room temperature and the pyridine removed in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the title compound (0.09 g, 28%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.70 (s, 1H); 7.42 (s, 1H); 3.78 (m, 1H); 3.73 (m, 1H); 3.60 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=311.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)(Cl)Cl.CO>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CCc1ccc(O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(O)c(Br)c1
Temperature: 25 °C

Procedure:
8.41 ml of bromine in 100 ml of CHCl3 were added dropwise within 2 hrs. to a solution, cooled to 0° C., of 20 g of 4-ethylphenol in 200 ml of CHCl3 and 100 ml of MeOH. The reaction mixture was left to warm to room temperature and was concentrated. The product was isolated by extraction. There were obtained 33.14 g of 2-bromo-4-ethyl-phenol as a light brown oil.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([C:16]1[S:15][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1

Procedure:
Using 3.04 g (16.4 mmol) of 2-chloro-3-nitrobenzaldehyde, 0.98 g (24.6 mmol) of sodium hydride (60% pure) and 2.09 g (19.7 mmol) of methyl mercaptoacetate, 3.68 g (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:22][CH2:21][CH2:20][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
65 mg (53%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(2-fluorophenyl)piperazine (44 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).