Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]2[C:16](F)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[C:10]=2[S:11][CH:12]=1.[NH2:20][C@@H:21]([C:25]([OH:27])=[O:26])[C@H:22]([CH3:24])[OH:23]>CS(C)=O>[Cl:7][C:8]1[C:9]2[C:16]([NH:20][C@H:21]([C@@H:22]([OH:23])[CH3:24])[C:25]([OH:27])=[O:26])=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[C:10]=2[S:11][CH:12]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c2c(Cl)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2scc(Cl)c12)C(=O)O
Temperature: 80 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
K2CO3 (850 mg, 6.15 mmol) was added to a mixture of 3-chloro-4-fluorobenzo[b]thiophene-7-carbonitrile (0.52 g, 2.46 mmol) and D-threonine (322 mg, 2.70 mmol) in DMSO (10 mL) at room temperature. The mixture was heated to 80° C. and stirred for 16 h. After cooling to room temperature, the reaction mixture was poured into ice-water (100 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave the crude (2R,3S)-2-(3-chloro-7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (0.73 g, 96%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.67 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 4.57 (m, 1H), 4.35 (dd, J=2.4, 8.4 Hz, 1H), 1.37 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[N:7]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:34])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2ncn(Cc3ccc4nc(SC)oc4c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 44.9 %

Procedure:
To a stirred solution of 6-((5,6-dimethoxy-1H-benzo[c]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (270 mg, 0.761 mmol) from Step 2 of Example 34 in DCM (5 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (262 mg, 1.14 mmol), and the mixture was allowed to warm to rt and stirred for a further 4.5 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (127 mg, 45%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.85-7.92 (m, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 5.62 (s, 2H), 3.76 (s, 6H), 3.18 (s, 3H). LCMS (ESI) m/z 372 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=1.O.[NH2:19][NH2:20]>CCO>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[O:11][CH2:10][CH2:9][O:8][C:4]1[CH:3]=[C:2]([NH:19][NH2:20])[CH:7]=[CH:6][N:5]=1
Reactant: Fc1ccnc(OCCOC2CCCCO2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccnc(OCCOC2CCCCO2)c1
Temperature: 80 °C
Yield: 89 %

Procedure:
Intermediate 67a (633 mg, 2.62 mmol) was suspended in EtOH (5 mL) and hydrazine hydrate (50-60%, 5 mL) in a microwave vial fitted with a stirrer bar and sealed with a crimped septum, and heated to 80° C. for 18 h. The reaction was cooled, and partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4, and concentrated in vacuo to afford the title compound as a colorless oil (593 mg, 89%). LCMS (Method 3) Rt 0.41 and 1.71 min, m/z 276.2 [M+Na].
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O:46][P:47](=[O:74])([O:71]CC)[O:48][CH2:49][C@@H:50]([N:56]([S:61]([C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:8])[NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]([N:56]([S:61]([C:64]1[CH:65]=[CH:66][C:67]([NH2:70])=[CH:68][CH:69]=1)(=[O:62])=[O:63])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:49][O:48][P:47]([OH:71])([OH:46])=[O:74])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)OC[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 139.6 %

Procedure:
(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1, step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of (2S)-phosphoric acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (IX) (example 3, step B) and the mixture stirred for 3 h. 20 g of Amberlite XAD-2 resin was then added and the beads were left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly with distilled water (400 mL) and 200 mL of 1M NaHCO3. The beads were then washed with 4×50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to yield 2.4 g (83%) of white solid after evaporation.
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Yield: 97 %

Procedure:
The title compound (151 mg, 98%) was prepared as a white solid 5-[4-(methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (0.15 g, 0.36 mmol), diisopropylethylamine (0.26 mL, 1.43 mmol), and isopropyl chloroformate (1.0M in toluene, 0.40 mL, 0.40 mmol) in a manner similar to Example 66, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.46 (d, 1H, J=2.4 Hz), 8.10-8.00 (m, 3H), 7.86 (d, 2H, J=8.3 Hz), 6.92 (d, 1H, J=8.5 Hz), 4.90-4.80 (m, 1H), 4.21 (d, 2H, J=6.3 Hz), 4.20-4.10 (m, 2H), 3.14 (s, 3H), 2.90-2.75 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 433 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (4.5 g, 19.9 mmol), chloromethyl methyl ether (2.3 mL, 30.3 mmol), potassium carbonate (5.5 g, 39.8 mmol) and potassium iodide (0.66 g, 3.98 mmol) in N,N-dimethylformamide (50 mL) was stirred at 70° C. for 20 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-1:9) to give the title compound (1.7 g, yield 32%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:7]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])=[N:6][CH:5]=[C:4]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:3]=1
Reactant: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ncc(S(=O)(=O)N(C)C)cc1Br
Reaction time: 48 h

Procedure:
A solution of 5-bromo-6-chloro-N,N-dimethylpyridine-3-sulfonamide (400 mg; 1.34 mmol) and diethyl malonate (204 μl; 1.34 mmol) in anhydrous THF (2 ml) was added to a suspension of sodium hydride (53 mg; 1.34 mmol) in anhydrous THF (2 ml). The resulting mixture was stirred for 48 hours, then quenched by careful addition of a saturated solution of NH4Cl in water. EtOAc was added and the phases separated. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:31])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Methoxyphenethyl alcohol (50 g) and triphenylphosphine (103 g) were dissolved in methylene chloride (600 ml), followed by the addition of N-bromosuccinimide (70 g) in small portions under ice-cooling, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated, and to the resulting residue was added hexane. The insoluble matters were filtered off, while the resulting filtrate was evaporated, to give the title compound as a colorless oil (50.32 g, yield: 71%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:16][CH2:17][N:18]([CH2:21][CH2:22]Cl)[CH2:19][CH3:20].Cl>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 5 h

Procedure:
9.0 g of 4-acetamido-phenylsulphinic acid are dissolved in 10 ml of water and 45 ml of 1N sodium hydroxide solution and 9.47 g of 2-chlorotriethylamine hydrochloride are added. The mixture is stirred for 5 hours at reflux temperature. After cooling, sodium hydroxide solution is added until an alkaline reaction is obtained, the mixture is extracted with ethyl acetate, dried over magnesium sulphate and finally the solvent is eliminated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.Cl.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:15])=[O:12])=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1cc2cc(O)ccc2[nH]1

Procedure:
A 4 N hydrogen chloride-methanol solution (80 mL) of 5-hydroxyindole-2-carboxylic acid (3.0 g) was heated overnight under reflux. The solvent was evaporated off from the reaction liquid under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the resulting residue, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to 3/2) to obtain methyl 5-hydroxy-1H-indole-2-carboxylate (2.3 g) as a pale brown solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18](O)=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH2:26]>>[CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([NH:26][CH3:25])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Product: CNC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid and methylamine (2M in THF) were reacted as described in Example 5, Step 6 to provide 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-N-methyl-benzamide.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:31])[C@@H:14]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1.CN(C1C=CC=CN=1)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@H:5]([C@H:13]([O:31][C:41](=[O:43])[CH3:42])[C@@H:14]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Yield: 100 %

Procedure:
A solution of ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropanoate (3.1 g, 7.054 mmole, obtained from Reference Example 42) in acetic anhydride (25 ml) and dry pyridine (50 ml) in the presence of dimethylaminopyridine (500 mg) was stirred at room temperature under nitrogen for 15 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride:ether:methanol=97:2:1) to give ethyl (2R,3R)-3-[(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-3-(acetyloxy)-2-{[(benzyloxy)carbonyl]amino}propanoate (3.4 g, 100%) as a white amorphous solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[C:27](OCC)=[O:28])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[CH2:27][OH:28])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
To a stirred solution of lithium aluminium hydride in THF (1 M, 49.6 mL, 49.6 mmol) at −5° C. under nitrogen was added, dropwise over 0.5 h, a solution of (1,4-dibenzyl-piperazin-2-yl)-carboxylic acid, ethyl ester (8.4 g, 24.8 mmol) in THF (30 mL), internal temperature kept <5° C. Resulting mixture was stirred at 0° C. for 1 h then at 20° C. for 18 h, then was quenched by addition of a mixture of water (4 mL) and THF (100 mL) with external cooling in an ice-methanol bath. The resulting suspension was treated with saturated aqueous potassium sodium tartrate (−50 mL) and mixture was allowed to stir at 0° C. for 1 h. The supernatant liquid was decanted and evaporated in vacuo. The resulting oil was dissolved in dichloromethane and the solution dried (Na2SO4) and evaporated in vacuo to give the title compound (8.04 g) as an oil. MS: [M+H]+=297.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13].Br[CH2:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1>CN(C=O)C.CC(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[N:11]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][C:3]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[C:2]([F:1])[CH:7]=3)[S:10][CH:22]=2)=[CH:26][CH:27]=1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)cc1F
Temperature: 95 °C
Yield: 46.8 %

Procedure:
The mixture of the 2-fluoro-N-thiazol-2-yl-4-thioureido-benzenesulfonamide (32 mg, 0.000048 mol) and 1-bromo-3-(4-chloro-phenyl)-propan-2-one (14 mg, 0.000058 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The crude product was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 min, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS. The appropriate fractions were combined and dried on a lyophilizer to give the desired product as a light yellow powder (10.8 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=[CH:16][CH:17]=2)[N:4]([CH3:30])[N:3]=1.O.NN>C(O)C>[CH3:30][N:4]1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=2)=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1nc(N)nc1NCCCOc1cccc(CN)c1
Yield: 71.7 %

Procedure:
A solution of 2-[[3-[3-[(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)amino]propoxy]phenyl]methyl]-1H-isoindole-1,3-(2H)-dione (1.62 g) and hydrazine hydrate (0.22 g) in ethanol (10 ml) was heated at reflux for 1.5 h. The solvent was evaporated and the residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was basified with sodium carbonate, evaporated to dryness and extracted with hot isopropanol to give an oil which was purified by column chromatography using methanol/0.88 ammonia 79:1 as eluant to give the title compound as a crystalline solid (0.79 g) TLC silica, methanol/0.88 ammonia 79:1 Rf 0.5 NMR (d4MeOH) 2.77 t (1H); 3.0-3.3 m (3H); 5.95 t (2H); 6.30 s (2H); 6.57 q (2H); 6.65 s (3H); 7.95 m (2H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h
Yield: 79.1 %

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (1.06 g, 6.26 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (1.00 g, 7.51 mmol) in DMSO (25 mL). K2CO3 (1.73 g, 12.52 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. Then the reaction mixture was cool down to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc (4:6) and then with EtOAc, 100% to get the title compound (1.40 g). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.16 (d, J=9 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][O:27][CH2:28][CH2:29][OH:30]>C(#N)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][CH2:28][CH2:29][OH:30])=[C:20]([F:19])[CH:21]=2)=[O:33])[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Reactant: O=C(Nc1ccc(COCCO)c(F)c1)Oc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(COCCO)c(F)c2)n(-c2ccc(F)cc2)n1
Yield: 73.3 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.247 mmol, 1.0 eq) in acetonitrile (6 mL) was added TEA (0.136 mL, 99 mg, 0.986 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-((2-hydroxyethoxy)methyl)-phenylcarbamate (76 mg, 0.252 mmol, 1.02 eq.) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2)) to get 1-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)urea (83 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[O:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:19])[CH:3]=1.[CH3:20][NH2:21].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:21]([CH3:20])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:19])[CH:3]=1
Reactant: O=c1oc(C(F)(F)F)ccc1-c1ccc(Cl)cc1F
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Reaction time: 2 h

Procedure:
9.3 g (32 mmol) of 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2H-pyran-2-one was added to 160 ml of methanol, and 3.8 g (48 mmol) of a 40% methylamine/methanol solution was dropwise added under cooling with ice, followed by stirring for 2 hours under cooling with ice. This reaction solution was acidified by an addition of a 10% citric acid aqueous solution and then extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The obtained residue was dissolved in 160 ml of toluene, and 0.4 g (2.1 mmol) of p-toluenesulfonic acid was added thereto, followed by refluxing for 4 hours. After cooling, the reaction solution was washed with water. Then, the organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 5.7 g (19 mmol) of the desired product. Melting point: 103-104° C.