Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5]C(OC(C)(C)C)=O.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:5]
Reactant: COC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](N)COCc1ccccc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyloxycarbonyl-O-benzyl-D-serine methyl ester (BF8-EZ0-275) (5.0 g, 16 mmol) stirring in dichloromethane (40 mL) and anisole (1 ml) at 0° C. was added trifluoroacetic acid (10 mL). After 4 h at room temperature, a saturated aqueous solution of sodium bicarbonate was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sufate, and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:4][C:3](=[C:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:1]2[CH2:4][C:3](=[C:5]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]2)[CH3:18])=[CH:22][CH:23]=1
Reactant: COC(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C1CN(C(C)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.142 g (0.5 mmole) of methyl azetidin-3-ylidene(3,5-difluorophenyl)acetate, 0.142 g (1 mmol) of 4-chloroacetophenone and 0.15 mL (12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.422 g (2 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 h. The reaction was quenched by addition of saturated KHCO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated KHCO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1) to afford the title compound; Mass Spectrum: m/e=378 (M+1 35Cl) and 380 (M+1 35Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[CH:6]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]4)[CH:8]=3)=[O:45])=[C:39]([F:47])[CH:38]=2)[CH:24]=[N:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:19]
Reactant: Cc1cnn(-c2cc(N)cc(C(F)(F)F)c2)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4cc(C)cn4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 16 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline (160 mg, 0.663 mmol) and 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (274 mg, 0.663 mmol) in pyridine (8 mL) was added T3P® (2111 mg, 3.32 mmol) in portions. Then the mixture was stirred at 16° C. for 1 h. LCMS analysis showed the starting material disappeared. 10 mL of water was added dropwise into the reaction solution and then the mixture was filtered. The filter cake was washed with water (20 mL) and dried in vacuo to afford pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (200 mg, 0.263 mmol, 39.7% yield). 1H NMR (400 MHz, CD3OD): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=9.0 Hz, 3H), 6.91 (d, J=8.8 Hz, 2H), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[CH:27][N:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][NH:31][C:29](=[O:30])[C:28]1[CH:23]=[CH:24][C:25]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:26][CH:27]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: CNC(=O)c1cnccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
6-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline (1.81 g, 6.35 mmol, 1 eq) was dissolved in 77 mL of dry toluene and purged with nitrogen. 4-Bromo-N-methyl-nicotinamide (1.49 g, 6.99 mmol, 1.1 eq), sodium tert-butoxide (885 mg, 9.2 mmol, 1.45 eq), Pd2(dba)3 (59 mg, 0.064 mmol, 0.01 eq) and BINAP (119 mg, 0.19 mmol, 0.03 eq) were sequentially added followed by an additional degassing with nitrogen. The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled to rt, transferred to a separatory funnel, diluted with water and brine and extracted with ethyl acetate (2×100 mL). The combined organics were dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel (200 g column; 50 mL/min; 10% MeOH in CH2Cl2). This resulted in 1.8 g (68%) of the title compound as a light orange solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.02 g, 5.82 mmol), methyl 4-hydroxybenzoate (0.89 g, 5.85 mmol), and Ph3P (1.98 g, 7.55 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.49 mL, 7.57 mmol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo and the residue was treated with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHC3:MeOH (50:1, v/v) to give 480 mg (2 steps 39%) methyl (S)-4-(2-amino-1-propoxy)benzoate as a pale yellow oil. 1H-NMR (CDCl3) δ1.19 (d, 3 H, J=6.4 Hz), 3.35-3.39 (m, 1 H), 3.72-3.76 (m, 1 H), 3.89 (s, 3 H), 3.90-3.94 (m, 1 H), 6.92 (d, 2 H, J=8.8 Hz), 7.99 (d, 2 H, J=8.8 Hz).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1>C(O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:20])[F:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCO
Product: O=C(O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 94.9 %

Procedure:
A solution of 61.1 g of the product of Step C in 900 ml of ethanol and 300 ml of 36° Be sodium hydroxide solution was refluxed for 7 hours and the ethanol was evaporated under reduced pressure. The mixture was poured into water and the mixture was extracted with ether. The ether phase was washed with water and the combined aqueous phases were acidified with hydrochloric acid and were iced and vacuum filtered. The recovered crystals were washed and dried to obtain 53.4 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid melting at 188° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C(O)Cc1ccc(O)cc1
Yield: 96.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid were dissolved in 50 ml of isopropyl alcohol, and 0.3 g of 10% palladium on charcoal was added thereto. The mixture was stirred at 25° C. under atmospheric pressure for 6 hours in a hydrogen stream. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 9.8 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OCCOCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.3 %

Procedure:
To a suspension of LAH (750 mg, 19.7 mmol) in ether (40 ml) was added crude t-butyl-2,2,2-trifluoroethoxyacetate (2.0 g, 9.3 mmol) in ether (10 ml) at 0° C. The mixture was stirred for 45 minutes at 0° C. Then, the mixture was poured into ice-water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude 2-(2,2,2-trifluoroethoxy)ethanol (1.09 g, 81%). To a solution of crude 2-(2,2,2-trifluoroethoxy)ethanol (150 mg, 11.0 mmol) in dichloromethane (3 ml) was added triethylamine (110 mg, 1.1 mmol) and p-toluenesulfonylchloride (200 mg, 1.1 mmol). The mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=5/1) gave 2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (188 mg, 63%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]([N:13]([C:26]2[C:31]([N+:32]([O-])=O)=[CH:30][CH:29]=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]([F:44])([F:43])[F:42])[N:27]=2)C(C2N(C)N=C(C(C)(C)C)C=2)=O)=O)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[NH:32][C:31]3[C:26]([N:13]=2)=[N:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:43])([F:42])[F:44])=[CH:29][CH:30]=3)[N:8]([CH3:10])[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)N(C(=O)c1cc(C(C)(C)C)nn1C)c1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(C(C)(C)C)cc1-c1nc2nc(-c3ccccc3C(F)(F)F)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (339 mg, 0.554 mmol, prepared as described in the previous step) was taken up in acetic acid (10 mL), treated with iron powder (124 mg, 2.22 mmol), and heated to 90° C. for 15 h. The resulting mixture was concentrated to a volume of 3 mL, treated with saturated aqueous NaHCO3 (75 mL) and extracted twice with EtOAc (75 mL, 40 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:19 v/v for 5 min, then 1:19 to 1:4 v/v over 40 min) to yield 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 8.13 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.61-7.68 (m, 1H), 7.52-7.59 (m, 2H), 7.40 (d, J=8.1 Hz, 1H), 6.56 (s, 1H), 4.37 (s, 3H), 1.37 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H20F3N5: 400.2 (M+H); Measured: 400.2.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br)#[N:22]>>[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])#[N:22]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2C#N)c1
Yield: 39.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (154 mg, yield: 39.5%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13].O>C(O)C.CCOC(C)=O>[C:1]1([CH:7]2[CH2:10][C:9](=[N:12][OH:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)C1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: ON=C1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.49 %

Procedure:
To a solution of 3-phenylcyclobutanone (0.198 g, 1.354 mmol) in 95% ethanol (7 ml) was added 50% hydroxylamine in water (0.8300 ml, 13.54 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 167 mg of the title compound (76.49% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:16]1[CH2:19][CH2:18][N:15]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: BrCCBr
Reactant: NC(=S)c1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(C3=NCCS3)cc2)=NN1
Yield: 30.6 %

Procedure:
A solution of 3.5 g of 4-(1,6-dihydro-6-oxo-3-pyridazinyl)benzenecarbothioamide, 3.1 g of 1,2-dibromoethane in 75 ml of DMF containing 4.2 g of K2CO3 is heated on a steambath for three hours. The inorganic salts are filtered and the filtrate is evaporated under reduced pressure. The residue is crystallized from ethanol/tetrahydrofuran to yield 1.2 g of the product, 6-[4-(4,5-dihydro-2-thiazolyl)phenyl]-4,5-dihydro3(2H)-pyridazinone mp 236°-238° C.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:10][CH:11]=[N:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: CN(CCN)c1nncs1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nncs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
3.25 g (≅4.0 mmol) PS carbodiimide was added to a solution of 317 mg (2.0 mmol) N1-methyl-N1-(1,3,4-thiadiazol-2-yl)ethane-1,2-diamine and 542 mg (3.0 mmol) 3-(3-chloro-phenyl)propiolic acid in DCM (20 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (chloroform) was performed with the residue, whereby 165 mg (0.51 mmol, 26%) 3-(3-chlorophenyl)-N-(2-(methyl(1,3,4-thiadiazol-2-yl)amino)ethyl)propiolamide was obtained.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 73 %

Procedure:
40 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 80 grams of powdered potassium hydroxide and 100 grams of hexadecyl bromide were stirred in 350 ml benzene and refluxed for 7 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 50 ml. The reaction mixture was cooled to room temperature, 300 ml of ice-cooled water was added, and the mixture was extracted 4 times with 150 ml dichloromethane. The combined organic phase was washed with water and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours. After cooling to room temperature, 200 ml water was added. The product was extracted thrice with 200 ml chloroform, and washed consecutively with 200 ml water, 200 ml of a saturated aqueous sodium carbonate solution, and again with 200 ml water. The solvent was removed under reduced pressure and the product was crystallized from 450 ml petroleum ether at 4° C., yielding 69.93 grams of pure (S)-1-hexadecyl-sn-glycerol. The yield was 73%.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][C:3]#[CH:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[C:24]#[N:25])/[C:17](/Cl)=[N:18]/[OH:19]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:17]2[CH:4]=[C:3]([CH2:2][CH2:1][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[O:19][N:18]=2)[CH:21]=[CH:22][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(/C(Cl)=N/O)cc1Cl
Reactant: C#CCCNC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cc(-c2ccc(C#N)c(Cl)c2)no1
Temperature: 40 °C
Yield: 54.2 %

Procedure:
tert-Butyl but-3-yn-1-ylcarbamate (0.7 g, 4.14 mmol) was dissolved in toluene (20 ml) and trietyhylamine (0.87 ml) was added at RT. (Z)-3-chloro-4-cyano-N-hydroxybenzimidoyl chloride (0.98 g, 4.55 mmol) was added in DMF (2 ml) to reaction mixture. After one hour in RT the reaction mixture was heated to 40° C. for 2 h. The white precipitate was filtered and the filtrate was washed with 1 M HCl, water and brine. Dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by Flash chromatography (Heptane-EtOAc 2:1). Product fractions were combined and evaporated to give pure title compound (0.78 g). 1H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 2.95 (t, 2H), 3.30 (m, 2H), 7.04 (m, 2H), 8.00 (d, 1H), 8.12 (d, 1H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].O>N1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: COC(=O)CCc1ccc(N)nc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-(6-aminopyridin-3-yl)propanoate (500 mg, 2.78 mmol) in pyridine (5 mL) was added 2-nitrobenzenesulfonyl chloride (924 mg, 4.17 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound (365 mg, yield 36%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:20]([CH3:22])[CH3:19])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 87.6 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (Example 143, step A) (0.285 g, 1.13 mmol)) and acetone (0.13 g, 2.26 mmol) was stirred in DCE (5 mL) at rt under N2. To this mixture was added sodium triacetoxyborohydride (0.60 g, 2.8 mmol) and HOAc (0.136 g, 2.26 mmol). The reaction was stirred for approximately 24 h. The reaction was diluted with DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and chromatographed on silica gel to give the title compound of step A (291 mg, 0.99 mmol, 88%) as a yellow solid. MS (ESI): 294 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=3[CH:25]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:24]=3[CH:25]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(C(F)(F)F)ccc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[5-(trifluoromethyl)-1-benzofuran-2-yl]quinoxaline-6-carboxylate (150 mg, 0.33 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated in vacuo and dissolved in water (15 mL), adjusted to pH 7 with HCl (3N). The product was collected by filtration to give 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[5-(trifluoromethyl)-1-benzofuran-2-yl]quinoxaline-6-carboxylic acid as a yellow solid (72.8 mg, 50%).