Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]=[CH:7]1)C.Cl>>[CH2:11]([C:9]1[N:8]=[CH:7][N:6]([CH2:5][C:4]([OH:13])=[O:3])[CH:10]=1)[CH3:12]
Reactant: CCOC(=O)Cn1cnc(CC)c1
Agent: Cl
Product: CCc1cn(CC(=O)O)cn1
Temperature: 25 °C

Procedure:
1.7 g (9.5 mmol) of (4-ethyl-imidazol-1-yl)-acetic acid ethyl ester are dissolved in 47 ml (190 mmol) 4N HCl and the mixture is heated to reflux. After 2 h the mixture is cooled to rt and the solvent is removed in vacuo. The resulting product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[C:37]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH:1][C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][C@@H:19]([C:21]4[CH:32]=[CH:31][C:24]5[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=5[CH:22]=4)[O:18][C:17]3=[O:33])[CH:3]=2)=[O:45])=[CH:41][CH:42]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccc(-c6ccccc6)cc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 19 h
Yield: 42.3 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.202 g) in dichloromethane (4 ml) was treated with 4-biphenylyl isocyanate (0.126 g) and the mixture stirred under nitrogen at 20° C. for 19 h. Isopropanol (15 ml) was added to quench excess isocyanate, and the mixture stirred for 2 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.119 g). LCMS RT=4.09 min, ES+ve 694 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:18]2[CH:19]=[CH:20][C:11]([F:10])=[C:12]([CH:17]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: CNC(=O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (45 mg, 0.06 mmol), copper (I) iodide (26 mg, 0.14 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.45 mmol) to a solution of 2-fluoro-5-iodo-N-methylbenzamide, (prepared as described in PREPARATION 39), (0.39 g, 1.39 mmol) in triethylamine (6 mL, 43 mmol) and heat at 70° C. After 10 min, add toluene (10 mL) to the solidified reaction mixture and heat at 70° C. for 1 h. Concentrate and purify using silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes, to give the title compound as a white solid (300 mg, 72%).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](O)[C:9]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)[Cl:20]>ClC(Cl)C>[Cl:20][C:8]1[C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=1
Reactant: ClP(Cl)Cl
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(O)c21
Solvent: CC(Cl)Cl
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Cl)c21
Temperature: 65 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
To mixture of 2-cyclopentyl-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (0.650 g, 2.42 mmol) in dichloroethane (10 mL) was added phosphorous trichloride (1.35 mL, 14.5 mmol). The mixture was stirred at 65° C. for 24 h. The reaction was quenched into a mixture of methylene chloride and a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.150 g, 22%) as a tan solid. MW=286.78. 1H NMR (CDCl3, 500 MHz) δ 3.49-3.42 (m, 2H), 3.31 (p, J=8.0 Hz, 1H), 3.11 (t, J=6.2 Hz, 2H), 2.53-2.45 (m, 2H), 2.13-2.04 (m, 2H), 1.94-1.78 (m, 4H), 1.75-1.65 (m, 2H); APCI MS m/z 287 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O1CCOCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1nc2cc(-c3ccccc3)cnc2n1C
Temperature: 70 °C
Yield: 106.6 %

Procedure:
h mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.35 g), tripotassium phosphate (0.42 g), phenylboronic acid (0.13 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.03 g), tris(dibenzylideneacetone)palladium(0) (0.01 g), and 1,4-dioxane (3 ml) was stirred with heating at 70° C. for 2 hours, and then heated to 90° C., and stirred with heating for further 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.37 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-phenyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 56).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[C:3](=[O:13])[O:2]1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:14][O:12][N:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2][C:3]1=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1OCc2ccccc2C1=NO
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C1C(=O)OCc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of isochroman-3,4-dione 4-oxime (90.4 HPLC-area %, 145.8 g, 0.74 mol) and potassium carbonate (153.4 g, 1.11 mol) in toluene (1000 mL) was stirred at ambient temperature for 1 h before dimethylsulfate (141.4 g, 1.11 mol) was added dropwise at 26° C. over a period of 2.5 h. The resulting mixture was stirred for 24 h at ambient temperature. After completion of the reaction, dist. water (1000 mL) was added to the mixture under stirring. The organic layer was separated, washed with dist. water (500 mL) and dried in vacuo at 30-50 mbar and max. 50° C. Isochroman-3,4-dione 4-(O-methyl-oxime) was obtained as a light orange solid (160.1 g, 88.7 HPLC-area %, quant. yield, diastereomeric ratio=58:42).
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:25]1([CH:37]=[CH:36][CH:35]=[CH:34][CH2:33]1)[CH:26]=[N:27][C:28](=O)[CH2:29][CH2:30][CH3:31])C>C(Cl)(Cl)Cl>[C:2]1([N:8]2[C:28]([CH2:29][CH2:30][CH3:31])=[N:27][C:26]([C:25]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
First, 14 g of phenyl hydrazine hydrochloride and 200 ml, of carbon tetrachloride were put into a 500-mL three-neck flask, 30 mL of triethylamine (Et3N) was added dropwise to the mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 17 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 of Synthesis Example 1 was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, this mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, toluene was used. The obtained fraction was concentrated, so that 1,3-diphenyl-5-propyl-1H-1,2,4-triazole (abbreviation: HPrp3tz1-Ph) was obtained (a red oily substance, 29% yield). The synthesis scheme of Step 1 is shown in (C-1) below.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[C:7]1=[O:18])[CH3:2]>CCO.C(O)(C(F)(F)F)=O>[O:18]=[C:7]1[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:10][CH2:9][NH:8]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)CC1CCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
tert-Butyl 2-oxopyrrolidine-1-carboxylate (10 g, 54.0 mmol) was dissolved in THF (75 mL) and cooled to −78° C. LDA (1.8 M in THF/heptane, 30.0 mL, 54.0 mmol) was added and the solution was stirred for 1 h. Ethyl 2-bromoacetate (9.02 g, 54.0 mmol) was added and the mixture was stirred for 1 h and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted two times with EtOAc and the combined extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide partially purified tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate (4.72 g, 17.40 mmol) was dissolved in EtOH (30 mL) and TFA (10 mL). The reaction was stirred at room temperature for 2 h and 20 mL of TFA was added. After stirring for an additional 2 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to provide the title compound (1.77 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H), 1.81-1.93 (m, 1H), 2.35-2.49 (m, 2H), 2.75-2.85 (m, 1H), 2.88 (dd, J=16.4, 3.9 Hz, 1H), 3.31-3.40 (m, 2H), 4.09-4.21 (m, 2H), 5.96 (bs, 1H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([O:12]CC)=O)=[CH:5][CH:4]=1>>[Cl:2][C:3]1[C:8](=[O:9])[NH:7][C:6]([C:10]([NH2:1])=[O:12])=[CH:5][CH:4]=1
Reactant: N
Reactant: CCOC(=O)c1ccc(Cl)c(=O)[nH]1
Product: NC(=O)c1ccc(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Aqueous ammonia (15 mL, 30% solution) was added to ethyl 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 0.65 g, 3.2 mmol) at 0° C. and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether, filtered and dried to afford 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2). Yield: 0.43 g, 75%; MS (ESI) m/z 173[M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([CH3:4])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH2:44][CH:43](O)[CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(OC3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-[4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (120 mg, 0.223 mmol, Example 406), tetrahydro-pyran-4-ol (22.7 mg, 0.223 mmol), triphenylphosphine (58.4 mg, 0.223 mmol) and toluene (10 mL) was treated dropwise with DIAD (45 mg, 0.223 mmol). The mixture was stirred under N2 at ambient temperature for 16 h and concentrated. The crude product was purified by radial chromatography (10-70% EtOAc/hexanes) to give 3-[2-(isopropoxycarbonylamino-methyl)-4-(2-{5-methyl-2-[4-(tetrahydro-pyran-4-yloxy)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid tert-butyl ester. The ester product was dissolved 4M HCl/dioxane (5 mL), stirred for 16 h and concentrated to give the title compound: MS [ES] m/z 525 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH:33]=[CH2:34]>C(C(C)=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:11]([O:13][CH2:34][CH:33]=[CH2:32])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: C=CCOC(=O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Yield: 73.3 %

Procedure:
To a 250 mL flask stirring under nitrogen was charged 3.55 g (0.010 mole) of a 4-(4-chlorophenyl)-2-phenyl-2-[(1,2,4-triazol-1-yl)methyl]butanoic acid in 40 mL of methyl ethyl ketone and 10 mL of dimethyl formamide. To the mixture was added 2.07 g (0.015 mole) of potassium carbonate and 1.85 g (0.011 mole) of allyl iodide. The reaction was stirred for 16 hours at 45° C. The reaction was quenched by adding 150 mL of ether and 25 mL of water. The organic phase was washed with 50 mL of saturated sodium bicarbonate and 20 mL of 10% sodium hydroxide, then 50 mL of water. After decolorizing with charcoal, the solvent was filtered and concentrated and gave 2.9 g (79.4% yield) of a solid, Example 137 of Table 1.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16].CO>ClCCl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:6][C:2]([O:1][C:15](=[O:17])[CH3:16])([CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)C(C)(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OC(C)(C)C(C)=O
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of 3-hydroxy-3-methyl-2-butanone (10.75 ml, 100 mmol) and triethylamine (21 ml, 150 mmol) in dichloromethane (125 ml) was treated with acetic anhydride (11.8 ml, 125 mmol) then with 4-dimethylaminopyridine (610 mg, 5 mmol) and the reaction was stirred at ambient temperature for 14 h. Methanol (10 ml) was added and stirring continued for 30 min before concentrating the reaction in vacuo. The residue was dissolved in ether (300 ml) and washed with 0.5N hydrochloric acid (2×300 ml), water, saturated aqueous sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford acetic acid 1,1-dimethyl-2-oxopropyl ester as a yellow liquid (13.5 g, 94%): δH (400 MHz, CDCl3) 1.46 (6H, s), 2.09 (3H, s), 2.12 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:19])[CH:17]=[CH2:18])[CH2:13][C:12]2=[O:20])[CH3:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:26][OH:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:19])[CH2:17][CH2:18][O:27][CH3:26])[CH2:13][C:12]2=[O:20])[CH3:10])=[CH:5][CH:4]=1
Reactant: CO
Reactant: C=CC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Agent: O=S(=O)(O)O
Product: COCCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(prop-2-enoyl)pyrrolidin-2-one 1.19 (12 g, 43.90 mmol, 1.00 equiv) in methanol (120 mL), followed by the addition of sulfuric acid (6.24 mL, 98%) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(3-methoxypropanoyl)pyrrolidin-2-one 1.20.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:17][O-:18].[Na+].[NH4+].[Cl-]>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[O:18][CH3:17]
Reactant: C[O-]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 2, 253 mg, 0.881 mmol) in MeOH (0.85 ml) under argon was treated with NaOMe (5.4 M in MeOH, 0.816 ml, 4.41 mmol), flushed with argon, treated with CuBr (253 mg, 1.76 mmol). The vial was sealed and the reaction mixture was stirred at 120° C. for 15 h. The reaction mixture was cooled to room temperature, treated with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined org. layers were washed again with brine, dried over Na2SO4 and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a pale yellow oil. (UPLC-MS 1) tR 0.73 min; ESI-MS 239.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].CCCCCCCCCCCC.[Bi].[OH-].[Na+].OO>[Pt].CC(CC(C)C)=O>[CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Agent: [Pt]
Agent: OO
Agent: [Bi]
Solvent: CCCCCCCCCCCC
Solvent: CC(=O)CC(C)C
Product: CCCCc1ncc(C=O)[nH]1
Yield: 88.2 %

Procedure:
1.5 g of 2-n-butyl-5-hydroxymethylimidazole, 1.5 g of dodecane as internal GC standard, 0.3 g of 5 percent platinum and 5 percent bismuth on activated carbon (comprising 61.3 percent water), 20 g of isobutyl methyl ketone and 2.5 g of 1.6 percent strength NaOH solution were heated to about 58° C. with stirring. At 58° to 64° C., 2.9 g of 15.7 percent strength aqueous H2O2 solution was added dropwise over the course of 45 min. The reaction mixture was then allowed to react for 15 min and then filtered. The filtrate was transferred to a separating funnel, the H2O phase was separated off, the organic phase was concentrated and cooled, and the product crystallized out and was filtered off. The yield was determined by GC (internal standard). The reaction yield was 88.2 percent (6.75 percent of starting material).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(I)cc1F
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(I)cc2F)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 2-fluoro-4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.77 (s, 1H), 7.86-7.37 (m, 7H), 7.29 (bs, 2H); (M+H)+ (452).
Reaction SMILES: [CH3:1][O:2][N:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[CH:5]=[CH:4]1.Cl.[NH:18]1[C:22]([C:23]2[CH:24]=[C:25]3[C:35](=[CH:36][CH:37]=2)[O:34][C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][C:26]3=[O:38])=[N:21][N:20]=[N:19]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH3:1][O:2][N:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([N:31]3[CH2:32][CH2:33][C:28]4([CH2:27][C:26](=[O:38])[C:25]5[C:35](=[CH:36][CH:37]=[C:23]([C:22]6[NH:21][N:20]=[N:19][N:18]=6)[CH:24]=5)[O:34]4)[CH2:29][CH2:30]3)=[O:14])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2OC
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc2c1ccn2OC
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (310 μl) and water (1.5 mL) were added to a solution of 1,4-dimethoxy-1H-indole-6-carboxylic acid (300 mg), 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (478 mg), WSC (311 mg) and HOBT (249 mg) in DMF (6 mL), and stirred at 90° C. for 30 minutes. Water was added thereto at room temperature, and a white precipitate was thus obtained. This was dried under reduced pressure, washed with a mixed solvent of methanol and diethyl ether, and dried again under reduced pressure to obtain the above-described compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.5, 2.2 Hz), 7.63 (1H, d, J=3.4 Hz), 7.33 (1H, d, J=8.5 Hz), 7.11 (1H, s), 6.58 (1H, s), 6.37 (1H, d, J=3.4 Hz), 4.34-4.18 (1H, br m), 4.05 (3H, s), 3.89 (3H, s), 3.73-3.14 (3H, br m), 2.98 (2H, s), 2.15-1.76 (4H, br m); MS [M+H]+=489.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].CO>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: COC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)C(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)O)cc1F

Procedure:
A solution of the product from step e) (140 mg) in NaOH (0.35 ml, 1 M), THY (2 ml) and MeOH (1 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue was washed with ether, acidified (2M HCl) and extracted with DCM (thrice). The organic extracts were dried (MgSO4), evaporated and crystallised from isohexane—DCM to give the title compound (105 mg). M.p. 170-1° C.