Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[C:18]([CH:20]=O)[CH:19]=1)=[O:14])[CH3:11].C([BH3-])#N.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.CO>[CH2:10]([O:12][C:13]([C:15]1[NH:16][CH:17]=[C:18]([CH2:20][N:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:7])[CH:19]=1)=[O:14])[CH3:11]
Reactant: CNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C=O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CN(C)c2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
4-chloro-N-methylaniline (0.225 mL, 1.86 mmol) was added to a stirring, room temperature solution of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.2585 g, 1.55 mmol) in 5% acetic acid in methanol under N2. After stirring at room temperature for 30 minutes, sodium cyanoborohydride (0.1585 g, 2.52 mmol) was added, and the reaction was stirred at room temperature overnight. About 3 mL of saturated K2CO3 were added, and the reaction was extracted twice with ethyl acetate. The combined organics were washed with saturated NaHCO3 (˜4 mL) and brine (˜4 mL), then the combined organics were dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 85:15 Hexanes:Ethyl acetate) to obtain 0.3419 g (76%) of 4-{[(4-chlorophenyl)-methylamino]methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (191) as a light tan solid. Note: Starting material 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester has an HPLC retention time=7.337 min. HPLC: 8.478 min.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][N:5]2[C:6](=[O:13])[C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:10]([C:7]1[C:6](=[O:13])[N:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][C:4]2=[N:9][CH:8]=1)=[O:12])[CH2:29][CH3:30]
Reactant: Cc1ccn2c(=O)c(C(=O)O)cnc2c1
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2cc(C)ccn2c1=O
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml of chloroform is dropped to the above mixture at -18° C. during 10 minutes. After stirring for 5 minutes, 5.2 g (0.088 mol) of propylamine dissolved in 80 ml of chloroform are dropped to the above solution at -18° C. during 60 minutes. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.3 g (88.2%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 194°-196° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[N+:1]([C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
A solution of 724 mg (3.51 retool) of 3-nitro-4-hydroxy-1,2-dihydroquinolin-2-one and 401 mg (3.97 retool) of KNO3 in 4 mL of 96% H2SO4 was stirred in an ice-bath for 30 min, then 25° C. for 20 h. The solution was added into 25 mL of ice-water to give a yellow precipitate and the mixture was stirred for 1 h, filtered and washed with water, and dried to leave 602 mg (68%) of title compound as a yellow solid, mp 197°-198° C. (decomposed, lit (Buckle et al., supra) 199° -200° C.). 1H NMR (CDCl3 +DMSO-d6), 7.114 (d, 1, J=9.12), 7.980 (dd, 1, J=2.27, 9.13), 8.628 (d, 1, J=2.28), 12.13 (mb, 1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29]CC)=[O:28])[CH2:22]2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.OS([O-])(=O)=O.[K+]>O.C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=[O:28])[CH2:22]2)=[O:20])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCN(C(=O)COC2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(C(=O)COC2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of ethyl 1-[2-(1-benzyloxycarbonyl-4-piperidyloxy)acetyl]-3-piperidinecarboxylate (2.06 g) and 1N NaOH aqueous solution (14.29 ml) in a solution of tetrahydrofuran (10 ml), ethanol (10 ml) and water (10 ml) was stirred for 1 hour at ambient temperature. The mixture was acidified with 10% aqueous solution of KHSO4 and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 1-[2-(1-benzyloxycarbonyl-4-piperidyloxy)acetyl]-3-piperidinecarboxylic acid (1.51 g).
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[CH3:40][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[CH3:39])[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 4-bromo-1,2-dimethylbenzene (596 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 3 hr and at 110° C. under nitrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (144 mg) as a pale yellow crystalline solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[BH4-].[Na+].CO>C1COCC1>[OH:19][CH2:18][C:17]1[CH:22]=[CH:23][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(CO)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 5.4 %

Procedure:
To a solution of methyl 4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)benzoate (60 mg, 0.25 mmol) in THF (5 mL) was added NaBH4 (48 mg, 1.25 mmol). The mixture was heated to reflux for 15 minutes. Then methanol (3 mL) was added. The mixture was heated to reflux overnight. The reaction was quenched with water, and the solvent was removed. The aqueous layer was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(hydroxymethyl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 5%). LC-MS Method 2 tR=1.29, min, m/z=370, 392; 1H NMR (CDCl3): 1.33 (m, 1H), 1.45 (m, 3H), 1.64 (m, 1H), 1.90 (m, 2H), 2.11-2.24 (m, 2H), 2.81 (m, 1H), 3.50 (m, 2H), 4.52 (s, 2H), 5.58 (m, 1H), 6.82 (m, 2H), 7.03 (m, 2H), 7.25 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)[CH3:2].I[CH:14](C)C>>[CH:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:14])[CH3:2]
Reactant: CC(C)I
Reactant: CCOc1cccc2cc[nH]c12
Product: CC(C)Oc1cccc2cc[nH]c12

Procedure:
Made according to the procedure described for 7-ethoxy-1H-indole using 2-iodopropane.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:45][NH2:46]>O1CCCC1.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:16]=2)[CH2:11][C:12]([NH:46][OH:45])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 87) (330 mg, 0.86 mmol) and N-methylmorpholine (160 μl, 1.46 mmol) in anhydrous tetrahydrofuran (14 ml) was cooled to 0° C., treated with isobutyl chloroformate (120 μl, 0.93 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (350 μl, 2.86 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a colourless oil (272 mg).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:43])[CH2:7][C:8]1[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[N:24][CH:25]=2)[N:13]=1>O.C1COCC1>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=4[CH2:7][C:6]([OH:43])=[O:5])[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:21][CH:22]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(=O)O
Temperature: 40 °C

Procedure:
LiOH.H2O (442 mg, 10.5 mmol) was added to a stirred solution of tert-butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A18) (115 mg, 0.211 mmol) in water (4 mL) and THF (40 mL) and the resulting mixture heated at 40° C. for 18 hours. On cooling the volatiles were removed in vacuo and the residue taken up in EtOAc (100 mL). The resulting solution was washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A19 as a clear oil (96 mg, 86%); LCMS-A: rt 5.137 min; m/z 532 [M+H]+.
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH3:9][O:10][CH2:11][C:12]([NH:18][CH3:19])=[CH:13][C:14]([O:16][CH3:17])=[O:15]>C(O)(=O)C>[OH:7][C:4]1[CH:3]=[C:2]2[C:1](=[CH:6][CH:5]=1)[N:18]([CH3:19])[C:12]([CH2:11][O:10][CH3:9])=[C:13]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CNC(=CC(=O)OC)COC
Solvent: CC(=O)O
Product: COCc1c(C(=O)OC)c2cc(O)ccc2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.9 %

Procedure:
3.1 g of 1,4-benzoquinone (28.7 mmol) was dissolved in 50 ml of acetic acid to which was subsequently added dropwise 2.28 g (14.3 mmol) of methyl 4-methoxy-3-methylamino-2-butenoate and the mixture was stirred for 5 hours at room temperature. After the solvent was distilled off under reduced pressure, the resulting residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column chromatography (eluent: hexane-ethyl acetate, 2:1) to obtain 0.78 g of the title compound with a yield of 22%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:10][CH:9]=1)=O.[O-2].[Ba+2].O.[NH2:25][NH2:26].C(O)C>O>[N:16]1([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH2:5][CH2:4][C:3](=[O:2])[NH:25][N:26]=3)=[CH:9][CH:10]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: COC(=O)CCC(=O)c1ccc(CCn2ccnc2)cc1
Reactant: NN
Agent: [Ba+2]
Agent: [O-2]
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(CCn3ccnc3)cc2)=NN1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7.5 g of 4-{4-[2-(1-imidazolyl)-ethyl]-phenyl}-4-oxo-butyric acid methyl ester, 0.2 g of barium oxide, 1.3 g of hydrazine hydrate and 30 ml of ethanol is stirred at 0° C. for 10 minutes and then at room temperature for 2 hours, and is subsequently heated under reflux for 1 hour. The reaction mixture is diluted with water and extracted with chloroform and the extract is washed with water and dried over Na2SO4. The solvent is stripped off and the residue is purified by column chromatography (silica gel/chloroform/methanol).
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.BrCCCC1C=NC=CC=1.ClC1C=CC(N(CCCC2C=NC=CC=2)N)=CC=1.C(OC(OCC)CCCNC)C.[Cl:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([CH2:61][CH2:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1)[CH:56]=[C:55]2[CH2:70][CH2:71][NH:72][CH3:73].C=O.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Cl:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([CH2:61][CH2:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1)[C:56]1[CH2:73][N:72]([CH3:3])[CH2:71][CH2:70][C:55]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1cn(CCCc2cccnc2)c2ccc(Cl)cc12
Agent: BrCCCc1cccnc1
Agent: C=O
Agent: CCOC(CCCNC)OCC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCc2c(n(CCCc3cccnc3)c3ccc(Cl)cc23)C1

Procedure:
The title compound is prepared by following General Methods 1, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, 3-(3-bromopropyl)pyridine, and triethylamine (General Method 1), 1-(4-chlorophenyl)-1-(3-(pyridin-3-yl)propyl)hydrazine and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(3-(pyridin-3-yl)propyl)-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([CH3:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([CH3:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22])=[O:14]
Reactant: Cc1cc(F)c(N)cc1C(=O)OC(C)C
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)c(C)cc2F)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Thionyl chloride (4.7 g, 0.040 mole was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (50 ml). The mixture was stirred overnight at room temperature, then evaporated under reduced Pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the chilled solution treated dropwise over about 1 hour with a solution of 1-methylethyl 5-amino-4-fluoro-2-methylbenzoate (7.9 g, 0.037 mole) and triethylamine (3.9 g, 0.039 mole) in methylene chloride (50 ml). The reaction mixture was left stirring overnight at room temperature and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). Evaporation of the solvent left a solid residue. Recrystallization from 100% ethanol (60 ml) gave yellow-tan crystals, m.p. 119°-122° C. (7.6 g, 57% yield).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>CN(C=O)C>[C:28]([O:27][C:23]([NH:24][NH:25][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N,N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N,N, N,N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:10])[CH:5]([Br:9])[CH2:6][CH2:7]Br.[H-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][N:3]1[CH2:7][CH2:6][CH:5]([Br:9])[C:4]1=[O:10]
Reactant: CONC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CON1CCC(Br)C1=O
Yield: 50.6 %

Procedure:
1400 g of a crude N-methoxy-2,4-dibromobutanamide was dissolved in 5 liters of benzene. Then 125 g of NaH was added little by little to the solution at 15° to 20° C. while the reaction mixture was cooled with an iced water bath. After the reaction, the remaining NaH was decomposed with ice and the product mixture was washed with a saturated, aqueous salt solution. It was dried with magnesium sulfate. Then benzene was distilled out. The product was purified with the column chromatography, using silica gel and a mixture of acetaone and benzene to obtain 500 g of the title compound 4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[SH-:14].[Na+]>C(O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:14])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(=S)cc[nH]c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 61.7 %

Procedure:
4-Chloro-7-methoxyquinoline(965 mg, 5 mmol) and 70% sodium hydrosulfide (800 mg, 10 mmol) were added to ethanol (100 ml) and stirred at room temperature for 6 days. Ethanol was removed under reduced pressure from the reaction mixture. The residue was chromatographed by silica gel column chromatography, eluted with mixed solution of methylene chloride with methanol (16 : 1) for collection of yellow bands. The solvent was removed and the residue was added with a small amount of methylene chloride. The resulting precipitates were collected by filtration to obtain 590 mg (62%) of the titled compound. This compound was completely the same as the compound 1 obtained in the Example 1.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]=3[CH:25]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:26][C:27]([C:29]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]=3[CH:25]=2)=[CH:9][CH:10]=1)#[N:1]
Reactant: COCCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: COCCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(3-(3-methoxypropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 11, step (iii), 151 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (121 mg) and the mixture was stirred for 18 h at room temperature. The solvent was partially evaporated and the mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:1) to yield the sub-titled compound (137 mg).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:21][C:22](=[O:47])[N:23]([CH2:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[S:18][C:19]=2[Cl:20])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:19]1[S:18][C:17]([NH:21][C:22](=[O:47])[N:23]([CH2:32][CH2:33][CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:16][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-tert-butyl-4-(5-chloro-2-(((3,3-diphenylpropyl)(2-(2-pyridinyl)ethyl)carbamoyl)amino)-1,3-thiazol-4-yl)benzenesulfonamide 84 (0.187 g, 0.272 mmol) in DCM (1 mL) was added anisol (0.20 mL) and TFA (2 mL). The reaction mixture was stirred at room temperature for 1 d and concentrated. The concentrate was diluted with EtOAc and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by crystallization from a mixture of DCM and hexanes gave 4-(5-chloro-2-(((3,3-diphenylpropyl)(2-(2-pyridinyl)ethyl)carbamoyl)amino)-1,3-thiazol-4-yl)benzenesulfonamide 85. Mass spectrum, calculated for C32H30ClN5O3S2 631.2; found 632.1 (M++1).