Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31]([C@@H:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][N:34]2C(OC(C)(C)C)=O)=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31]([C@@H:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][NH:34]2)=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)c(Cl)c2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Yield: 94.6 %

Procedure:
N-[(1R)-1-[(3,4-Dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl)) carboxamide was prepared from tert-butyl 3-{N-[(1R)-1-[(3,4-dichlorophenyl) methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step 3) (590 mg, 0.80 mmol) according to the procedure for Preparation XVI. The resulting crude material was diluted with EtOAc and washed with satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The material was purified by preparative HPLC to give the title compound (477 mg) as the TFA salt. MS (ESI, pos. ion) m/z: 630 (M+H), (ESI, neg. ion) m/z: 628 (M−H). Calc'd for C30H33Cl2N5O4S: 629.16. Anal. Calc'd for C30H33Cl2N5O4S-1.5C2HF3O2-0.5H2O: C, 48.89; H, 4.41; N, 8.64; Cl, 8.75. Found C, 49.33; H, 4.47; N, 8.94; Cl, 8.61.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[N:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[C:8]([C:7]1[C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[N:3][C:4]([C:10]([F:19])([F:18])[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[N:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cnc(C(F)(F)C(F)(F)C(F)(F)F)nc1N
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1nc(C(F)(F)C(F)(F)C(F)(F)F)ncc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-heptafluoropropyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[CH3:19]>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[C:9]1[C:22]1([OH:26])[CH2:23][CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CCCC(=O)C1
Reactant: Clc1nccc2c1ncn2Cc1ccccc1
Product: CCN1CCCC(O)(c2nc3c(Cl)nccc3n2Cc2ccccc2)C1

Procedure:
Following the procedure of Example 13 and using 1-benzyl-4-chloro-1H-imidazo[4,5-c]pyridine (0.60 g, 2.5 mmol) and (0.36 g, 2.8 mmol) of N-ethyl-3-piperidone gave the free base of the title compound which was purified by flash chromatography on silica gel eluting with EtOAc to give, after preparation of the salt, the dihydrochloride, 0.59 hydrate as an amorphous solid, 0.30 g (26%):
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NNc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NNc1ccc(N)cn1
Reaction time: 2 h
Yield: 81.64 %

Procedure:
Into a Parr hydrogenation bottle was added 2-BOC-hydrazino-5-nitropyridine (1 equivalent), 1(7% palladium on charcoal (0.3 gm Pd/gm of pyridine) and ethanol (100 ml/gm of pyridine). The reaction was hydrogenated at 50 psi H2 for 2 hours at room temperature on a Parr hydrogenator. The reaction mixture was filtered through a filter cell plug and rinsed with ethanol. The yellow green solution was concentrated under reduced pressure to give a pale yellow solid. The product was recrystallized from ethanol; yield 81.64%; m.p. 140°-142°. IR (KBr): 3360, 3200, 2980, 1650, 1635, 1580, 1490, 1390, 1360, 1300, 1260, 1160, 1020, 880, 860, 830, 750, 590, 530 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1([O:28][CH2:29][CH3:30])[CH2:25][NH:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:18]>>[CH2:29]([O:28][C:20]1([O:19][CH2:17][CH3:18])[CH2:25][N:24]([C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:16])[CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)[CH3:30]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CCOC1(OCC)CCC(CO)NC1
Product: CCOC1(OCC)CCC(CO)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to general procedure A using 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid and rac-(5,5-diethoxypiperidin-2-yl)methanol.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.OS(C(F)(F)F)(=O)=O>>[I:1][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[C:10]([F:9])([F:22])[F:23])[NH:17][C:16](=[O:20])[C:15]2=[O:21]
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1Nc2cc(C(F)(F)F)c(I)cc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.8 %

Procedure:
N-Iodosuccinimide (25.0 g, 119.5 mmol) was added to a stirred mixture of 6-trifluoromethylisatin (10.3 g, 47.8 mmol) and triflic acid (75 g) at 0° C. under nitrogen. The ice bath was removed and stirring at room temperature was continued for 7 h. The mixture was poured into ice-water and was extracted with EtOAc. The combined organic extracts were evaporated under reduced pressure and the residue was triturated with CHCl3 to produce a yellow-orange solid. Filtration of the crude solid and purification by recrystallization from CHCl3 gave 5-iodo-6-trifluoromethylisatin xxxiii (10.4 g) as an orange solid. 1H NMR (DMSO-d6) δ 7.17 (s, 1H), 8.08 (s, 1H), 11.27 (s, 1H); ms 340.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]2)[CH:7]=1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:18][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(CNc2cc(Br)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C1(CNc2cc(Br)ccc2N)CC1
Temperature: 70 °C
Yield: 75.7 %

Procedure:
Iron powder (448 mg, 8.0 mmol) was added to a mixture of ethyl 1-((5-bromo-2-nitrophenylamino)methyl)cyclopropanecarboxylate (684 mg, 2.0 mmol), ammonium chloride aqueous (6 mL) and ethanol (20 mL). The reaction was heated to 70° C. and maintained at the 70° C. for 2 hours. The mixture solution was filtered. The filtrate was evaporated, diluted with water (100 mL), extracted with ethyl acetate (100 mL), and dried by sodium sulfate. The mixture was filtered. The filtrate was concentrated and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 1-((2-amino-5-bromophenylamino)methyl)cyclopropanecarboxylate (474 mg, 76%) as off-white solid.
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:18])=[O:17]
Reactant: NN
Reactant: O=C(CC(=O)c1ccccc1C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na][Na]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccccc2)[nH]n1

Procedure:
To a slurry of 100 g of the disodium salt of 2-benzoylacetylbenzoic acid in 400 ml of methanol is added first 12.5 g concentrated hydrochloric acid, followed by 11 g of hydrazine hydrate. This reaction mixture is heated at reflux for 1/2 hour, cooled to 5°-10°, acidified to pH 3 with concentrated hydrochloric acid, and diluted with 300 ml of water. The crystals are filtered off and recrystallized from ethanol-water, yielding 59 g of 3-(2-carboxyphenyl)-5-phenylpyrazole, mp 204°-205.5°.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])=[CH:19][CH:18]=2)[C:5]1=[O:36])(=O)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:38]1([NH:37]/[C:16](=[C:6]2\[C:5](=[O:36])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])=[CH:21][CH:22]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
Prepared analogously to Example 146 from 1-acetyl-3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone, aniline, N-ethyl-N,N-diisopropyl-amine and DMF.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1>CO.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:11][CH:12]=1
Reactant: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: O=[Pt]=O
Solvent: CO
Product: CC(Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Reaction time: 4 h
Yield: 23.8 %

Procedure:
A solution of 50 mg of 3-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-acrylamide in 10 ml methanol is treated with 4 mg of platinum dioxide and hydrogenated at RT and normal pressure for about 4 h. The catalyst is filtered off and the filtrate evaporated to dryness. Trituration of the residue in about 2 ml diethylether yields 12 mg (23%) of a colorless solid. MS: m/e=288.2 (M++H).
Reaction SMILES: [ClH:1].O.[H][H].[N:5]1([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[ClH:1].[N:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C1CC(N2CCOCC2)CCN1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A stirred mixture of Pd(OH)2 (20% on carbon (<50% wet), 390 mg, 25 wt %), methanol (50 mL), and ≦1.7 M HCl (3 eq, ˜10.6 mL—including water added later when ppt was seen) under nitrogen was exchanged to 1 atm. hydrogen atmosphere by flushing (˜20 sec) using a balloon of nitrogen into the vessel and out through an oil bubbler. After 20 min. the reaction mixture under hydrogen was heated to 50° C. and 4-(morpholin-4-yl)-1-benzylpiperidine (1.56 g, 6.0 mmol) in methanol (8 mL) was added dropwise over 30 min. After 10 h, tlc indicated all starting amine was consumed to a more polar spot (ninhydrin active). The reaction mixture was then filtered through Celite and evaporated to yield the 4-(morpholin-4-yl)piperidine dihydrochloride as an off-white solid. This material was subjected to free-basing using excess basic resin (>16 g, Bio-Rad Laboratories, AG 1-X8, 20-50 mesh, hydroxide form, methanol washed two times) and a methanol mixture of the amine hydrochloride. After swirling with the resin for 30 min., the methanol solution was decanted and evaporated to yield 932 mg of 4-(morpholin-4-yl)piperidine free base as a waxy crystalline solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH:18][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCC[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
L-methionyl-L-proline benzylester hydrochloride (1.86 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C. and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-methionyl-L-proline benzylester (yield 1.99 g, 83.5%)
Reaction SMILES: [C:1]1([C:7](=[N:28][OH:29])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[C:1]1([C:7](=[N:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CC(=NO)c4ccccc4)CC3)ccc2N1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)ON=C(CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.3 Grams of 6-[4-(2-phenyl-2-hydroxyiminoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril, 1.91 ml of acetic anhydride and 5.64 ml of triethylamine were dissolved in 60 ml of methylene chloride, and the resulting solution was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water, and was made alkaline by adding sodium carbonate, then this mixture was extracted with methylene chloride. The methylene chloride extract was dried, then the solvent was removed by evaporation, and the residue was converted into an oxalate by stirring with oxalic acid in acetone. The oxalate was recrystallized from ethanol-water to yield 5.28 g of 6-[4-(2-phenyl-2-acetoxyiminoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.oxalate.monohydrate.
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>O1CCOCC1>[CH2:14]([O:8][C:7]([C:6]1[CH:10]=[CH:11][C:3]([B:2]([OH:12])[OH:1])=[CH:4][CH:5]=1)=[O:9])[CH3:15]
Reactant: CCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(B(O)O)cc1
Reaction time: 1.5 h

Procedure:
A suspension of 4-(dihydroxyboryl)benzoic acid (5.0 g, 30.13 mmol) in ethanol (16.0 mL) was treated with 4N HCl in dioxane (34.0 mL), heated to reflux, stirred for 1.5 hours, and concentrated. The concentrate was partitioned between water (150.0 mL) and diethyl ether (100.0 mL) and the aqueous layer was extracted with diethyl ether (2×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 194 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 2H), 7.81 (m, 211), 4.41 (q, 2H), 1.41 (t, 3H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[CH3:36][NH:37][C:38](Cl)=[O:39]>ClCCl>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH:20][C:38]([NH:37][CH3:36])=[O:39])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CNC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Methylcarbamic chloride (0.003 g, 0.030 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(3-methylureido)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 455 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[Cl:20][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCCOc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][CH:7](O)[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2].Cl.[NH2:38][OH:39].C1CCN2C(=NCCC2)CC1.ClN1C(=O)CCC1=O>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8]/[C:7](=[N:38]\[OH:39])/[C@H:6]1[O:33][C:34](=[O:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O/C(=N\O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
Compound from step A (142 mg, 0.27 mmol) and hydroxylamine hydrochloride (57 mg, 0.82 mmol) were dissolved in pyridine (1.4 ml). The reaction was stirred for 6 hours, diluted with EtOAc, washed with 1 M aq. NaHSO4, H2O, sat. aq. NaHCO3, and brine (with back extraction), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in CH2Cl2, cooled to −78° C., and treated with DBU (49 μL, 0.33 mmol) followed by N-chlorosuccinimide (44 mg, 0.33 mmol). The reaction was stirred for 20 minutes at −78° C., then allowed to warm to room temperature over 15 minutes The reaction was diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (12 g SiO2, 0-50% EtOAc:Hex.) to give acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-[(Z)-hydroxyimino]-tetrahydro-pyran-3-yl ester (97 mg, 0.18 mmol, 67%).
Reaction SMILES: CCOCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20](=[O:24])[C:21](Cl)=[O:22].[C:25]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:25]([CH:33]1[CH2:38][CH2:37][N:36]([C:21](=[O:22])[C:20]([C:11]2[C:10]3[C:14](=[CH:15][C:16]([O:17][CH3:18])=[C:8]([O:7][CH3:6])[CH:9]=3)[NH:13][C:12]=2[CH3:19])=[O:24])[CH2:35][CH2:34]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: COc1cc2[nH]c(C)c(C(=O)C(=O)Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)N3CCC(C(=O)c4ccccc4)CC3)c2cc1OC

Procedure:
The above ether suspension of 5,6-dimethoxy-2-methyl-3-indoleglyoxylyl chloride is added portionwise to a cooled stirring mixture of 4-benzoylpiperidine [Example 9(a)], 150 ml of water, 150 ml of chloroform and 25 g of potassium carbonate. The mixture is stirred for 16 hours at ambient temperature, the organic layer is separated and the solvent is removed, leaving a brown oil which is triturated with cyclohexane and then stirred for 16 hours with ether. A white solid results which is collected, dried and recrystallized thrice from methanol to give the compound, mp 188°-190° C., 4-benzoyl-1-(5,6-dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH2:2][CH3:3]>C(O)C.[Pd]>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C(=O)c1ccc(N)cc1

Procedure:
An amount of 44.3 gm (0.2 mol) of the p-nitrobenzoic acid dipropylamide from step (a) was dissolved in 500 ml of ethanol and, after addition of 5 gm of palladium active charcoal (5%), hydrogenated at 50° C. and 60 bar pressure. After filtration, evaporation of the ethanol solution, and recrystallization of the residue (34.1 gm) from ether, 26.7 gm of p-aminobenzoic acid dipropylamide with a melting point of 78°-79° C. were obtained.