Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)#[N:39].C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][N:11]([S:46]([C:43]1[CH:42]=[CH:41][C:40]([C:38]#[N:39])=[CH:45][CH:44]=1)(=[O:48])=[O:47])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCC(C)C)N1CCN(Cc2cccnc2)C1=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(C#N)cc1)N1CCN(Cc2cccnc2)C1=O
Yield: 74.1 %

Procedure:
Example 785A (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) and combined with p-cyanobenzenesulfonyl chloride (24 mg, 1.2 equivalents) and triethylamine (41 μL, 3 equivalents) at 25° C. for 16 h. The mixture was quenched with 1N NaHCO3 and extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified using ethyl acetate to give 49 mg (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH2:15]1)=[O:13].[C:21](Cl)(=[O:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH2:15]1)=[O:13])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CC1CCCC(C(=O)c2[nH]c3cc(Cl)ccc3c2N)C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)C2CCCC(C)C2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylcyclohexylcarbonyl)indole (Example 144) and acetyl chloride. m.p.: 202-203° C. (ethyl acetate/hexane)
Reaction SMILES: [C:1]1([NH:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:29]=3)[CH3:27])=[CH:17][CH:16]=2)[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([NH:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:32][CH:33]=3)[CH3:27])=[CH:17][CH:16]=2)[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NOCCOc1ccc(CC(Nc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 91 %

Procedure:
The reaction was carried out according to Example 4 using 260 mg of ethyl 2-phenylamino-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 5 and 1.00 ml of a 1N aqueous sodium hydroxide solution. After the reaction, the reaction mixture was concentrated and diluted with water. The pH of the reaction mixture was adjusted to a value of 4 with 1N hydrochloric acid, and precipitate was obtained by filtration. The precipitate was washed with water and isopropyl ether to obtain 224 mg of the desired compound.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].IC.[C:14]([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)C>[CH3:14][O:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CC(O)C(=O)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOCC
Product: COC(C)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-hydroxypropiophenone (3.00 g, 20.0 mmol), iodomethane (3.40 g, 24.0 mmol), and K2CO3 (granular, anh.; 13.8 g, 99.9 mmol) was refluxed in acetone (75 mL) for 18 h. The reaction mixture was cooled to room temperature and the inorganic salts were removed by filtration. The filtrate was evaporated under vacuum to give an oil which was subsequently dissolved in diethyl ether (200 mL) and then washed with 0.1N NaOH (3×50 mL) followed by H2O (50 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated to an orange oil (3.17 g, 96.9%). This material was used in the following step without further purification. TLC, Rf 0.55 (1% MeOH:l % IPA:CHCl3); GC, tr 4.58 min; MS, m/z 164 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Yield: 95.8 %

Procedure:
To a solution of 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20.22 g; 53 mmol) in MeOH (400 mL) was added palladium hydroxide (0.74 g; 5.30 mmol). The mixture was treated with H2, at normal pressure, overnight. The reaction mixture was filtered over Kieselguhr. The filter-cake was washed with a solution of ammonia in MeOH. Evaporation of the solvent afforded 2-(4-octyloxy-phenyl)-morpholine (14.80 g), which was used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH2:55]([NH2:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>COCCOC.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]>[F:18][C:17]([F:20])([F:19])[C:16]([NH:15][C@H:14]1[C@@H:9]2[N:10]([C:4]3[CH:3]=[C:2]([NH:62][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH:27]=[CH:26][C:5]=3[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=32)[CH2:11][CH2:12][CH2:13]1)=[O:21]
Reactant: O=C(N[C@@H]1CCCN2c3cc(Br)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: COCCOC
Product: O=C(N[C@@H]1CCCN2c3cc(NCc4ccccc4)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 75 °C
Reaction time: 48 h
Yield: 4.1 %

Procedure:
To a solution of trans-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]-oxazepin-1-yl)-2,2,2-trifluoroacetamide (0.5 g, 1.1 mmol) in DME (16 mL), Pd2(dba)3 (12.5 mg, 13.5 μmol), 2-(di-t-butyl-phosphino)biphenyl (25 mg, 80 μmol), sodium-tert-butoxide (218 mg, 2.3 mmol) and benzylamine (243 mg, 2.3 mmol) were added. The resulting reaction mixture was heated to 75° C. and stirred at this temperature for 48 h. The reaction mixture was quenched with sat NaHCO3 (aq) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The crude product was chromatographed with heptane/ethyl acetate 8:2 and purified with HPLC to afford the title compound (21 mg, 32%). Data: 1H-NMR (400 MHz, DMSO) 1.54-2.02 (m, 4H), 2.95 (t, J=9.2, 1H), 3.68 (d, J=14.0, 1H), 4.02 (d, J=10.0, 1H), 4.17 (d, J=6.0, 2H), 4.37 (m, 1H), 5.90-7.33 (12 ArH, 1 NH), 9.11 (d, J=10.0, 1H). (m/z)=468 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]O)(=[O:14])[CH:12]=[CH2:13].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl>[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)c1ccc(O)cc1
Reaction time: 4 h
Yield: 5.2 %

Procedure:
2000 g of dichloromethane, 40.0 g of 4-hydroxybenzoic acid, 39.6 g of 4-hydroxybutyl acrylate and 0.05 g of methoquinone were charged into a separable flask of the same type as used in Reference Example 3, and then a liquid mixture consisting of 54.0 g of N,N'-dicyclohexylcarbodiimide, 5.9 g of dimethylaminopyridine and 60 g of dichloromethane was dropwise added thereto at room temperature over 4 hours, while replacing the flask inside gas with a nitrogen gas. After the same treatment as in Reference Example 1, 3.8 g of p-hydroxybenzoyloxybutyl acrylate of the following chemical formula was obtained (yield: 5%): ##STR4##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:8][S:9][C:10](SC)=[CH:11][C:12]#[N:13].[H-].[Na+]>CN(C=O)C>[CH3:8][S:9][C:10]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:11][C:12]#[N:13]
Reactant: CSC(=CC#N)SC
Reactant: Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=CC#N)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and 3,3-Bis-Methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at room temperature, was added powdered 4A molecular sieves. The mixture was stirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaH dispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr. and it was stirred at 0° C. for an additional 2 hrs. The cold bath was removed and the mixture was stirred at room temperature for 20 hrs. DMF was removed in vacuo and the crude was purified by column chromatography (gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product as an off-white solid (1.9 g, 89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])CCC.[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2([OH:21])[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]2)=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCCCCCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a stirring solution of 1-bromo-4-(heptyloxy)benzene (668 mg, 2.46 mmol) in THF (5 mL) at −78° C. was added butyllithium (985 μl, 2.46 mmol). After 30 min, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (491 mg, 2.46 mmol) in THF (2 mL) was added. After 10 min, the cooling bath was removed and the reaction mixture stirred for 16 h. The reaction mixture was poured onto NH4Cl (50 mL) and extracted with Et2O (3×20 mL). The combined organics were washed with water (20 mL), dried over MgSO4 and evaporated. The crude product was purified by column chromatography (5-70% AcMe in iso-hexanes) to afford 0.4 g (33%) of tert-butyl 4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate. LCMS-ESI (m/z) calculated for C23H37NO4: 391.5; found 414.0 [M+Na]+, tR=2.24 min. (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(Cl)c(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c1
Agent: BrB(Br)Br
Product: CC(c1cc(O)ccc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 147, step 5, 5-[2-(2-chloro-5-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as a light yellow foam. MS (m/e, ISP neg. ion)=360.0 [M−H+].
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N:10]1[O:9][N:8]=[C:7]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[CH3:11])=[CH:14][CH:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Clc1cccc2nonc12
Product: CN(C)c1ccc(-c2cccc3nonc23)cc1

Procedure:
Starting from 4-chloro-benzo[1,2,5]oxadiazole and 4-(dimethylamino)phenylboronic acid. Orange powder. MS(ES+): 240 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH2:8][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC1CCNC1
Reactant: O=Cc1ccccc1
Product: OCC1CCN(Cc2ccccc2)C1

Procedure:
In a manner similar to Preparation 7 react 3-pyrrolidinemethanol with benzaldehyde to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:30][CH2:31][CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:18])=[O:17])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].S([O-])(O)(=O)=O.[K+]>C1COCC1.CCOCC.O.CCOCC>[C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:21][C:20]=1[O:30][CH2:31][CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:18])=[O:17])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Temperature: 25 °C

Procedure:
To (S)-N-methoxy-N-methyl-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonylamino]-succinamic acid tert-butyl ester (1.0 g, 1.60 mmol) solution in dry THF/Et2O (2:1, 30 mL) at −65° C. was added LiAlH4 (6.50 mL, 6.5 mmol, 1.0 M solution in Et2O). The reaction mixture temperature was maintained for 2 h. The excess hydride was quenched by the addition of potassium hydrogen sulfate (2 equiv) dissolved in water. After warming to room temperature, Et2O was added (100 mL) and the organic layer was washed with water and then with brine. The solvent was dried (MgSO4), filtered, and evaporated to dryness. The resulting crude product was purified on silica gel flash chromatography (25% EtOAc in hexanes) to give (S)-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonyl amino]-4-oxo-butyric acid tert-butyl ester as a off white foam (0.60 g, 68%). MS (APCI) m/z 551.3 (M−1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-])=O)[C:16]=1[OH:25])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=1[OH:25])(=[O:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of N-(2-benzyloxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (157 mg, 0.4mmol) in THF (15 mL) and 5% aq. NaHCO3 (10 mL) was stirred at room temperature, sodium dithionite (1.5 g) was added in 0.2 g potion. The mixture was acidified with 1 N aq. HCl, extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to give the desired product (120 mg, 82%). LC-MS (m/z) 357.0 (M+).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[N:12]1([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cccn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](n2cccn2)CC1

Procedure:
A solution of trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester (95 mg, 0.43 mmol) in 1,4-dioxane (4.3 ml) and 2 M aqueous sodium hydroxide solution (2.2 ml, 4.4 mmol) was stirred at room temperature for 20 h. The pH was adjusted to 2 by addition of 2 M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (80 mg, 96%) as light brown solid. MS m/e: 193 ([M−H]−)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccccc1Cl
Product: O=[N+]([O-])c1cccnc1COc1ccccc1Cl
Yield: 85 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2-chlorophenol, the titled compound was obtained as yellow oil. (Yield: 85%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:27][CH2:18][C:13]1[C:12]([Cl:19])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: Cc1ccc(F)c(Oc2cc(Cl)cc(C#N)c2)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Yield: 61.2 %

Procedure:
The title compound was prepared as described herein using 3-chloro-5-[(2-chloro-6-fluoro-3-methylphenyl)oxy]benzonitrile (940 mg, 3.17 mmol), NBS (593 mg, 3.33 mmol) and AIBN (26.1 mg, 0.159 mmol) in CCl4 (30.0 ml) to give the title compound as a white solid (728 mg, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (1H, dd, J=8.7, 5.3 Hz) 7.36 (1H, s) 7.18 (1H, s) 7.12-7.16 (1H, m) 6.99 (1H, s) 4.58 (2H, s). LCMS: m/z 375 (M+1).
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16]1)[CH3:11]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of cyclobutanone (0.3 mL, 3.94 mmol) in acetic acid (0.19 mL, 3.28 mmol) was added to a stirred solution of piperidin-4-yl acetic acid ethyl ester (562 mg, 3.28 mmol, obtained in above step) in dichloromethane cooled at 0° C. Solid sodium triacetoxyborohydride (1.39 grams, 7.2 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain (1-Cyclobutyl piperidin-4-yl) acetic acid ethyl ester (652 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:59][C:57]1[S:56][C:46]2[C:47]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=2[N:58]=1)=[O:7]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 455 mg (2.25 mmol) 2-bromo-isonicotinic acid in 8 ml THF were added 914 mg (2.40 mmol) HATU and 0.50 ml (4.51 mmol) N-methylmorpholine and stirring continued at 50° C. for 16 h. 200 mg (0.75 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 60° C. for 4 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (methanol/dichloromethane) afforded 208 mg (62%) 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 452 (M{81Br}+H+, 95), 450 (M{79Br}+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5][C:4]=2[C:3]=1[C:17]([O:19]C)=[O:18].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5][C:4]=2[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c2c1C(=O)O

Procedure:
To a suspension of 6-methyl-7-nitro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid, methyl ester (0.80 g, 2.87 mmol) in THF (50 mL) was added aqueous 1.0N NaOH (4.3 mL, 4.3 mmol), and the reaction mixture was refluxed for 23 hours. The product is precipitated upon acidification with conc. HCL and recrystallized from water to give 0.73 g (96%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.[Ag]=O>[CH3:12][O:11][C:1]([C:2]1[C:3](=[O:4])[CH:5]=[CH:6][C:7](=[O:8])[CH:9]=1)=[O:10]
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=[Ag]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(=O)C1=CC(=O)C=CC1=O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
A mixture of 0.2 g (0.00119 mol) of methyl gentisate (14), 0.2 g (0.0014 mol) of potassium carbonate and 0.6 g (0.0026 mol) of silver oxide in 10 mL of benzene (freshly distilled) was stirred at 50° C. (bath temperature) under argon for 10 min under dark. The reaction mixture was cooled to room temperature, filtered through Celite, rinsed with small amount of ether, concentrated on a rotary evaporator and then under vacuum to give 0.198 g (100% yield) of methoxycarbonyl-1,4-benzoquinone (15); 1H NMR (CDCl3) d 7.13 (s, 1H, C3 H), 6.84 (s, 2H, C5,6 Hs), 3.92 (s, 3H, OMe). The proton NMR spectrum indicates the material is about 100% pure and is used in the next step without purification.