Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:21]=[C:20](O)[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:21]=[C:12]([C:11]([O:10][CH3:9])=[O:23])[CH:13]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: OCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCCCCCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
13.02 g (95.3 mmol) of 6-chlorohexanol were added to a solution of 20.04 g (95.3 mmol) of 5-hydroxyisophthalic acid dimethyl ester and 47.4 g (180.5 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran. The colourless solution was cooled to 0° C. and then 79 ml (180.5 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise over a period of 2 hours and 45 minutes. The mixture was allowed to react for another 30 minutes at 0° C. and then for 22 hours at room temperature. The reaction mixture was concentrated by evaporation under vacuum. The residue was filtered through silica gel using dichloromethane:diethylether (85:15) as eluent. The filtrate was concentrated in vacuum and further purified by column chromatography on silica gel with hexane:ethyl acetate (9:1) to give 17.12 g (55%) of 5-[(6-chlorohexyl)oxy]isophthalic acid dimethyl ester as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]([NH2:15])=O)=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13]#[N:15])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(N)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C#N

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide with triphosgen/triethylamine in THF. mp 105-107° C., 1H NMR(CDCl3) d 6.90(s,2H), 6.26(brs,1H), 6.05(s,1H), 4.24(m,1H), 2.28(s,3H), 2.25(s,3H), 2.17(s,6H), 1.72(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3F)CC2)c(Oc2ccccc2)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34]C)=[O:33])[CH:27]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[ClH:21].[C:36]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[Cl:21])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 81.2 %

Procedure:
A solution of N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxyphenoxy)propylamine (65 mg, 0.11 mmol) in MeOH (5 mL), H2O (1 mL), and 2.5N NaOH (0.5 mL) was heated at 50° C. for 3 h. The reaction was cooled, diluted with H2O, acidified with 3N HCl to pH=4, and extracted with EtOAc. The extracts were dried and the solvent removed. The residue was dissolved in Et2O and treated with 4N HCl in dioxane. The precipatated solid was filtered, washed with Et2O, dried, and concentrated to yield the titled compound (27 mg, 42%). MS (ESI) 569 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:14]([NH:16][CH3:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:4]2[C:3]([C:1]#[N:2])=[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:6][C:5]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of 4-cyano-3-iodo-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (0.055 g, 0.14 mmol), 4-chlorophenylboronic acid (0.046 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.014 mmol) and sodium carbonate (0.046 g, 0.44 mmol) in 1,2-dimethoxyethane (0.71 mL) and water (0.37 mL) was allowed to stir at 80° C. overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give 3-(4-chlorophenyl)-4-cyano-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (69) (0.030 g, 57%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([C:36](=[O:38])[NH2:37])[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH2:29]([O:28][C:25]1[CH:26]=[C:27]2[C:22](=[C:23]([C:36]([NH2:37])=[O:38])[CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:7][CH3:6])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN(CC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1ccccc1
Reaction time: 8 h
Yield: 78 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(6-benzyloxy-8-carbamoyl-quinazolin-4-ylamino)-2-phenyl-ethyl]-methyl-carbamic acid tert-butyl ester (81 mg, 0.15 mmol) and THF, (3 mL). Then, 4 M HCl in dioxane, (3 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 50 mg, 0.12 mmol, 78% yield. LCMS (ESI) 428 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=1[NH2:26]>>[NH2:26][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[N:1]=2)[CH:24]=[CH:25][C:17]=1[O:16][CH3:15]
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (554 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 111 mg (10%). 1H NMR (CDCl3) δ 7.84(s, 1H), 7.72–7.38(m, 9H), 6.93(d, J=8.3 Hz, 1H), 3.96(s, 3H). MS 316 m/z (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH2:17][N:18]([CH2:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49](N1C=CN=C1)=[O:50]>CN(C=O)C>[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH:48][C:49]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]([CH2:17][C:12]2[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:9])[CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:25][C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:23]1)=[O:50]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCNCC2)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a warm (70° C.), stirred, solution of {3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.141 g, 0.30 mmol) and DIPEA (0.32 mL, 1.84 mmol) in DMF (3 mL) was added imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 157 mg (85%) of COMPOUND 275 as a white solid. 1H NMR (CDCl3) δ 1.28-1.39 (m, 2H), 1.58 (s, 6H), 1.65-1.71 (m, 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.56-2.65 (m, 3H), 3.36 (s, 2H), 3.68 (s, 2H), 4.10-4.14 (m, 2H), 6.68 (s, 2H), 6.83-6.85 (m, 2H), 7.07-7.10 (m, 2H), 7.17-7.21 (m, 2H), 7.81 (d, 1H, J=6.9 Hz), 8.09 (s, 1H), 8.50 (d, 1H, J=3.3 Hz); 13C NMR (CDCl3) δ 18.78, 19.21, 28.81, 31.76, 43.11, 45.08, 55.15, 55.65, 58.55, 122.21, 127.81, 129.21, 132.10, 132.30, 133.51, 134.67, 139.48, 143.61, 145.93, 147.15, 147.46, 149.05, 155.28, 156.16, 158.91; ES-MS m/z 572 (M+1) & 574 (M+1). Anal. Calcd. For C32H38N7OCl.0.4CH2Cl2: C, 64.20; H, 6.45; N, 16.18; Cl, 10.53. Found: C, 63.83; H, 6.43; N, 15.88; Cl, 10.92.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[N:7]=1.[CH2:15]([NH:22][CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]([N:22]([CH2:13][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCN(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCN(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of 3-chloro-5-[methyl(propyl)amino]pyrazine-2-carbaldehyde (427 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (579 mg, 74%).
Reaction SMILES: [C:1]1([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[I:32]I.Cl>C1COCC1.CCCCCC>[I:32][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[C:1]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)oc1cccc(-c3cccc4oc5ccccc5c34)c12
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1ccc(-c2cccc3oc4ccccc4c23)c2c1oc1ccccc12
Temperature: -80 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
Into a 200-mL three-neck flask was put 3.0 g (9.0 mmol) of 4,4′-bidibenzofuran, and the air in the flask was replaced with nitrogen. To this flask was added 45 mL of THF to dissolve 4,4′-bidibenzofuran, and the mixture was cooled down to −80° C. Then, 5.6 mL (9.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, the mixture solution was stirred for 2 hours while its temperature was increased to room temperature. After the stirring, this solution was cooled down to −80° C. Then, a solution in which 2.5 g (10 mmol) of iodine had been dissolved in 20 mL of THF was dripped into this solution with a dripping funnel, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After the stirring, approximately 10 mL of dilute hydrochloric acid (1.0 mol/L) was added to this solution, and the mixture was stirred for 2 hours. After the stirring, an aqueous layer of the mixture was extracted with ethyl acetate, and the extracted solution and an organic layer of the mixture were combined and washed with a saturated solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried with magnesium sulfate and gravity-filtered. The obtained filtrate was concentrated to give a light brown solid. The obtained solid was purified by HPLC and washed with toluene to give 2.2 g of white powder, which was an objective substance, in 53% yield. Synthesis Scheme (c-2) of Step 2 is shown below.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[F-].[K+].Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].O>CN(C=O)C>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:5]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: CN1N=C(c2ccccc2)CC1=O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccccc3)nn1C)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
To a solution of 2,4-dihydro-2-methyl-5-phenyl-3H-pyrazol-3-one (0.63 g; 3.62 mmol) in DMF (20 ml) was added 230 mg (3.96 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.29 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then poured into water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.4 g (27%) of 4-isopropyl-6-methoxy-2-(1-methyl-3-phenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =CH3 ; R2 =Ph; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 126°-128° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:46]=[CH:45][C:38]([O:39][CH2:40][C:41](=[N:43]O)[NH2:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]2[N:43]=[C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[O:11][N:42]=2)=[CH:45][CH:46]=1
Reactant: NC(COc1ccc(Cl)cc1)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. 2-(4-chlorophenoxy)-N′-hydroxyethanimidamide (Patent US 97-815671 970313) (197 mg, 0.98 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (220 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 4-methyl-3-nitroanisole (16.53 mL; 119.64 mmol; 1 eq), in CCl4 (500 mL) is added N-bromosuccinimide (21.29 g; 119.64 mmol; 1 eq) and azoisobutyronitrile (392.9 mg; 2.39 mmol; 0.02 eq). The mixture is heated at 85° C. for 20 h. The solution is cooled down to room temperature and the precipitate of succinimide is removed by filtration. The filtrate is concentrated to afford a yellow oil. The oil crystallizes after one night at −25° C. It is redissolved in EtOAc (15 mL) and petroleum ether is added. After 2 h at −25° C., the compound recrystallizes. After filtration and washing with petroleum ether, the solid is dried under vacuum to afford 17.4 g (59%) of the title compound as a liquid. 1H NMR (DMSO-d6) δ 7.68 (d, J=8 Hz, 1H), 7.56 (d, J=3 Hz, 1H), 7.33 (dd, J=8.0, 3.0 Hz, 1H), 4.89 (s, 2H), 3.87 (s, 3H). HPLC (max plot) 99%; Rt 4.09 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml) in 1 ml of DMSO was heated at reflux for 15 hours. The mixture was quenched with sat. ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 445.6 mg of yellow solid. The solid was purified through silica gel column chromatography using 1:1 ratio of chloroform:hexane as eluent to give (289 mg, 50%)of the title compound as white crystals, mp 98-102° C.; 1H NMR (CDCl3) δ8.04 (d, 1H), 6.85 (s, 2H), 6.06 (s, 1H), 3.85 (s, 3H), 3.32 (m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.62 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([NH2:33])=[N:11][C:12]2([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=2)[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:8]([F:34])[CH:7]=1>C(Cl)Cl>[NH2:33][C:10]1[C:9]2[C:13](=[CH:14][C:6]([Cl:5])=[CH:7][C:8]=2[F:34])[C:12]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1
Reactant: COc1cccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cc(Cl)cc32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=NC(c2cccc(O)c2)(c2ccnc(C(F)(F)F)c2)c2cc(Cl)cc(F)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.7 %

Procedure:
Boron tribromide (0.472 mL, 4.99 mmol) was added to a solution of 6-chloro-4-fluoro-1-(3-methoxyphenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (870 mg, 2.00 mmol) in DCM (10 mL) at 0° C. under an argon atmosphere. The cooling bath was removed and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° C. and subsequently ice was added. The pH was adjusted to ˜8 with 4 M aq NaOH. The DCM was removed in vacuo and the resulting residue was extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to afford 200 mg (24%) of the title compound.
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](Cl)=[O:16]>C1COCC1.C(Cl)Cl>[C@H:1]1([N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: N[C@@H]1CCCc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Yield: 73.2 %

Procedure:
To a solution of (R)-1,2,3,4-tetrahydro-1-naphthylamine (6.0 g) in THF (150 mL) at 0° C. was added TEA (18.5 mL) and phthaloyl chloride (8.2 g), and the resultant mixture was stirred at room temperature overnight and 70° C. for 3 h. The mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over MgSO4, and concentrated in vacuo. The resulting crude was chromatographed on silica gel (EtOAc/hexane, 5/95 to 30/70) to afford 8.2 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]4=[O:38])=[CH:24][C:23]=3[F:39])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:39][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:26]=[CH:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:18]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCN(C(=O)OC(C)(C)C)CC4)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCNCC4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 200 mg of 4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-yl)ethyl]piperazine-1-carboxylic acid tert butyl ester (0.36 mmol) in 2 ml dichloromethane and 2 ml trifluoracetic acid was stirred for 10 min. The solvents were evaporated, the residue was digested in ether and the solid filtered. The solid was dissolved in water and neutralized with a saturated solution of sodium bicarbonate. The water was evaporated and the product dried as a mixture with the salts.