Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][OH:36])[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16].[F:37][C:38]1[CH:43]=[C:42](O)[CH:41]=[CH:40][C:39]=1[CH2:45][C:46]([O:48][CH3:49])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][O:36][C:42]3[CH:41]=[CH:40][C:39]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[C:38]([F:37])[CH:43]=3)[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16]
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIAD (0.955 ml, 4.91 mmol) was added to a stirred mixture of 2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (1 g, 3.27 mmol), methyl (2-fluoro-4-hydroxyphenyl)acetate (0.724 g, 3.93 mmol) and triphenylphosphine (1.288 g, 4.91 mmol) in toluene (10 ml). The mixture was stirred at RT for 5 hrs. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 472 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[C:12](=[O:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[CH:1]1([C:6]2[C:15]([C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=3)=[O:27])=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[CH:12]([OH:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)c(F)c2)C1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.1 g (4 mmol) of 2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one were dissolved in 20 ml of tetrahydrofumn and, at 0° C., added dropwise to a solution of 0.2 g (1.2 mmol) of 1R,2S-aminoindanol and 2.7 ml (16 mmol) of boranediethylaniline complex in 2 ml of THF. The mixture is stirred at RT overnight. After about 20 hours, the reaction was quenched using 2.4 ml of 1,2-ethanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 60 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of ethanolamine, to the title compound (150 mg, 60%) which was obtained as a white solid. MS: m/e=414.1 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([F:20])[C:14]([O:18][CH3:19])=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=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>[F:17][C:15]1[CH:16]=[C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[C:13]([F:20])[C:14]=1[O:18][CH3:19]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccncc1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)cc(-c2ccncc2)cc1F

Procedure:
In a microwave vial, a mixture of pyridin-4-ylboronic acid (160 mg, 1.3 mmol), 5-bromo-1,3-difluoro-2-methoxybenzene A5a (223 mg, 1 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) is dissolved/suspended in dimethylformamide (3 mL). To the mixture are added cesium carbonate (978 mg, 3 mmol) and water (3 mL). The vial is sealed and subjected to microwave irradiation (150° C., 15 min). The mixture is filtered through a syringe filter and washed with ethyl acetate. Water is added and the mixture extracted with ethyl acetate (4×). The organic phase is dried over sodium sulfate and concentrated. The crude material is purified by flash chromatography (ethyl acetate/hexanes gradient) to afford 4-(3,5-difluoro-4-methoxyphenyl)pyridine A5b as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=6 Hz, 2H), 7.44 (d, J=6 Hz, 2H), 7.22 (d, J=9.6 Hz, 2H), 4.09 (s, 3H); MS calcd. for C12H10F2NO ([M+H]+): 222.1, found: 222.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][Br:12]
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1Br
Reaction time: 23 h
Yield: 90.4 %

Procedure:
A stirred solution of 1-bromo-2-methyl-6-nitrobenzene (16.2 g, 0.075 mole) in 200 ml of carbon tetrachloride was irradiated and heated at reflux with a 250 watt brooder lamp. N-bromosuccinimide (13.5 g, 0.075 mole) was added to the refluxing reaction mixture, and the mixture was stirred for approximately 23 hours. The mixture was cooled, filtered, and washed with two 200 ml portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper. The filtrate was evaporated under reduced pressure to give 2-bromo-1-bromomethyl-3-nitrobenzene (20 g).
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:7][CH:6]=1.[C:22]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:29]([O:28][C:22](=[O:27])[CH2:23][CH:24]([N:13]1[CH2:14][CH2:15][O:16][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:2]=3[CH3:1])=[CH:10][CH:9]=2)[CH2:12]1)[CH3:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1cccc(Oc2ccc(C3CNCCO3)cc2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cccc(Oc2ccc(C3CN(C(C)CC(=O)OC(C)(C)C)CCO3)cc2)c1C

Procedure:
A mixture of 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine (1.00 g; 3.13 mmol), tert-butyl acetoacetate (2.07 mL; 12.5 mmol), sodium triacetoxyborohydride (1.86 g; 8.75 mmol), and a drop of acetic acid, in 1,2-dichloroethane (20 mL) was stirred overnight, at RT. The resulting mixture was treated with 5% aqueous NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography (SiO2, Et2O/hexanes 1:3) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholin-4-yl}-butyric acid tert-butyl ester (1.17 g
Reaction SMILES: F[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][NH:41][CH3:42]>CN(C=O)C.C(OCC)(=O)C>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][N:41]([CH3:42])[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CNCCN(C)C
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)cc2C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(N(C)CCN(C)C)c(C(F)(F)F)c3)cc2C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4-fluoro-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide (0.10 g, 0.22 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) in DMF (2 mL) was heated to 100 deg. C. for 48 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 6 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 48 h. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid. Purification by reverse-phase HPLC using acetonitrile/water/TFA as eluent gave 4-((2-(dimethylamino)ethyl)(methyl)amino)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide as a white solid. MS m/z=580 [M+1]+. Calc'd for C30H32F3N7O2: 579.62.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=2)[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])[CH:24]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl(2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (25.0 g, 49.4 mmol) in methanol (200 ml) was added 2N aqueous sodium hydroxide solution (49.0 ml, 98.0 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (21 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1Oc1cccc(NCc2cccnc2)c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccccc2OC)c1

Procedure:
Using the method of Example 342 using N-(3-(2-methoxyphenoxy)phenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 98:2 to 96:4 DCM/MeOH gave the title compound. Anal Calcd for C21H22N2O4S: C, 63.30; H, 5.56; N, 7.03. Found: C, 63.16; H, 5.51; N, 6.64. MS found 398.9 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:20][CH3:21])[CH2:9][C@H:10]([CH2:15][CH2:16][CH2:17][CH:18]=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][C:24]=1[CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:18][CH2:17][CH2:16][CH2:15][C@@H:10]([CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:20][CH3:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:25][C:24]=1[CH3:31]
Reactant: COC(=O)[C@@H](CCCC=O)C[C@@H](OC)c1ccc(F)cc1
Reactant: Cc1cc(CN)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)[C@@H](CCCCNCc1ccc(F)c(C)c1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)-6-oxohexanoate (40 mg, 0.13 mmol) in 2 mL DCE was added 4-Fluoro-3-methyl-benzylamine (21 mg, 0.15 mmol) followed by NaBH(OAc)3 (39.9 mg, 1.4 mmol) and AcOH (9.3 mg, 9 μL, 0.15 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 10 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[N:6]=[C:7]([NH2:19])[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=1.[S:20]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21]1.CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[NH2:19][C:7]1[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=[C:5]([C:4]#[C:3][CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)(=[O:27])=[O:26])[N:6]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: NCC#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C#CCNS(=O)(=O)c2ccsc2)cn2nc(-c3ccco3)nc12
Reaction time: 8 h

Procedure:
To a solution of 6-(3-amino-prop-1-ynyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (0.1 mmol, see Example 26 below) in THF (1 mL) was added thiophene-3-sulfonyl chloride (23.7 mg, 0.13 mmol), a catalytic quantity of DMAP and Hünig's base (52 uL, 0.3 mmol) successively. The reaction was stirred overnight and diluted with water. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was then evaporated. The residue was purified using preparative HPLC (C18, H2O:MeCN gradient) to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ8.16 (1H), 8.09 (1H), 7.86 (1H), 7.68 (1H), 7.54 (1H), 7.31 (1H), 7.07(1H), 6.65 (1H), 4.23 (2H), 3.53 (d, J=7 Hz, 2H). MS: m/z 401 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:11]=1[O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][C:14]=1[Cl:24]>N1C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([S:20]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)(=[O:22])=[O:21])[CH:17]=[C:18]([Cl:19])[C:13]=1[O:12][C:11]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:10]=1[Cl:9]
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Nc3cccc(Cl)c3)cc2Cl)c(Cl)c1

Procedure:
A solution of 3-chloroaniline (38 μL, 0.35 mmol) and 4-(2-chloro-4-nitrophenoxy)-3,5-dichloro-benzenesulfonyl chloride (100 mg, 0.24 mmol), was stirred in pyridine (2 mL) at room temperature for three days. The reaction mixture was concentrated by rotary evaporator and dissolved in dichloromethane. The solution was washed successively with 1N HCl, and NaHCO3 (sat.)/brine. The organic fraction was dried over MgSO4, filtered, and concentrated. The compound was purified by radial silica gel chromatography (1:20 to 1:1 ethyl acetate:hexanes) to afford the product which was subsequently freeze-dried from H2O/acetonitrile to produce a white solid which was 97% pure by LCMS analysis (67 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13](I)[C:14]([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: CC(C)(C)CI
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c([N+](=O)[O-])ccc(OCC(C)(C)C)c1Cl
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Reaction of 2-chloro-3-methyl-4-nitrophenol (2.26 g) with neopentyl iodide (4.78 g) in 1-methyl 2-pyrrolidinone (30 ml) in the presence of potassium carbonate (3.34 g) was conducted at 140° C. overnight. The crude product was partitioned between 2M HCl and ethyl acetate, and the organic phase was washed with water, dried (MgSO4) and evaporated to dryness. The residue was chromatographed (SiO2 ; hexane/ether) to give 2-chloro-3-neopentyloxy-6-nitrotoluene as a yellow solid (2.44 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:18]O>C(OCC)C>[CH3:18][O:4][C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)[C@H](O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (R)-2-hydroxy-3-phenylpropionic acid (1.5 g, 12.9 mol) in methanol (18 mL) at 0° C. was added concentrated sulfuric acid (0.2 mL). The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature for 24 h. Concentration in vacuo gave a residue which was diluted with diethyl ether (200 mL) and washed with water, saturated sodium bicarbonate and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo giving a white solid 1.62 g (85%), which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[C:10]([F:17])[C:9]=1[O:18][CH3:19].C[N:21](C=O)C.N1C(Cl)=NC(Cl)=NC=1Cl>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]#[N:21])=[C:10]([F:17])[C:9]=1[O:18][CH3:19]
Reactant: COc1c(Br)ccc(C(=O)O)c1F
Reactant: CN(C)C=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(Br)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (20 mL) was added dropwise at 0° C. to a suspension of 4-bromo-2-fluoro-3-methoxybenzoic acid (8.30 g, 33.3 mmol) in 100 mL of DCM with 0.5 mL of DMF. The mixture was stirred at 25° C. for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue dissolved in 60 mL of anhydrous acetonitrile was added to 600 mL of aqueous NH3.H2O at 0° C. and stirred for 2 hours then extracted with EtOAc twice. The combined EtOAc layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue (6.9 g) was dissolved in 60 mL of DMF and cooled to 0° C. with ice/water bath. Cyanuric chloride (7.70 g, 41.7 mmol) was added and stirred for 2 hours at 0° C. before poured to ice/water. The solid was collected by filtration and was washed with water, dissolved in DCM, dried over anhydrous Na2SO4 and concentrated to afford 4-bromo-2-fluoro-3-methoxybenzonitrile.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:12][CH2:13][C:14]([CH3:16])([OH:17])[CH3:15])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixed solution of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (4.24 g) synthesized in accordance with the method described in [WO 2009/067613 pamphlet, Example 308], 4-bromo-3,5-dimethylphenol (3.0 g), and potassium carbonate (3.09 g) in N,N-dimethylformamide (15 mL) was stirred at 80° C. for 3 hours. To the reaction mixture, ethyl acetate (200 mL) and water (100 mL) were added and the mixture was extracted with ethyl acetate. The organic phase was successively washed with water (50 mL) and brine (50 mL) and then dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=80:20 to 70:30). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (3.9 g).
Reaction SMILES: [Cl-].C[N+](C)=CS(Cl)(=O)=O.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=1.[CH2:20]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=O)=[CH:26][CH:25]=1)[CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[O:17][C:28]([C:27]3[CH:32]=[CH:33][C:24]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)=[N:30][N:31]=2)=[CH:13][N:12]=1
Reactant: CC(C)Cc1ccc(C(=O)NN)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: C[N+](C)=CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(Cl)nc3)o2)cc1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
N,N-Dimethyl(chlorosulphonyl)methaniminium chloride (1.57 g, 0.01 mol) was added to a solution of 6-chloronicotinic acid (1.58 g, 0.01 mol) and dichloromethane (20 mL) at 0° C. and stirred for 10 minutes. 4-isobutylbenzohydrazide (5.29 g, 0.03 mol) was added to the reaction mixture, followed by the dropwise addition of a solution of triethylamine (12.3 mL, 0.09 mol) in dichloromethane (30 mL). The resulting mixture was stirred at room temperature for 12 hours, quenched with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was recrystallized from methanol:acetone (10:1) to give the title compound (2.57 g, 82% yield) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[CH2:21][C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)=[C:15]([CH3:33])[CH:14]=2)[CH2:9]1)(C)(C)C.[ClH:35]>CO.O1CCOCC1>[ClH:35].[ClH:35].[NH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[CH2:21][C:22]34[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]3)[CH2:29]4)=[C:15]([CH3:33])[CH:14]=2)[CH2:9]1
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(N2CCC(N)C2)ccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
{1-[4-(2-(tricyclo[3.3.1.13,7]dec-1-yl)acetylamino)-3-methylphenyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (0.20 g, Example 35c) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to 2/3 original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.15 g)