Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.O.Cl>C(O)C>[NH2:1][C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1-n1cccn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccnc1-n1cccn1
Yield: 63.1 %

Procedure:
To a suspension of 3-nitro-2-(pyrazol-1-yl)pyridine (670 mg, 3.72 mmol) in ethanol (10 mL) was added a 1M solution of SnCl2.H2O in 6N aqueous HCl (14.5 mL, 14.5 mmol). The mixture was heated at reflux for 10 min, and the solvent was removed with a rotary evaporator. 10% aqueous sodium hydroxide solution was added until most of the material dissolved, and the mixture was extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to afford 376 mg (68%) of 3-amino-2-(pyrazol-1-yl)pyridine as a brown oil. 1H NMR (CDCl3) δ5.62 (br s, 2), 6.46 (m, 1), 7.05 (dd, 1, J=5, 8), 7.24 (dd, 1, J=2, 8), 7.74 (m, 1), 7.85 (dd, 1, J=2, 5), 8.54 (d, 1, J=3).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 1 and 2-hydroxy-4-n-octyloxybenzophenone, the title compound is obtained as an off-white crystalline solid melting at 128°-130° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:10]([CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH3:9])(=[O:7])=[O:6])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CNS(=O)(=O)CCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)CCCN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 3-chloro-N-methylpropane-1-sulfonamide (29 mmol), NaN3 (29 mmol) in DMF (50 ml) was stirred at 100° C. for 2 h. The mixture was poured into 40 ml of brine. The mixture was extracted with ether (3×30 ml). The organic layers were combined and washed with 20 ml of brine. The organic layer was dried with Na2SO4, filtered and the filtrate was evaporated. Yield: 4.2 g (90% purity, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12](O)[CH3:13].P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:16][CH:12]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[Cl:1])[CH3:13]
Reactant: CC(O)c1cccc(C(F)(F)F)c1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 194.8 %

Procedure:
To an ice cooled solution of (±)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanol (1.1 g, 4.9 mmol) in DCM (16 mL) was added phosphorus tribromide (0.23 mL, 2.5 mmol) dropwise. The reaction was allowed to warm to rt and stirred for 3 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give the desired product as a yellow oil (1.4 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.93-7.81 (m, 1H), 7.69-7.64 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 5.73 (q, J=7.0 Hz, 1H), 2.05 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=[O:4])=[O:3].N.C1COCC1>CO.[Ni]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][NH2:18])=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CN)cc1

Procedure:
A solution of 1.0 g (3.9 mmol) of 2′-methanesulfonylbiphenyl-4-carbonitrile in a mixture of 10 ml of methanol saturated with ammonia and 3 ml of THF is treated with 400 mg of Raney nickel and hydrogenated at room temperature and normal pressure. The catalyst is filtered off and the filtrate is evaporated. A colourless solid is obtained; FAB 262
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O.CC(C)([O-])C.[K+].O>C1COCC1>[CH:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]12
Reactant: CCOC(=O)Cc1ccccc1NC(=O)CCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c2n(c3ccccc13)CCCC2
Yield: 19 %

Procedure:
A solution of ethyl 2-(5-chlorovalerylamino)phenylacetate (8.10 g, 0.027 mole) in dry THF (50 ml) was added to a stirred suspension of potassium t-butoxide (7.62 g, 0.068 mole) in dry THF (200 ml) at room temperature under nitrogen. After 1 h the purple solution produced was treated with water (10 ml) and concentrated in vacuo. The residue was shaken with ethyl acetate (200 ml) and sat.ammonium chloride solution (150 ml), then the organic layer separated, dried (Na2SO4) and concentrated in vacuo to afford an orange oil. This was chromatographed on silica gel eluting with ether to afford the title compound as a yellow solid (1.25 g, 20%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=O)[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:56]=[CH:55][CH:54]=[CH:53][N:52]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([C:31]4([C:58](=[N:4][O:2][CH3:3])[CH3:59])[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]5[CH2:44][CH2:43][N:42]([C:45]6[CH:50]=[CH:49][C:48]([C:51]7[N:52]=[CH:53][CH:54]=[CH:55][N:56]=7)=[CH:47][N:46]=6)[CH2:41][CH:40]5[CH3:57])=[O:38])[CH2:32]4)=[O:30])[CH:26]=3)[NH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cn3)CC2C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Added methoxylamine hydrochloride (100 mg, 1.197 mmol) and triethylamine (0.2 ml, 1.43 mmol) to a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (11N) (100 mg, 0.15 mmol) in MeOH (5 ml), then stirred for 3 hours at room temperature. The solvent was evaporated and the residue was extracted with MeCl2, washed with water, dried over Na2SO4, filtered and solvent was evaporated yielding a solid which chromatographed on silica gel eluting with 7% v/v MeOH/MeCl2 containing 2% NH4OH yielding 2 isomers:
Reaction SMILES: [OH2:1].[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15](=[O:16])[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:25])([CH3:24])[CH2:12]2)=[CH:7][CH:6]=1>C1COCC1.CO.O>[C:20]([O:19][C:17]([NH:14][C:13]([CH3:25])([CH3:24])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[C:15]([OH:1])=[O:16])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)cc2)CC1(C)C
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Lithium hydroxide hydrate (6.44 mL, 232 mmol) was added to a stirred solution of tert-butyl 4-(4-chlorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (7.5 g, 23.2 mmol) in THF/MeOH/H2O (30 mL/30 mL/30 mL) at room temperature. The mixture was stirred at room temperature overnight and concentrated in vacuo. The mixture was taken up into water (200 mL), washed with EtOAc (100 mL), acidified with concentrated HCl and extracted into EtOAc (2×200 mL). The mixture was dried over Na2SO4 and concentrated in vacuo. Residual HCl was removed by evaporating from toluene to give 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (5.0 g, 63.2% yield) as a solid. LCMS (APCI+) [M-Boc+H]+ 242.0; Rt: 2.8 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:9]2=[O:27])=[C:4]([OH:28])[CH:3]=1.[C:29]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:29][O:28][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:9]3=[O:27]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2ccc(Br)cc2O)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc(Br)ccc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(4-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one was obtained (78%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.16-7.03 (m, 3H), 6.69 (d, J=7.9 Hz, 1H), 6.93 (dd, J=8.2, 1.8 Hz, 1H), 6.77-6.71 (m, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.42-6.37 (m, 1H), 5.06 (d, J=16.1 Hz, 1H), 4.97 (d, J=9.4 Hz, 1H), 4.86 (d, J=16.1 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.5, 161.5, 151.8, 141.4, 131.6, 129.3, 128.0, 124.5 (d), 124.0, 114.2, 112.6 (d), 109.2 (d), 80.1, 57.5, 36.9; MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).
Reaction SMILES: [OH-].[K+].CC1C=C(C=CC=1)C([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13][CH2:12]1)=O>C(O)C.O>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][OH:9])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cc1cccc(C(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)N2CCC(CO)CC2)c1

Procedure:
A solution of 12.76 g (0.23 mol) of potassium hydroxide in 75 ml of ethanol and 75 ml of water is added to a solution of 80 g (0.23 mol) of [1-(3-methylbenzoyl)-4-piperidyl]methyl 3-methylbenzoate in 400 ml of ethanol. The mixture is stirred at 20° C. for 3h, the solvent evaporated off under reduced pressure and the aqueous phase extracted with ethyl acetate. The organic phase is washed with water and then with saturated aqueous sodium chloride solution, and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure and 53 g of alcohol are obtained, this being used without further treatment in the following stage.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:12][O:13]S(OC)(=O)=O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:3]([CH2:12][OH:13])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)c[n+]([O-])cc1C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)cnc(CO)c1C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
3.5-Dimethyl-4-methoxypyridine-N-oxide (61.2 g) obtained in Example 2 was dissolved in CH3OH (458 ml). Dimethylsulfate (38 ml 0.4 moles) was added dropwise during 15 minutes and pH adjusted to 5.0 using 10M NaOH. The mixture was stirred for 15 minutes and thereafter refluxed for 1 hour. An additional amount of dimethylsulfate (3.8 ml, 0.04 moles) was added dropwise and the mixture was refluxed for 1.5 hours. Stirring was continued overnight at room temperature. Thereafter the mixture was heated to reflux and (NH4)2S2O8 (91.2 g, 0.4 moles) dissolved in water (169 ml) was added during 1.75 hours, followed by refluxing for 1.5 hours and stirring at room temperature overnight. Thereafter CH3OH (452 ml) was added. Precipitated salts were filtered off and discarded. After evaporation of CH3OH, the remaining water phase (pH 0.6) was adjusted to pH 10.0 using 10M NaOH (145 ml). The water phase was extracted three times with CH2Cl2. The combined CH2Cl2 phases were dried over Na2SO4, evaporated and dried, yielding 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine (44.2 g). The identity of the product was confirmed with 1H and 13C NMR and the purity checked with gas chromatography.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccn1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 77.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (165 mg, 0.56 mmol, 1.0 eq), L-isoleucine pyridin-2-ylmethylamide (246 mg, 1.11 mmol) and dichloromethane (2 mL), was treated with triethylamine (475 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (721 uL, 2.0 eq), to provide 214 mg (77%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-2-ylmethylamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([N+:10]([O-])=O)[CH:7]=[CH:8][CH:9]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH2:10]
Reactant: COCc1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: COCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
EX-514B) The 3-(methoxymethyl)nitrobenzene (4.18 g, 25 mmol) from EX-514A was dissolved in 160 mL of acetic acid. Zinc dust (5 g, 76.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no 3-(methoxymethyl)nitrobenzene starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with water, then dried over MgSO4, and concentrated in vacuo to give 3.4 g (99%) of the desired 3-(methoxymethyl)aniline as a brown oil. The crude product was used without further purification. HRMS calcd. for C8H12NO: 138.0919 [M+H]+, found: 138.0929. 1H NMR (CDCl3) δ3.4 (s, 3H), 3.7 (s, 2H), 4.4 (s, 2H), 6.6 (d, 1H), 6.7 (m, 2H), 7.2 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)[S:9]1(=[O:35])=[O:34].[ClH:36]>CCOCC.CO.CCOCC>[ClH:36].[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[S:9]1(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Reaction time: 16 h
Yield: 87 %

Procedure:
tert-butyl (1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-yl)carbamate (0.40 g, 0.80 mmol) was dissolved in ether:methanol (9:1) and 2 mL of 2N HCl in ether added. The solution was allowed to stand for 16 hr whereupon a colorless solid had formed. The solid was removed by filtration and washed with ether to afford 0.33 g (87%) 1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-amine dihydrochloride. HPLC purity 98.7% at 210-370 nm, 5.5 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff.Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C20H25FN4O2S+H+, 405.17550; found (ESI, [M+H]+Obs'd), 405.1768.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH3:32])[C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[C:25]([CH3:32])=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-cyano-3-methylpicolinic acid [S. Badiger et al. WO2011009943 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=436.5 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:23][CH:22]([NH2:24])[CH2:21]2)[CH2:16]1.C(N(CC)CC)C>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:24][CH:22]1[CH2:23][N:20]([CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[CH2:21]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CN(C2CCOC2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC2CN(C3CCOC3)C2)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
4-Fluoro-3-nitrobenzenesulfonamide (0.084 g), 1-(tetrahydrofuran-3-yl)azetidin-3-amine (0.090 g) and triethylamine (0.266 ml) in tetrahydrofuran (3 mL) was heated to 60° C. After stirring for 4 hours, the reaction was cooled, the tetrahydrofuran was removed and the residue was partitioned between dichloromethane (200 mL) and water (20 mL). The organic layer was separated, washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].[CH3:19][O-:20].[Na+]>CN(C=O)C.[Cu]Br>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:18])=[C:2]([O:20][CH3:19])[C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: C[O-]
Reactant: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Agent: [Cu]Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A solution of 4-bromo-2-(4-Hydroxyphenyl)-benzofuran-5-ol 130 (0.100 g, 0.32 mmol) and copper (I) bromide (0.047 g, 0.32 mmol) in DMF (4 mL) was treated with sodium methoxide (0.73 mL, 3.2 mmol, 25% by weight in MeOH) and heated at 150° C. for three hours under a nitrogen atmosphere. The reaction was quenched at room temperature with 1 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed once with a saturated sodium bicarbonate solution, then dried over magnesium sulfate and filtered. Then the material was purified by column chromatography using 30% ethyl acetate in hexane as the eluent to yield 132 (0.030 g, 36.6%) as a brown solid: Mp. 165-168° C.; 1H NMR (DMSO-d6) δ 7.72 (d, 2 H, J=8.6 Hz), 7.23 (s, 1 H), 7.1 (d, 1 H, J=8.7 Hz), 6.86 (d, 2 H, J=8.6 Hz), 6.76 (d, 1 H, J=8.6 Hz), 3.94 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:47](=[O:48])[N:46]([CH3:50])[CH3:45])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (36 mg, 0.26 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 145 as a white solid (41 mg, 84%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.81 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=12.0 Hz), 2.73-3.05 (m, 9H), 3.23-3.28 (m, 1H), 3.51-5.56 (m, 1H), 3.75 (s, 2H), 3.87-3.93 (m, 1H), 6.50 (d, 2H, J=7.8 Hz), 6.86 (d, 2H, J=8.1 Hz), 6.93-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42-8.44 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.53, 29.34, 30.75, 31.32, 36.75, 36.87, 37.04, 38.99, 40.24, 43.97, 48.81, 52.57, 57.43, 60.97, 112.84, 114.79, 119.36, 122.74, 127.68, 128.77, 129.57, 130.45, 130.83, 131.40, 134.47, 139.04, 142.64, 143.47, 146.18, 155.88, 162.90, 170.23. ES-MS m/z 582 (M+H). Anal. Calcd. for C35H43N5O3.1.0H2O: C, 70.09; H, 7.56; N, 11.68. Found. C, 70.35; H, 7.56; N, 11.95.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH:16][S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)cc1
Temperature: -80 °C
Yield: 75.9 %

Procedure:
To a suspension of N-(2,6-diisopropyl-4-nitro-phenyl)-4-methyl-benzenesulfonamide (3.72 g) in ethanol (50 mL) was added stannous(II) chloride dihydrate (11.2 g) and the mixture was heated to −80° C. for 1.5 hour. It was then poured onto ice (300 mL), made strongly basic with solid sodium hydroxide (20 g) and diluted with ethyl acetate (100 mL). The suspension was filtered and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 2.60 g (76%) of the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): 0.95 (d, 12H), 2.40 (s, 3H), 3.02 (m, 2H), 3.68 (b, 2H), 5.74 (s, 1H), 6.39 (s, 2H), 7.23 (d, 2H), 7.60 (d, 2H).