Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.C([Li])CCC.CON(C)[C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:19]([C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])[CH:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CON(C)C(=O)c1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(C#Cc1cc(Cl)cc(Cl)c1)c1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of the 1,3-dichloro-5-ethynylbenzene (200 mg, 1.16 mmol) in anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (800 μL, 1.28 mmol). After 5 minutes a solution of the intermediate from step A (380 mg, 1.75 mmol) in THF (3 mL) was added. The reaction was gradually warmed to room temperature over 30 minutes and quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 15% ethyl acetate-hexanes to afford the product as a light yellow solid. 1H NMR (CDCl3, 500 MHz): 9.63 (s, J=2.1 Hz, 1H), 8.96 (d, J=1.6 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.94 (t, J=8.0 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.64 (d, J=1.8 Hz, 2H), 7.55 (t, J=2.0 Hz, 1H). LC-MS: 3.99 min; (M+H)=326.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]([CH2:60][CH2:61][CH2:62]O)[CH3:59]>CN(C=O)C>[CH3:57][N:58]([CH3:59])[CH2:60][CH2:61][CH2:62][O:31][C:30]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:11]=1[CH3:29])=[O:32]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCCN(C)C)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of Example 9 (42 mg, 0.095 mmol) in DMF (1 mL), was added diiosopropylethylamine (33 μL, 0.19 mmol) followed by HATU (72 mg, 0.19 mmol). After 1 hour, N, N-dimethylpropanolamine (67 μL, 0.57 mmol) was added, and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to RT then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-6% (2 M NH3 in MeOH) in DCM to give the title compound as a white solid (15 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) in pyridine (2 ml) was added a solution of ethyl chloroformate (68.8 mg) in dichloromethane (0.5 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was diluted with dichloromethane. The mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-ethoxycarbonylhydrazino)quinoline (115 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:18]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:21](=[O:23])[CH3:22])[C:7]3[C:16]([S:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1cc([N+](=O)[O-])ccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a 3 necked 500 ml round bottom flask fitted with a thermometer and a condenser was added 3,7-dinitro-10H-phenothiazine (MW 289.27 g/mol, 29.00 g, 100 mmol), dimethylformamide (58 ml), acetic anhydride (MW 102.09 g/mol, 102.09 g, 1000 mmol) and triethylamine (MW 101.19 g/mol, 40.88 g, 401 mmol). The mixture was heated to 105° C. and stirred at this temperature for 3 hours. The mixture was cooled to ambient temperature (21° C.) before being cooled to 5° C. whereby it was stirred for 1 hour. The product was isolated by filtration and washed with methanol (3×30 ml) to give a light yellow crystalline solid, which was dried at 50° C. for 15 hours (MW 331.31 g/mol, 26.94 g, 81%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2cc(F)ccc2F)n1
Yield: 80 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2,5-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,5-difluorophenyl)-5-fluoropicolinic acid in 80% yield. LC/MS=254.1 (M+H), Rt=0.74 min.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:28][CH:17]2[C:18]3[CH:19]=[C:20]([O:26][CH3:27])[CH:21]=[CH:22][C:23]=3[C:24](=O)[CH:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:7]([N:14]1[CH2:15][CH:16]2[C:24](=[CH2:1])[C:23]3[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[CH:19][C:18]=3[CH:17]2[CH2:28]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc2c(c1)C1CN(Cc3ccccc3)CC1C2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1c2ccc(OC)cc2C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 8.1 g (82%—two steps) of the subtitle compound. MS calculated for C20H21NO+H: 292, observed: 292.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([C:23]2[S:24][C:25]([CH2:29][O:30][CH3:31])=[CH:26][C:27]=2Br)=[N:21][OH:22])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>COCCO.[Cu](I)I>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:23]3[S:24][C:25]([CH2:29][O:30][CH3:31])=[CH:26][C:27]=3[O:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COCc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCO
Product: COCc1cc2onc(C3CCN(C(=O)OC(C)(C)C)CC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add cesium carbonate (1.13 g, 3.46 mmol, 1.50 equivalents) and copper iodide (44 mg, 0.23 mmol, 0.10 equivalents) to a stirred solution of 4-[1-(3-bromo-5-methoxymethyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.31 mmol, 1.00 equivalents) in 2-methoxy ethanol (23.30 mL). Stir the resulting mixture at room temperature overnight or up to 3 days and filter through celite. Evaporate the filtrate, partition the residue between ethyl acetate (70 mL) and water (23 mL) and separate. Extract the aqueous layer with ethyl acetate (3×70 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of hexane:ethyl acetate (4:1) to yield the desired product as a yellow oil. LC/MS (ESI), m/e 375 (MNa+), retention time 1.98 minutes. Condition II.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Brc1cncnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=339.3 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-Bromopyridine.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([Br:15])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])=[O:6]>C1COCC1.CO>[Br:15][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=1
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1N sodium hydroxide solution (4 mL) was added to a solution of 5-bromo-3-nitrothiophene-2-carboxylic acid methyl ester (975 mg) in 1:1 THF/methanol (4 mL) and the solution was stirred at room temperature for 1 h. The solution was partitioned between water and ethyl acetate. The aqueous phase was brought to pH 1 with 2N HCl, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The product with the molecular weight of 252.04 (C5H2BrNO4S) was obtained in this way; MS (ESI): 252 and 254 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([OH:22])=O)[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[O:62][NH2:63]>CN(C=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([NH:63][O:62][CH:57]4[CH2:58][CH2:59][CH2:60][CH2:61][O:56]4)=[O:22])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (358 mg, 1.1 mmol) in DMF (8 mL) was added triethylamine (333 mg, 3.3 mmol), HATU (627 mg, 1.65 mmol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine. The resulting mixture was stirred for 2.5 h at room temperature. The mixture was concentrated. Purification by flash chromatography (Biotage) over silica gel (100% ethyl acetate) afforded the title product as brown oil (149 mg, 32% yield). LC-MS (APCl, M+H+): 428.2. HPLC: 96% purity.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:25])[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one synthesized in Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30 mL) was added sodium hydride (a 60% fluidized paraffin dispersion, 314 mg, 7.84 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (1.11 g, 7.84 mmol) and the mixture was stirred for at room temperature 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%) of the title compound as an oily matter.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:24]I>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH3:24])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CI
Product: COC(=O)CCC(=O)N(C)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
(prepared from 4-cyano-4'-[(3-methoxycarbonylpropionyl)amino]biphenyl by methylation with methyl iodide)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].O.[OH-].[Na+]>O.CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: c1ccc(CSC2CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(Cc1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
0.37 g (0.00124 mol) of 1-benzyl-4-benzylsulfanyl-piperidine was suspended in a mixture of 20 ml of water/methanol (1:1) and treated with 2.66 g (0.0124 mol) of sodium periodate. The mixture was stirred at room temperature for 3 hrs., 150 ml of water were added, the pH was adjusted to 8-9 with 1N aqueous NaOH, the mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel with methanol/dichloro-methane (1:19). The fraction having Rf 0.31 was the desired product. 0.17 g (44%) of (RS)-1-benzyl-4-benzylsulfinyl-piperidine was obtained as white crystals; m.p. 123°-125`0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:29][CH2:28]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Yield: 69.8 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (210 mg, 0.680 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (229 mg, 1.36 mmol) to afford the desired product (210 mg, 70%) as a yellow semisolid: ESI MS m/z 443 [C23H28BrN3O+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:30]=[C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 59.7 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3 ml) was added DMAP (23 mg, 0.18 mmol) and phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (117 mg, 0.3 mmol) described in Example 306A to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea (109 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.57 (s, 6H), 4.04 (s, 6H), 6.55 (s, 1H), 7.25 (d, J=6 Hz, 1H), 7.33-7.49 (m, 5H), 7.55-7.60 (m, 4H), 7.80 (s, 1H), 8.59 (s, 1H), 8.69 (s, 1H), 9.29 (s, 1H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.CCOC(C)=O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:48])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (33.3 mg, 0.172 mmol) and THF (718 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (172 μl, 0.172 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 74.12 mg, 0.144 mmol) in THF (0.6 mL with a 0.4 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min of stirring, the mixture was concentrated, and the residue was taken up in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 30 min, then diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane) to give white solid. The solid was taken up in EtOAc, filtered, washed with EtOAc (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (25.5 mg, 0.059 mmol, 41.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.89-7.89 (m, 0H), 7.91-7.81 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.20 (dd, J=1.9, 8.1 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 433.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)CC1
Yield: 77.1 %

Procedure:
2-(1-Ethylpiperidine-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 178, 0.165 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.290 g) in DCM (5 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 21 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M NH3 in methanol and DCM with a gradient of 0-20% to give methyl (1aRS,7bSR)-5-[2-(1-ethyl-piperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.200 g) as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[NH:16][C:15]([CH3:25])=[C:14]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].B(Br)(Br)Br.C([O-])([O-])=O.[K+].[K+].C(O)C>ClCCCl>[CH3:24][C:17]1[NH:16][C:15]2([CH3:25])[CH:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]([C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1[C:5]3[C:10]([CH:11]=[CH:12][C:3]=1[O:2]2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1c(OC)ccc2ccccc12
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2(C)Oc3ccc4ccccc4c3C1C2C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.25 g (5.5 mm) of diethyl 1,4-dihydro-4-(2-methoxy-1-naphthalenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate 20 in 12.0 mL of dry 1,2-dichloroethane was stirred under Ar at 25° C. and treated with 2.40 g (7.68 mm) of BBr3.CH3SCH3 complex. After stirring at 25° C. for 20 hours, 10.0 g of anhydrous powdered K2CO3 and 100 mL of absolute ethanol were added. Stirring was continued for 60 hours at 25°. The reaction was quenched with saturated aqueous NH4Cl and extracted with 500 ml of CH2Cl2. The organic layer was washed with pH 7 phosphate buffer and brine, dried (anhydrous Na2SO4), filtered, evaporated and flash chromatographed (silica gel, 2% acetone in CH2Cl2).