Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1.N1C=CC=CC=1.[C:37]1([C:43](Cl)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:43]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1)(=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF was added to the crude product of Step 1, followed by pyridine (2 eq.) and PhCOCl (1 eq.). After being stirred at room temperature overnight, the reaction mixture was evaporated to give the crude title product.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)=S.[ClH:15].Cl.Cl.[OH:18][NH:19]C(NC)=NCCSCC1NC=NC=1C.CNC(=NCCCCC1N=CNC=1)SC.NO.Cl.Cl.Cl.ON(CCSCC1NC=NC=1C)C(N)=NCCSCC1NC=NC=1C>>[ClH:15].[ClH:15].[CH3:1][NH:2][C:3]([NH:19][OH:18])=[N:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Reactant: CNC(=S)NCCCCc1c[nH]cn1
Agent: CNC(=NCCCCc1c[nH]cn1)SC
Agent: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCCCc1c[nH]cn1)NO

Procedure:
When N-methyl-N'-[4-(4-imidazolyl)butyl]thiourea is reacted with methanolic hydrogen chloride by the procedure of Example 1 (i) the product is N,S-dimethyl-N'-[4-(4-imidazolyl)butyl]isothiourea which on treatment with hydroxylamine by the procedure of Example 1 (ii) gives the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCCCCC>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCNCc1ccc(CCCC)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCCCCC
Product: CCCCCCCN(Cc1ccc(CCCC)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.55 g of 2,4-diflurophenylisocyanate in hexane was added to a solution of 2.61 g of N-heptyl-4-butylbenzenemethanamine in 15 ml of hexane and the solution was stirred at room temperature for 4 hours, then evaporated. The residual oil was distilled to yield 1-[(4-butylphenyl)methyl]-1-(n-heptyl)-3-[2 4-difluorophenyl]urea as a colorless oil, bp 160°-165° C./120μ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CN(C)C=O.Cl.[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[CH:14]=[CH:15][S:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:32]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:24]([CH3:37])[CH3:23])=[CH:36][CH:35]=2)=[O:33])=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(C(=O)N2CCc3sccc3C2c2ccc(Cl)cc2)cc1

Procedure:
Similarly as described in example 22 using a solution of 4-(4-chlorophenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 ul), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 g in 8.3 ml) affords the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[C:39]([NH2:45])=[C:40]([NH2:44])[CH:41]=[N:42][CH:43]=2)[CH2:34][CH2:33]1.[S].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([NH:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][N:4]=[C:3]3[C:1]2[NH:44][C:40]3[CH:41]=[N:42][CH:43]=[C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)[C:39]=3[N:45]=2)[CH:13]=1)=[O:24]
Reactant: CC(C)CC(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Reactant: CN1CCN(c2cncc(N)c2N)CC1
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CC(=O)Nc1cncc(-c2ccc3[nH]nc(-c4nc5c(N6CCN(C)CC6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide (LXXXIV) (52 mg, 0.127 mmol), 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (LVIII) (29 mg, 0.13 mmol) and sulfur (45 mg, 0.13 mmol) in dry DMF (10 mL) was heated at 140° C. overnight. The reaction was cooled and evaporated under vacuum. The viscous residue was dried overnight under vacuum. The solid was washed with cold water and dried under vacuum. The crude product (LXXXV) was dissolved in DCM (5 mL) followed by Et3SiH (48 pt, 0.30 mmol) and slowly addition of TFA (2.5 mL). The reaction was stirred until TLC (10% MeOH/DCM) showed the reaction was complete. The reaction was evaporated under vacuum and the residue was treated with water, sonicated and then basified with aq. ammonia. The solids were filtered, washed with cold water and dried. The crude product was heated in EtOAc and filtered hot to remove impurities. The hot EtOAc solution was allowed to slowly cool to room temperature and filtered to give 3-methyl-N-(5-(3-(7-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide 1 as a pink solid (36 mg, 0.071 mmol, 59% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.97 (d, 6H), 2.13 (m, 1H), 2.27 (m, 4H), 3.45 (m, 4H), 6.70 (s, 1H), 7.79 (dd, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 8.66 (s, 1H), 8.84 (s, 1H), 10.26 (s, 1H), 12.97 (s, 1H), 13.82 (s, 1H); ESIMS found for C28H31N9O m/z 510.5 (M+H).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])([CH3:9])([CH3:8])[CH3:7].[P:16](Cl)(=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].C1C=CC=CC=1>CCCCCC.O>[C:6]([O:10][C:11](=[O:15])[CH:12]([P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23])[N+:13]#[C-:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: [C-]#[N+]C(C(=O)OC(C)(C)C)P(=O)(OCC)OCC

Procedure:
1 ml of an approximately 2 molar solution of butyllithium in hexane is added over a period of 15 minutes to a solution, cooled to -10° C., of 282 mg (2 mmols) of isocyanoacetic acid tert.-butyl ester in 3 ml of dry hexane (distilled over sodium), whilst stirring vigorously and in a nitrogen atmosphere. The suspension which forms is stirred for a further 10 minutes and a solution of 413 μl (2 mmols) of diethyl phosphorochloridate in 5 ml of dry hexane is then added over a period of 15 minutes. The reaction mixture is stirred for a further 30 minutes, then treated with 20 ml of benzene and 5 ml of water and stirred vigorously for a further 10 minutes. The organic phase is washed with 3 times 5 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel. Benzene/ethyl acetate, 3:1, elutes diethylphosphono-isocyanoacetic acid tert.-butyl ester as a pale yellow oil; IR spectrum (in methylene chloride): characteristic bands at 3.4; 4.64; 5.70; 7.30; 8.00; 8.70 and 9.80μ.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1.[NH2:38][C@H:39]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl.CC(C)=O>[NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[C@H:2]([C:18]([NH:38][C@H:39]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Fmoc-Phe(4-NHBoc)-OH (210 mg, 418 μmol, 1 equiv.) was dissolved in DCM and HCl.H-Leu-OMe (77 mg, 460 μmol, 1.1 equiv.), HBTU (190 mg, 502 μmol, 1.2 equiv.) and DiPEA (242 μl, 1.46 mmol, 3.5 equiv.) were added and the mixture stirred for 1 hour. after which it was washed with 1M HCl (2×), sat. aq. NaHCO3 (4×) and brine and dried over MgSO4. Column chromatography (10% acetone:PE->20% acetone:PE) yielded the title compound (206 mg, 294 μmol, 70%). 1H NMR (400 MHz, CDCl3): δ ppm 7.76 (d, J=7.5 Hz, 2H), 7.54 (t, J=6.9 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 7.35-7.20 (m, 4H), 7.11 (d, J=7.1 Hz, 2H), 6.54 (s, 1H), 6.29 (d, J=6.6 Hz, 1H), 5.44 (d, J=7.2 Hz, 1H), 4.55 (td, J=8.4, 5.4 Hz, 1H), 4.41 (dd, J=10.3, 7.2 Hz, 1H), 4.32 (s, 1H), 4.18 (t, J=6.9 Hz, 1H), 3.68 (s, 3H), 3.15-2.94 (m, 2H), 1.65-1.39 (m, 3H), 1.51 (s, 9H), 0.97-0.78 (m, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 172.74, 170.69, 155.89, 152.64, 143.67, 143.60, 141.16, 137.31, 130.58, 129.83, 127.64, 127.01, 124.98, 119.88, 118.55, 80.41, 67.11, 55.88, 52.17, 50.75, 46.95, 41.31, 37.78, 28.25, 24.63, 22.58, 21.81.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 49-3 (1.93 g, 6.01 mmol) and NaOH (530 mg, 13.26 mmol) in dioxane (15 mL) and H2O (15 mL) was stirred at 80° C. for 2 hours. Dioxane was removed by rotary evaporation and the resulting solution was acidified to pH around 4 by 1N HCl aqueous solution, followed by extraction with ethyl acetate (60 mL×3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation to afford 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid 49-4 as a yellow solid. MS m/z 308.1 (M+1)
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20]C(=O)OC(C)(C)C.B(OC(C)C)(OC(C)C)OC(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:48]1[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][N:49]=1>C1COCC1.C1(C)C=CC=CC=1.CO.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>[Br:54][C:51]1[CH:52]=[CH:53][C:48]([C:16]2[C:15]([NH2:20])=[N:14][CH:19]=[CH:18][CH:17]=2)=[N:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ncccc1-c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
n-Butyllithium (1.6 M in hexane, 48.3 mL) was added dropwise to a solution of N1,N1,N2,N2-tetramethylethane-1,2-diamine (8.08 g) and tert-butyl pyridin-2-ylcarbamate (5 g) in THF (dry) (50 mL) at −78° C. The mixture was stirred at 0° C. under N2 for 2 hr. Triisopropyl borate (16.95 g) was added to the mixture at −78° C. The mixture was stirred at 0° C. under N2 for 30 min. The mixture was quenched with sat. NH4Cl aq. at 0° C. and added with Et2O to give a yellow precipitate (11.68 g, wet). A mixture of potassium carbonate (438 mg), tetrakis(triphenylphosphine)palladium(0) (61.0 mg), 2,5-dibromopyridine (250 mg) and the precipitate (250 mg) in toluene (10 mL) and MeOH (5 mL) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (132 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C@H:9]2[C@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C@@H:3]1[OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Cl:1][C:2]1([Cl:11])[C@H:9]2[C@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10]
Reactant: O[C@H]1[C@H]2CCC=C[C@H]2C1(Cl)Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1[C@H]2CCC=C[C@H]2C1(Cl)Cl
Yield: 80.3 %

Procedure:
A mixture of 3.9 g of (1R,6S,7S)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-ol, prepared as shown in Preparation 22, 9.0 g of pyridinium chlorochromate and 14 g of magnesium sulfate in 200 ml of methylene chloride under nitrogen was refluxed for 4 hours. The mixture was cooled and filtered through celite, then Florisil. Solvent was removed from the eluate under reduced pressure and the residue distilled under vacuum to give 3.1 g of (1R,6S)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, [α]D =+71.4° C., (C=0.7, CHCl3).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][NH:21][C:3]([S:2][CH3:1])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])=[CH:16][CH:15]=1
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Reactant: NCc1ccc(Cl)nc1
Solvent: CCO
Product: CSC(=CC(=O)C(F)(F)F)NCc1ccc(Cl)nc1
Temperature: 20 °C

Procedure:
The product of Example 1, 1, 1-bismethylthio-4,4,4-trifluoro-1-buten-3-one, (4.32 g, 0.02 mol) and the product of Example 4, 6-chloro-3pyridylmethylamine (2.85 g, 0.02 mol) were dissolved in ethanol (50 ml). The resulting solution was heated under reflux for 2 hours under an atmosphere of nitrogen. The resulting mixture was cooled to ambient temperature (20° C.) and the solvent removed by evaporation under reduced pressure. The residue was chromatographically purified using a silica gel column eluted with dichloromethane/ether (19:1) to give the product, 1-(6-chloro-3- pyridylmethyl) amino-1-methylthio-4,4,4-trifluoro-1-buten-3-one, as a solid which recrystallized from ethanol, in a yield of 3.32 g (53%), melting point 112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][C:2]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)nc1Cl
Temperature: 50 °C

Procedure:
2,6-Dichloropyridine, 25.0 gm (0.168 mole) was added slowly under constant stirring to concentrated sulfuric acid at 20°–25° C. To this solution, 75.0 gm of concentrated nitric acid (98.0%) was added slowly, keeping the reaction temperature below 50° C. After the addition, the resulting mixture was heated to 100°–105° C. for 5.0 hrs. The progress of the reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 50° C. and poured in ice water. The resulting precipitate was filtered and washed with water. The wet cake thus obtained was dried to give 24.5 gm of 2,6-dichloro-3-nitropyridine. The yield of 2,6-dichloro-3-nitropyridine was 75.38% and the GC purity was 99.5%.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([Cl:40])[CH:19]=1>>[Cl:40][C:20]1[CH:19]=[C:18]([N:11]2[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]2(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[CH2:28][CH2:27]1)=[O:25]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 22.8 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (586 mg) described in Preparation Example 1 and (4-bromo-2-chlorophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (990 mg) described in Preparation Example 131 and by the reaction and treatment in the same manner as in Example 32, the title compound (265 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:24]=[C:23]2[C:17]([N:18]([CH3:29])[C:19](=[O:28])[CH2:20][CH2:21][N:22]2[CH:25]([CH3:27])[CH3:26])=[CH:16][N:15]=1)[C:7](O)=[O:8])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:24]=[C:23]2[C:17]([N:18]([CH3:29])[C:19](=[O:28])[CH2:20][CH2:21][N:22]2[CH:25]([CH3:26])[CH3:27])=[CH:16][N:15]=1)[C:7]([NH:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1)=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred solution of 3-ethoxy-4-[(6-methyl-5-oxo-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]benzoic acid (Intermediate 163; 80 mg, 0.20 mmol), HATU (115 mg, 0.30 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 35 mg, 0.30 mmol) in DMF (5 mL) was added diisopropylethylamine (105 μl, 0.60 mmol). The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a white foam (87 mg, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=3[CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a stirred solution of 5.6 parts of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate in 90 parts of N,N-dimethylformamide were added portionwise 1.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 30 minutes. A solution of 3.1 parts of (chloromethyl)benzene in 18 parts of N,N-dimethylformamide was added dropwise. Upon completion, the whole was stirred for 22 hours at 70° C. The reaction mixture was evaporated. Water was added. The product was extracted with 1,1'-oxybisethane. The extract was washed with a sodium chloride solution 10%, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (76.9%) of ethyl 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxylate as a residue (intermediate 29).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Cl:26][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:27])[N:14]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: O=C(O)c1ccccn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccccn1
Yield: 73.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)picolinamide was prepared using the method of Example 34(d) starting from picolinic acid (0.227 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). Yield 73.7%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.31 (dd, 1H), 4.45 (dd, 1H), 4.62 (m, 1H), 6.63 (d, 1H), 7.46 (m, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.81 (dd, 1H), 7.86 (m, 1H), 8.09 (d, 1H), 8.19 (m, 1H), 8.65 (m, 1H), 8.86 (d, 1H).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[C:20]([O:24][C:25](=[O:28])[CH2:26][NH2:27])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([CH2:26][N:27]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:28])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: C1CCOC1
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)OC(C)(C)C

Procedure:
13.0 g (0.05 mol) of 6-phthalimido-2,5-hexanedione and 6.6 g (0.05 mol) of glycine tert.-butyl ester are stirred in 250 ml of tetrahydrofuran at 80° C. for 20 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([OH:20])=O)=[N:10]2)=[C:4]([F:21])[CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O.CCOC(C)=O.CO>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:24]([O:25][CH3:26])[CH3:23])=[O:20])=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(=O)N(C)OC)c1=O
Yield: 31 %

Procedure:
A mixture of 1-(4-bromo-2,5-difluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid. (25 g, 83 mmol), N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91 mmol), HOBt (12 g, 91 mmol), triethylamine (24 mL, 174 mmol) and WSC (17 g, 91 mmol) in DMF (160 mL) was stirred at room temperature for 18 h. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with Hexane/AcOEt (1/0 to 0/1) and then AcOEt/MeOH (10/1) to give the title compound (11 g, 31% yield) as a yellow solid: LC-MS (ESI) m/z 405 [M+H]+.