Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3,3-Dimethyl-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide was added to KNO3 in H2SO4 cooled to 0° C. and stirred for 15 min. The reaction was warmed to RT and stirred overnight. The mix was poured into ice and extracted with EtOAc (3×), washed with H2O and brine, dried and evaporated to give the compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[F:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[F:11]
Reactant: Fc1c(Br)ccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: Fc1c(Br)ccc2c1ncn2C1CCCCO1
Yield: 78.3 %

Procedure:
To a solution of 144 (24 g, 0.111 mol) in dry THF (720 mL) was added 3,4-dihydro-2H-pyran (28.1 g, 0.334 mol) and camphorsulfonic acid (2.6 g, 0.011 mol) then heated to reflux for 16 h. The resulting mixture was concentrated and the residue purified by SiO2 chromatography eluting with 20% EtOAc/petroleum ether to afford 26 g (78%) of 5-bromo-4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (146) as pale yellow oil: 1H-NMR (400 MHz, RT, DMSO-d6): δ 1.57-1.63 (m, 2H), 1.70-1.74 (m, 1H), 1.91-2.04 (m, 2H), 2.15-2.19 (m, 1H), 3.73-3.77 (m, 1H), 3.96-4.03 (m, 1H), 5.68-5.71 (dd, 1H), 7.50-7.53 (d, 2H), and 8.51 (s, 1H); MS (ESI): m/z=301.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].[OH:17]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:17][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[CH:10]=[CH:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)C=CC1=C(C)CCCC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCCC(O)C=CC1C(C)(C)CCCC1(C)O

Procedure:
The entitled compound was prepared from 1-(2,6,6-trimethylcyclohex-1-enyl)hex-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:32]2[C:23](=[N:24][C:25]3[C:30]([N:31]=2)=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH:26]=3)[CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[I:46]I.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:32]2[C:23](=[N:24][C:25]3[C:30]([N:31]=2)=[CH:29][CH:28]=[C:27]([I:46])[CH:26]=3)[CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:4][CH2:5][O:6][C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2nc3c(C(=O)NCCN(CC)CCOc4cccnc4F)cccc3nc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(CCNC(=O)c1cccc2nc3cc(I)ccc3nc12)CCOc1cccnc1F
Yield: 54.1 %

Procedure:
To a stirred solution of compound 83 (270 mg, 0.37 mmol) in chloroform (7 mL), was added during 4 h, a solution of diiodine (192 mg, 0.76 mmol) in chloroform (14 mL), dropwise. The mixture was then stirred 14 h at room temperature before addition of an aqueous saturated sodium carbonate solution (40 mL). The solution was decanted and the organic layer was washed with a 5% aqueous sodium hydrogenosulfite solution (2×15 mL), dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, AcOEt/cyclohexane, 7/3, v/v) to give compound 84 (112 mg, 0.20 mmol) as a yellow oil. Yield 54%; Rf (Al2O3, AcOEt/cyclohexane, 7/3, v/v) 0.68; IR (CCl4) ν 1119, 1189, 1246, 1286, 1458, 1509, 1649, 2800-3000, 3246 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.14 (t, 3H, J=7.1 Hz), 2.86 (m, 4H), 3.05 (t, 2H, J=5.5 Hz), 3.76 (q, 2H, J=5.5 Hz), 4.10 (t, 2H, J=5.5 Hz), 6.80 (dd, 1H, J=4.9, 7.9 Hz), 6.97 (m, 1H), 7.53 (m, 1H), 7.83 (dd, 1H, J=1.4, 9.2 Hz), 7.93 (m, 2H), 8.25 (dd, 1H, J=1.5, 8.7 Hz), 8.60 (se, 1H), 8.92 (dd, 1H, J=1.5, 7.2 Hz), 10.92 (m, 1H); ESI-MS m/z 560.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].C(P(=O)(OCC)OCC)#N>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:20]([C:16]1[CH:15]=[C:14]([C:13]2[N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[N:11]=[C:10]3[C:9]=2[C:8](=[O:34])[N:7]([CH3:35])[C:6](=[O:36])[N:5]3[CH2:1][CH:2]([CH3:3])[CH3:4])[N:18]([CH3:19])[CH:17]=1)=[O:22]
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)NCCN(C)C)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d}pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent Mass: 559.35 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product. Purification by column chromatography over silica gel afforded the title compound (0.02 g, 20%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]([O:38][CH2:39][CH2:40][OH:41])=[C:27]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[CH:26]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:26]=[C:27]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[C:28]([O:38][CH2:39][CH2:40][OH:41])=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a flamed dried round bottom flask with 8-phenyloctyl amine (0.484 mL, 2.43 mmol) and THF (5 mL) cooled to 0° C. was added n-BuLi (0.972 mL, 2.5 M in hexane, 2.43 mmol) dropwise over a 5 min. period. The resulting solution was allowed to stir 5 min. and then warmed to room temperature for 30 min. This solution was then added dropwise to a solution of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.300 g, 0.696 mmol) in THF (15 mL) at −20° C. This final mixture was stirred at −20° C. for 15 min and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (10 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/petroleum ether gradient) to afford the product (0.267 g, 65%) as a clear oil; 1H NMR (CDCl3) δ 1.09–1.48 (m, 9H), 1.48–1.72 (m, 4H), 2.58 (t, J=6.8 Hz, 2H), 3.30–3.35 (m, 2H), 3.35–3.41 (m, 2H), 3.46 (dd, J=6.8, 13.0 Hz, 2H), 6.07–6.18 (m, 1H), 7.11–7.19 (m, 3H), 7.21–7.31 (m, 2H), 7.35–7.44 (m, 4H), 7.44–7.57 (m, 2H), 7.63 (s, 2H), 7.77 (s, 2H); mass spectrum [(+) ESI], m/z 590 (M)+.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[F:26][C:27]([F:35])([F:34])[CH2:28][CH2:29][C:30]([NH:32][OH:33])=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:33][N:32]=[C:30]([CH2:29][CH2:28][C:27]([F:35])([F:34])[F:26])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(CCC(F)(F)F)NO
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(CCC(F)(F)F)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4,4,4-trifluoro-N-hydroxy-butyramidine following a procedure analogous to that described in Example 1. LC (method 8): tR=1.30 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[CH:26]=[N:27][C:28](=[O:39])[N:29]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[CH:26]=[N:27][C:28](=[O:39])[N:29]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH:30]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: O=c1ncc(Br)cn1CCN1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1ncc(-c2cc3nccc(Cl)c3s2)cn1CCN1CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
To a solution of the tributyltin derivative 6 (1.88 g, 4.1 mmol) (scheme 2) in toluene (39 mL) was added 5-bromo-1-(2-morpholinoethyl)pyrimidin-2(1H)-one (413, 1.29 g, 4.5 mmol) and Pd(PPh3)4 (474 mg, 0.41 mmol). The reaction mixture was stirred at 100° C. for 16 h. The mixture was filtered and the solvent was evaporated. The residue was triturated in hexanes, then triturated in EtOAc to produce title compound 414 (236 mg, 15% yield). MS (m/z): 377.0 (M+H). 1H NMR (DMSO-d6) δ (ppm): 9.18 (d, J=3.5 Hz, 1H), 8.76 (d, J=3.3 Hz, 1H), 8.64 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.57 (d, J=5.1 Hz, 1H), 4.06 (t, J=5.9 Hz, 2H), 3.54 (t, J=4.5 Hz, 4H), 2.64 (t, J=5.9 Hz, 2H), 2.49-2.43 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:21]C(OC(C)(C)C)=O)[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]([CH3:20])[CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1)(=[O:3])[NH2:2].O1CCOCC1.[ClH:35]>CO>[ClH:35].[NH2:21][CH:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]([CH3:19])[CH3:20])[CH:16]=[CH:17][C:12]=2[O:11][N:10]=1
Reactant: CN(C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1ccc2onc(OCC(N)COC(N)=O)c2c1

Procedure:
To a solution of 0.94 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-dimethylamino-1,2-benzoisoxazole in 19 ml of methanol is added 7.5 ml of a dioxane solution (2.2N) of hydrogen chloride at 5°-10° C., and they are subjected to reaction at 20°-25° C. overnight. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from 2-propanol, after which the crystals are collected by filtration, to obtain 0.34 g of colorless, crystalline 3-(2-amino-3-carbamoyloxypropoxy)-5-dimethylamino-1,2-benzoisoxazole hydrochloride having a melting point of 183°-186° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: Cl
Product: Cc1ccc(C)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 500-mL, three-necked, round bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 2,5-dimethylbenzoic acid (50.0 g, 332.9 mmol). The apparatus was cooled in an ice bath and thionyl chloride (125 mL, 1714 mmol) was added over a period of about 5 minutes. After complete addition, the ice bath was removed and the reaction mixture was warmed to about 50° in order to completely dissolve the 2,5-dimethylbenzoic acid. The reaction mixture was allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation to afford 2,5-dimethylbenzoyl chloride as an oil, which was used without further purification. This material was transferred immediately to an addition funnel and added dropwise with stirring to a commercial 40% dimethylamine solution (188 mL, 1670 mmol) which was maintained between -5° and 5° by periodic immersion in a dry ice-acetone bath. After complete addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ether. The combined organic extracts were washed with water, dried, and concentrated. The resulting pale yellow oil was distilled under vacuum to afford N,N,2,5-tetramethylbenzamide (29.1 g, 164.2 mmol, 49% yield) as a clear, colorless oil: bp 100° (1.0 torr); IR(CHCl3) 1637 cm-1 ; MS m/e 178(M+ +H); 1H NMR(CDCl3) δ 7.00-7.13(m,2H), 6.90-7.00(m,1H), 3.13(s,3H), 2.84(s,3H), 2.31(s,3H), 2.23(s,3H). Anal. Calcd for C11H15NO: C,74.54; H,8.53; N,7.90. Found: C,74.30; H,8.77; N,7.73.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][CH:16]([F:27])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[OH:26]>C(#N)C>[CH2:7]([O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH:16]([F:15])[F:27])[CH:22]=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OC(F)F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (3.91 g, 28.3 mmol) and benzyl bromide (2.5 mL, 21.1 mmol) were added to a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde described in Production Example 19-1 (2.66 g, 14.2 mmol) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and then the solvent was evaporated. The resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2). The target fraction was concentrated under vacuum and then the title compound was quantitatively obtained.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:36]2([CH2:40][CH2:39][NH:38][CH2:37]2)[CH2:35][N:34]1C(OC(C)(C)C)=O>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:38]3[CH2:39][CH2:40][C:36]4([CH2:33][NH:34][CH2:35]4)[CH2:37]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC3(CNC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate to afford an off-white powder. UPLC-MS (Condition 3) tR=0.79 min, m/z=475.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04 (t, J=6.65 Hz, 2H) 3.14 (d, J=4.69 Hz, 3H) 3.46 (s, 2H) 3.76 (q, J=10.04 Hz, 4H) 6.39 (s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.78-7.92 (m, 3H) 8.08 (br. s, 1H) 8.74 (br. s, 1H) 10.27 (s, 1H) 12.90-13.01 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[ClH:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([Cl:19])=[O:18].C(OCC)C>O1CCCC1>[ClH:19].[ClH:10].[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COc1ccc(N)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(NC(=O)c2ccccn2)cn1
Yield: 73.8 %

Procedure:
5-Amino-2-methoxypyridine (4.40 g, 35.4 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a stirred solution of pyridine-2-carbonyl chloride hydrochloride (7.12 g, 40.0 mmol) in tetrahydrofuran (75 mL). After stirring overnight at room temperature diethyl ether was added. The solids were isolated by suction, washed with diethyl ether and dried in a vacuum oven at 45° C., yielding the title compound (7.89 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21](=O)[CH3:22])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH:21]([NH2:30])[CH3:22])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2nnn[nH]2)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanone (85 mg, 0.26 mmol), ammonium acetate (198 mg, 2.57 mmol) and sodium cyanoborohydride (32 mg, 0.51 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (45 mg, 53%). LCMS calculated for C6H13ClFN4 (M−NH2)+: m/z=315.1. found: 315.1.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CN(C)C=O.CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(C2(C(=O)c3ccc(Cl)cc3)CC2)CC1
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A solution of 29.6 g (0.1 mol) of 4-chlorophenyl 1-bromo-3-chloropropyl ketone in 30 ml of dimethylformamide is added dropwise to a mixture of 10.4 g of N-methyl piperazine and 14 g of potassium carbonate in 30 ml of dimethylformamide at room temperature. Stirring is continued for 3 hours, after which a solution of 9 g of potassium hydroxide in 30 ml of methanol is added dropwise. The reaction mixture is stirred for a further hour at 50° C. and evaporated down in vacuo. The residue is taken up in ethyl acetate/water, and the organic phase is separated off, washed with water, dried over sodium sulphate and evaporated down in vacuo. The residue is chromatographed over silica gel using chloroform/ethanol (97:3). 14 g (50.3% of theory) of 1-(4-chlorobenzoyl)-1-(4-methylpiperazin-1-yl)-cyclopropane are obtained as a reddish oil, which can be directly used further.
Reaction SMILES: CO[C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].O.[NH2:26][NH2:27]>CCO>[NH:26]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)=[O:5])[NH2:27]
Reactant: NN
Reactant: COC(=O)C(=O)Nc1cnc(N2CCC(C(=O)OC)CC2)c(C)c1
Solvent: CCO
Solvent: O
Product: COC(=O)C1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1
Reaction time: 17 h
Yield: 87.6 %

Procedure:
Methyl 1-(5-{[methoxy(oxo)acetyl]amino}-3-methylpyridin-2-yl)piperidine-4-carboxylate (2.01 g; 5.99 mmol) was dissolved in EtOH (140 mL) and treated with dropwise addition of hydrazine hydrate (320 μL; 6.59 mmol). Within a few minutes a flocculent precipitate formed. Vigorous stirring was continued for 17 hrs. A further 32 μL (0.65 mmol) hydrazine hydrate was added and stirring continued at ambient temperature for 24 hrs. The precipitated solid was filtered off, washed with ether on the filter and dried under high vacuum at 60° C. to give the title compound (1.76 g, 88% yield). This was used in the next stage without further purification. 1H NMR δ 1.59-1.80 (m, 2H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 2.52-2.60 (m, 1H), 2.66-2.84 (m, 2H), 3.22-3.37 (m, 2H), 3.58 (s, 3H), 4.54 (d, 2H), 7.89 (d, 1H), 8.47 (d, 1H), 10.14 (s, 1H), 10.48 (s, 1H). MS m/e MH+ 336.24.
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:17]1([OH:21])[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([O:21][C:8]2[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCC1
Reactant: O=C(O)c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ncccc1OC1CCC1
Reaction time: 18 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (358 mg, 3.19 mmol) was suspended in cyclobutanol (0.5 mL), 3-fluoropyridine-2-carboxylic acid (150 mg, 1.06 mmol) was added and the reaction was stirred at 100 C for 18 h. The mixture was evaporated under vacuum to afford the title compound (100% conversion assumed), which was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=194. Found: m/z=194, Rt=0.83 min (100%).