Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([S:18]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:20])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (1.5 g, 9.5 mmol) in CH2Cl2 (70 mL) was added with TEA (1.1 mol eq, 1.45 mL) and the mixture was stirred at r.t. for 10 minutes. Then 3,4-difluorobenzensulfonyl chloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethylic ether to afford 2G as a pale orange solid (2.85 g, 94% yield). 1HNMR (DMSO, 200 MHz) δ 3.45 (s, 3H), 3.54 (m, 2H), 3.95 (m, 1H), 5.01 (t, 1H), 7.66 (m, 2H), 7.88 (m, 1H), 8.46 (d, 1H, J=8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[NH2:8].Cl[C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[NH:8][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1cccc(-c2cc(F)c(N)c(F)c2)c1
Product: COc1cccc(-c2cc(F)c(Nc3ncccc3C(=O)O)c(F)c2)c1

Procedure:
In another embodiment (step c2), the aminium salt of 3,5-difluoro-3′-methoxybiphenyl-4-amine from step b) is optionally, dried or semidried to remove or partially remove the solvent. Subsequently, said aminium salt is hydrolyzed in the presence of water under well-known reaction conditions to 3,5-difluoro-3′-methoxybiphenyl-4-amine and finally, 3,5-difluoro-3′-methoxybiphenyl-4-amine in the amine form is reacted with 2-chloronicotinic acid to obtain 2-[(3,5-difluoro-3′-methoxy-1,1′-biphenyl-4-yl)amino]nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[N:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:38]1[CH:37]=[C:36]([O:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]3[O:17][C:13]([NH:12][C:3]4[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][N:15]=3)=[CH:19][CH:20]=2)[CH:41]=[N:40][CH:39]=1
Reactant: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Reactant: Brc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1ccc(Cl)c(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
4-(5-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (95.4 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (129.1 mg). Yield 59.5%.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[F:23])(=O)=O.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1>CN1C(=O)CCC1.O>[Br:22][C:19]1[CH:20]=[N:21][C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([F:23])=[C:9]([CH:14]=2)[O:8][CH2:7][CH2:6][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]2)=[N:17][CH:18]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCOc1cc(Nc2ncc(Br)cn2)ccc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCN(CCOc2cc(Nc3ncc(Br)cn3)ccc2F)CC1
Temperature: 90 °C

Procedure:
2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl methanesulfonate 46b (0.24 mmol) and methyl piperidine-4-carboxylate (0.48 mmol) are dissolved in NMP (2 mL) and heated to 90° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with EtOAc (2×30 mL). The organic layer is washed with water, brine, dried over sodium sulfate, and concentrated to dryness. The crude product is purified by short SiO2 chromatography using DCM:hexane=9:1 as eluant to yield methyl 1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 47 as light brown solid. MS (m/z) (M+1)+: 454.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16].[NH:17]1[CH2:20][CH2:19][C:18]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]([O:15][CH3:16])=[C:2]([N:17]2[CH2:20][CH2:19][C:18]2=[O:21])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1CCN1
Reactant: COc1c(Br)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1c(N2CCC2=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 106.6 %

Procedure:
An oven-dried Schlenk tube was charged with the above nitroanisole (500 mg, 1.74 mmol), 2-azetidinone (150 mg, 2.1 mmol), tris(dibenzylideneacetone) dipalladium(0) (32 mg, 0.035 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol) and cesium carbonate (795 mg, 2.44 mmol). The tube was capped with a rubber septum, purged with argon and 1,4-dioxane (7 mL) was then added through the septum via a syringe. The tube was sealed with a teflon screwcap and the reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the crude product was purified by column:chromatography (2:1 hexane-EtOAc) to give 1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-azetidin-2-one (516 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cccc(Cc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=344.0 [M+H]+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:20]>O>[C:12]1([C:10]2[O:11][C:7]3[C:8](=[C:3]([CH:2]=[O:20])[CH:4]=[CH:5][CH:6]=3)[N:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: BrC(Br)c1cccc2oc(-c3ccccc3)nc12
Solvent: O
Product: O=Cc1cccc2oc(-c3ccccc3)nc12

Procedure:
5.5 g (14.9 mmol) of the compound from Example XII were stirred at 100° C. with 30 ml of concentrated sulphuric acid for 1 h, the mixture was poured into water, and the precipitate was filtered off with suction and dried.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([NH:20][C:21](OCC)=O)=[C:18]([CH2:26][S:27][CH3:28])[C:17]([C:29]#[N:30])=[N:16]1>CO>[Cl:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([Cl:3])[C:5]=1[N:15]1[C:19]([NH:20][CH3:21])=[C:18]([CH2:26][S:27][CH3:28])[C:17]([C:29]#[N:30])=[N:16]1
Reactant: CCOC(=O)Nc1c(CSC)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1c(CSC)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
Sodium borohydride (420 mg) was added portionwise to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-ethoxycarbonylamino-4-methylthiomethlpyrazole (854 mg) in methanol. The mixture was evaporated, diluted with dichloromethane and water, and the organic phase dried (magnesium sulfate) and evaporated to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-methylamino-4-methylthiomethylpyrazole.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:30][C:27]2[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (1.0 g, 5.3 mmol) and DIEA (0.77 ml, 4.4 mmol) in THF (20 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (0.50 g, 3.5 mmol). The reaction mixture was stirred at 25° C. for 3 days and 60° C. for 1 hour. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.62 g, 59%). 1H NMR (400 MHz) 12.25 and 11.66 (s, 1H), 10.46 and 10.13 (s, 1H), 8.56 (m, 1H), 7.11 and 7.02 (d, J=8.4 Hz, 1H), 6.08 and 5.97 (s, 1H), 4.70 and 4.48 (m, 1H), 1.32 and 1.27 (d, J=6.0 Hz, 6H). MS: Calcd.: 297; Found: [M+H]+ 298.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:61]1[N:66]=[C:65]([CH:67]([N:70]2[CH2:75][CH2:74][O:73][CH2:72][CH2:71]2)[CH2:68][OH:69])[CH:64]=[CH:63][CH:62]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:61]3[CH:62]=[CH:63][CH:64]=[C:65]([CH:67]([N:70]4[CH2:75][CH2:74][O:73][CH2:72][CH2:71]4)[CH2:68][OH:69])[N:66]=3)=[C:3]([C:17]([NH2:19])=[O:18])[N:4]=2)=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(C(CO)N4CCOCC4)n3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (60 mg, 0.22 mmol), Pd2(dba)3 (5.9 mg, 6.5 μmol), X-PHOS (15.5 mg, 0.032 mmol), and potassium carbonate (33 mg, 0.24 mmol). The tube was evacuated and backfilled with argon three times. 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 3, Step 1) (62 mg, 0.22 mmol) was placed in a separate vial which was also evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (500 μl) was added to 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol and the resulting solution was transferred to the sealed tube via syringe. The tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate (2×) and brine (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was performed by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier, monitoring at 230 nM). Desired fractions were poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was extracted, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light yellow powder. 1H NMR (500 MHz, d6-DMSO) δ 11.25 (s, 1H), 7.84 (d, 2H), 7.70 (s, 1H), 7.68 (t, 1H), 7.59 (s, 1H), 7.55 (d, 2H), 7.05 (d, 1H), 6.92 (d, 1H), 5.08 (s, 1H), 4.51 (t, 1H), 3.98 (m, 2H), 3.65 (t, 1H), 3.53 (m, 4H), 3.75 (m, 4H), 3.42 (s, 6H). LRMS (APCI) calc'd for (C24H30N5O4S) [M+H]+, 484.2; found 484.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([C:16](=[O:19])[CH2:17]Br)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]([CH:17]=[P:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)O
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To chloroform (200 ml) are added ethyl α-[2-methoxy-4-(2-bromoacetyl)phenoxy]acetate (20 g) and triphenylphosphine (20.6 g) in an ice-bath, and the mixture is stirred for one hour. After confirming that the starting compounds are well consumed, the mixture is washed with an aqueous potassium carbonate solution. The mixture is dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. To the residue is added methanol (200 ml), and thereto is added dropwise sodium hydroxide in an ice-bath. After confirming that the starting compounds are well consumed, to the mixture is added conc hydrochloric acid. The precipitated crystals are washed with water and diethyl ether, and dried to give (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (25 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Yield: 33.8 %

Procedure:
The title compound (76 mg, 34%) was prepared using (2S,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (95 mg, 0.46 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[NH:16])=[CH:5][CH:4]=1.[Cl:17][CH2:18][C:19](O)=[O:20].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[Cl:17][CH2:18][C:19]([N:16]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]1[CH2:9][C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:20]
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCl)N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
70 mg (0.27 mmol) of the 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride obtained by the method described in another method of Synthetic Example P1 was dissolved in 4 ml of anhydrous dichloromethane, 82 mg (0.67 mmol) of DMAP, 25 mg (0.27 mmol) of chloroacetic acid and 62 mg (0.32 mmol) of EDC-HCl were added thereto in sequence, and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane was added thereto to dilute the mixture, and the mixture was washed with water and a 1% HCl aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the subject material. Amount obtained 4 mg (yield 5%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(CO)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-(Hydroxymethyl)piperidine (Maybridge)(76.3 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (27) as a brown solid (106.3 mg; 42%). 1H NMR (DMSO-d6, 300 MHz) δ 1.05-1.30 (m, 2H), 1.65-1.87 (m, 3H), 2.14 (s, 3H), 2.50 (s, 3H), 2.86 (m, 1H), 3.20 (m, 1H), 3.28 (m, 2H), 4.48 (m, 1H), 4.52 (t, J=4.5 Hz, 1H), 5.16 (m, 1H), 7.97 (s, 1H), 12.16 (s, 1H). M− (ESI): 379.20; M+ (ESI): 381.19. HPLC (method A), Rt: 2.47 min (purity: 99%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[S:14](Cl)(=[O:16])=[O:15].O>O1CCCC1>[Br:5][C:6]1[C:7]2[S:14](=[O:15])(=[O:16])[N:4]([CH:1]([CH3:3])[CH3:2])[C:12](=[NH:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1cccc(Br)c1S(=O)(=O)Cl
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1C(=N)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
70 mg of isopropylamine is added at ambient temperature to a solution of 150 mg 2-bromo-6-cyano-benzenesulfonyl chloride in 5 ml of tetrahydrofuran. After stirring for 16 h at ambient temperature the mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue with cyclohexane—ethyl acetate (2:1) affords 99 mg of 7-bromo-2-isopropyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-ylideneamine (P2.1).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH:16]12[NH:24][CH:20]([CH2:21][CH2:22][CH2:23]1)[CH2:19][C:18](=O)[CH2:17]2.Cl.C(O)(=O)C>>[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][C:18]1[CH2:17][CH:16]3[NH:24][CH:20]([C:19]2=1)[CH2:21][CH2:22][CH2:23]3
Reactant: O=C1CC2CCCC(C1)N2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Temperature: 25 °C

Procedure:
In a 30 mL microwave reaction tube were combined 4-(trifluoromethoxy)phenyl-hydrazine hydrochloride (1062 mg, 5.0 mmol; Maybridge), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (878 mg, 5.0 mmol; Accela ChemBio), and 1 N HCl in acetic acid (15 mL, 15 mmol; Aldrich). The reaction mixture was microwaved at 150° C. (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to ˜pH 12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.33-1.52 (m, 2H), 1.64-1.78 (m, 2H), 1.89-2.06 (m, 2H), 2.68 (d, J=17 Hz, 1H), 3.25-3.34 (m, 1H), 3.62 (t, J=5 Hz, 1H), 4.43 (t, J=3 Hz, 1H), 6.93 (ddd, J=9, 2, 1 Hz, 1H), 7.22 (d, J=1 Hz, 1H), 7.31 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH2:4][CH2:3]1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH2:6][CH2:7]1
Reactant: CN1CCC(=Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CCO
Product: CN1CCC(Cc2ccc(N)cc2C(F)(F)F)CC1

Procedure:
A solution of 2.2 g (8.15 mMol) 4-(1-methyl-piperidin-4-ylidenemethyl)-3-trifluoromethyl-phenylamine in 50 ml EtOH is hydrogenated in the presence of PVC for 32 h at ambient temperature. The catalyst is then removed by filtration over hyflo and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:26](I)[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:26][CH3:27])[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCI
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Product: CCn1nc(-c2ccc(OC)c(F)c2)c(-c2ccc(OC)c(F)c2)cc1=O
Yield: 97.2 %

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 97.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][N:15]([C@H](C3C=CC=CC=3)C)[CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](C2(N(C)C(=O)OC(C)(C)C)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine (7.19 g, 20.9 mmol) was dissolved in ethanol (78 ml), and after adding a 10% palladium carbon catalyst (water content: 50%; 3.9 g), it was stirred at 40° C. for 4 hours under a hydrogen atmosphere at atmospheric pressure. After performing filtration through cellite (ethanol washing), the filtrate was concentrated under a reduced pressure. As a result, 4.38 g (quantitative) of the title compound was obtained in the form of a colorless syrup. The 1H-NMR data and the TLC Rf value of this resulting compound agreed with the data indicated previously.