Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:34][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)=[O:28])=[CH:23][CH:24]=2)[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:12]=[CH:11]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(-n2cnc3cnccc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-n2cnc3cnccc32)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.15 ml of DIEA are added dropwise to a cold (0° C.) mixture of 55 mg of crude (4-imidazo[4,5-c]pyridin-1-yl-phenyl)-acetic acid, 39 mg of 3-aminobenzotrifluoride and 77 mg of TBTU in 0.5 ml of DMF. The mixture obtained is allowed to warm to rt, stirred for 2 hours, diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3, H2O, and brine. The organic phase obtained is dried (Na2SO4), filtered and concentrated in vacuo. The evaporation residue obtained is purified by silica gel column chromatography. 2-(4-Imidazo[4,5-c]pyridin-1-yl-phenyl)-N-(3-trifluoromethyl-phenyl]-acetamide is obtained in the form of a solid: ES-MS: 397.0 [M+H]+; single peak at tR=3.52 min (System 1); Rf=0.18 (CH2Cl2/MeOH, 94:6).
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Agent: Cl
Product: C[C@@]1(c2cc(N)ccc2F)COCC(=S)N1

Procedure:
In a manner analogous to the preparation of Building block E the hydrolysis of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione with hydrochloric acid yielded the title compound as a light brown foam. Mass (calculated) C11H13FN2OS [240.301]; (found) [M+H]+=241.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[CH:21][CH:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2)cs1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(N3CCN(c4ccccc4)CC3)cc2)cs1
Yield: 52 %

Procedure:
Under nitrogen atmosphere, 2-({4-[2-(4-bromophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (800 mg) synthesized in Example 67-1 and 1-phenylpiperazine (425 mg) were dissolved in toluene (5 mL), sodium tert-butoxide (185 mg), tris(dibenzylideneacetone)dipalladium (80.1 mg) and 2-(di-tert-butylphosphino)biphenyl (52.2 mg) were added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (490 mg) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:26]Br.[C:28]([O-:31])(=[O:30])[CH3:29].[Na+]>CN(C)C=O>[C:28]([O:31][CH2:26][C:3]1[CH:4]=[C:5]([N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:30])[CH3:29]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(CBr)c2)ccc1C#N
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(COC(C)=O)c2)ccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of tert-butyl 4-bromo-3-(bromomethyl)phenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (4.46 g, 8.98 mmol) in N,N-dimethylformamide (60 mL) was added sodium acetate (3.68 g, 44.9 mmol). The reaction was stirred at 50° C. for two hours. The mixture was cooled to room temperature and extracted with ethyl acetate and water in portions. The organic layer of each portion was washed three times with water and brine, and dried over sodium sulfate, and filtered. The portions were combined and the solvent was removed under reduced pressure. The residue was purified by Combiflash to give 2-bromo-5-(tert-butoxycarbonyl(5-cyano-6-methoxypyridin-2-yl)amino)benzyl acetate (1.99 g, 2 steps 46%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: CSc1cccc(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CSc1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 85.3 %

Procedure:
Using 3-methylthioaniline (1.40 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.46 g (85.2%) of the title compound in the form of yellow powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.Cl.[NH2:24]O.O>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3C)cnc21
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(-c4ccccc4C)c3cnc21
Yield: 44.1 %

Procedure:
4-Chloro-1-ethyl-5-(2-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (5.40 g) was refluxed for 2 hours in 300 ml of glacial acetic acid containing 10 ml of concentrated hydrochloric acid and 10 g of hydroxylamine hydrochloride. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed four times with water and once with saturated sodium bicarbonate solution. It was then evaporated and chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane) to give 2.21 g of product, mp 168°-170°. This product was recrystallized from ethyl acetate together with the product of another run to give analytically pure material, mp 170°-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
For example, a mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (3.5 g), 1-BOC-piperazine (2.76 g) and trimethylorthoformate (4.05 mL) was stirred in 1,2-dichloroethane (300 mL) for 1 hr at room temperature. To this was added sodium triacetoxyborohydride (3.92 g) and the reaction mixture was stirred for 24 hours at room temperature. The mixture was then quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (3.4 g). Treatment with HCl in dichloromethane/methanol yielded 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([CH3:17])[C:13]([NH:15][NH2:16])=O)=[C:10]([F:18])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>C(O)CCC>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]2[N:15]([C:13]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:18])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:17])=[N:21][N:22]=2)[N:16]=1
Reactant: CC(C(=O)NN)c1c(F)cc2ncccc2c1F
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: CC(c1c(F)cc2ncccc2c1F)c1nnc2ccc(Cl)nn12

Procedure:
A solution of 2-(5,7-difluoro-quinolin-6-yl)-propionic acid hydrazide (2.404 g, 9.404 mmol) and 3,6-dichloropyridazine (2.138 g, 14.35 mmol) in butan-1-ol (60 mL) was stirred at 135° C. in a sealed tube overnight. Solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford 1.476 g (45% for two steps) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.93 (dd, 1H), 8.36 (dd, 1H), 8.07 (d, 1H), 7.62 (dd, 1H), 7.43 (dd, 1H), 7.05 (d, 1H), 5.26 (q, 1H), 2.13 (d, 1H). LCMS (method A): [MH]+=346, tR=5.00 min.
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])#N.C(C1C=CC=CC=1)(=O)C.[OH-].[Na+].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH:30](C2C=CC=CC=2)[C:31](=O)C)=[CH:26][CH:25]=1)#[N:23].OS([O-])(=O)=O.[K+]>C(O)C>[CH:9]1[CH:8]=[CH:7][C:4]([C:5](/[CH:31]=[CH:30]/[C:27]2[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][CH:28]=2)=[O:6])=[CH:3][CH:10]=1
Reactant: N#Cc1ccccc1C=O
Reactant: CC(=O)C(c1ccccc1)c1ccc(C#N)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)c1ccccc1
Solvent: CCO
Product: N#Cc1ccc(/C=C/C(=O)c2ccccc2)cc1

Procedure:
1 Mol of cyanobenzaldehyde is reacted with 1 mol of acetophenone and sodium hydroxide in ethanol. The resulting 3-(p-cyanophenyl)-3-phenylpropanone is reacted with KHSO4 to obtain p-cyanochalcone. The p-cyanochalcone is hydrogenated in the presence of a platinum catalyst to produce 3-(p-cyanophenyl)-1-phenylpropanone. The resulting compound is reacted with hydrazine and potassium hydroxide in triethylene glycol to produce p-cyanodiphenylpropane. The p-cyanodiphenylpropane is reacted with fuming nitric acid and acetic acid anhydride to produce 1-(p-cyanophenyl)-3-(p-nitrophenyl)-propane.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:33])([CH3:32])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:33])([CH3:32])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccc(F)cn2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to a solution of 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxyethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (207 mg, 0.45 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride then with 0-100% ethyl acetate/hexane afforded the title compound. Chiral HPLC eluting with IPA/heptane afforded the two individual enantiomers. (M+H) found: 410.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2ccc(F)cc2N1

Procedure:
The title compound was prepared from {4-fluoro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M5) (245 mg, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (145 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.[NH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:25]([CH3:34])[CH:24]=1)[CH3:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:34][C:25]1[CH:24]=[C:23]([C@H:21]([NH:20][C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:3]([CH3:4])([CH3:5])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH3:22])[CH:28]=[CH:27][C:26]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(c1ccc(OCC(=O)O)cc1)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C(F)(F)F)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a N,N-dimethylformamide (DMF) (3 ml) solution of [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetic acid (131 mg, 0.5 mmol) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (132 mg, 0.5 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (HOBt) monohydrate (85 mg, 0.55 mmol) and triethylamine (0.21 ml) were added and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 92 mg (39% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]3)[N:6]=[CH:5]2.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]6)=[CH:35][CH:34]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc2c(cnn2-c2ccc3[nH]ccc3c2)c1
Product: O=C(Nc1ccc2c(cnn2-c2ccc3[nH]ccc3c2)c1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 1043 was prepared according to the procedure described in Scheme IV from 5-amino-1-(indol-5-yl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoic acid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
A mixture of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (3 g) and sodium borohydride (0.34 g) in methanol (110 ml) was stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was poured into a mixture of ethyl acetate and water. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of n-hexane and diethyl ether to give a 5-(1-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (2.3 g).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([Cl:21])([Cl:20])[Cl:19])[N:15]=[C:14]([N:22]4[CH2:27][CH:26]5[CH2:28][CH2:29][CH:23]4[CH2:24][N:25]5C(OC(C)(C)C)=O)[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[ClH:19].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:17]=[C:16]([C:18]([Cl:20])([Cl:19])[Cl:21])[N:15]=[C:14]([N:22]4[CH2:27][CH:26]5[CH2:28][CH2:29][CH:23]4[CH2:24][NH:25]5)[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC1CN2c1nc(-c2ccc(N3CCCC3)cc2)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: ClC(Cl)(Cl)c1nc(-c2ccc(N3CCCC3)cc2)nc(N2CC3CCC2CN3)n1
Temperature: 25 °C
Yield: 181.3 %

Procedure:
Deprotected a solution of the product of Step 1 (1.1 g, 1.98 mmol) in anhydrous CHCl3 (18 mL) with 4N HCl in dioxane (18 mL, 71.6 mmol) under N2. Stirred at room temperature for >18 h, then concentrated. Added diethyl ether (60 mL) and CH2Cl2 (5 mL) and stirred for 1 h. Filtered resulting solid, washed with ether and CH2Cl2, and dried to give the title compound (0.88 g) as a yellow solid. MS, calc'd=452.10. Obsv'd m/z: 453.10 (M+1).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][C:23]=2[F:27])=[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.[NH:28]1[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]1>CCCCCCC.CCO.CO>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][C:23]=3[F:27])[C:2]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Reactant: O[C@@H]1CCNC1
Solvent: CO
Solvent: CCCCCCC
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 5 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)nicotinamide (Stage 25.1) and (R)-pyrrolidin-3-ol to afford a white powder. HPLC (Condition 4) tR=4.89 min, HPLC Chiral (CHIRALCEL® OD-H, 250×4.6 mm, eluent:n-heptane/EtOH/MeOH (85:10:5), 1 mL/min, UV 210 nm) tR=9.34 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.92 (m, 2H) 3.00 (d, J=11.73 Hz, 1H) 3.19-3.33 (m, 2H) 3.43 (m, J=7.00 Hz, 1H) 4.22 (br. s, 1H) 4.87 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 7.90-8.10 (m, 2H) 8.77 (br. s, 1H) 10.18 (s, 1H) 12.83-13.19 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:32][C:33]([NH2:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:8]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:32][C:33]([NH2:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(C(=O)CCl)CC3)cc2)cc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCNCC
Product: CCN(CC)CC(=O)N1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 119.1 %

Procedure:
25 mg of 4-(benzylamino)-6-({4-[4-(chloroacetyl)piperazin-1-yl]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 269) was dissolved in 2 mL of acetonitrile, to which 0.1 mL of diethylamine and 15 mg of potassium carbonate were added, and stirred at 80° C. for 1 hour. After cooling, the insoluble substances were filtered off, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 16 mg (59%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.[Ni]>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Reactant: C1=COCCC1
Agent: [Ni]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(COC2CCCCO2)cccc1[N+](=O)[O-]
Yield: 98.4 %

Procedure:
A solution of 100 g (0.598 mol) of 2-methyl-3-nitrophenylmethanol, 75.5 g (0.897 mol) of dihydropyran, and 15.0 g (0.06 mol) of the pyridinium salt of 4-methylbenzenesulfonic acid in 1 L of methylene chloride was stirred at ambient temperature for 24 hours. The reaction mixture was washed with two portions of 200 mL each of a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to give a residual oil. The oil was dissolved in 1 L of toluene, and was stirred in a Morton flask for 19 hours in the presence of 5 g of powdered Raney nickel. The mixture was filtered, and the filtrate concentrated under reduced pressure to give 147.8 g of 3-nitro-2-methylbenzenemethanol tetrahydropyranyl ether.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[CH:12][C:13](Cl)=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=1.CN1CCOCC1.C(OCC)(=O)C>O1CCCC1.O>[NH2:24][C:19]1[CH:18]=[C:17]([Br:16])[CH:22]=[CH:21][C:20]=1[NH:23][C:13](=[O:14])[CH:12]=[CH:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(Cl)C=CC1CCC2(CC1)OCCO2
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)ccc1NC(=O)C=CC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A solution of 3-(1,4-dioxa-spiro[4.5]dec-8-yl)acryloyl chloride (21.7 mmol) in tetrahydrofuran (20 mL) was added slowly to a solution of 4-bromo-benzene-1,2-diamine (5.2 g, 27.9 mmol) and N-methylmorpholine (7.1 mL, 83.7 mmol) in THF (50 mL) at 0° C. The resulting solution was allowed to warm up to room temperature. After 18 h the resulting solution was poured into a solution of ethyl acetate and water (1:1, 80 mL). The layers were separated. The organic layer was washed successively with water and brine dried over sodium sulfate, filtered and concentrated to yield N-(2-amino-4-bromo-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-acrylamide.