Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:27]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.0341 g, 0.0981 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0151 g, 0.103 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}piperidine-1-carboxylate (0.0446 g, 96%).
Reaction SMILES: [N+:1](=[C:3]1[N:7]=[CH:6][N:5]=[C:4]1[C:8]([NH2:10])=[O:9])=[N-:2].[N:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]=[O:13]>CS(C)=O>[CH3:19][S:16]([CH2:15][CH2:14][N:11]1[C:12](=[O:13])[N:7]2[CH:6]=[N:5][C:4]([C:8]([NH2:10])=[O:9])=[C:3]2[N:1]=[N:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)CCN=C=O
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-diazoimidazole-4-carboxamide (0.5 g, 12.0 mmol) in dry DMSO (5 mL) was added 1-Isocyanato-2-methanesulfonyl-ethane (1.04 g, 3.65 mmol). The mixture was stirred at room temperature for 16 hours, whereupon it was poured onto crushed ice and the resultant precipitate collected by filtration. The filter cake was washed with Et2O (3×1 reaction volume) and dried to give the title compound as an off white solid (990 mg, 95%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.89 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 4.73 (2H, t, J=6.8 Hz), 3.70 (2H, t, j=6.8 Hz), 2.44 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C(=O)C>[Br:19][C:17]1[CH:16]=[N:15][N:14]([CH3:18])[C:13]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(NC(C)=O)cc1-c1c(Br)cnn1C
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl]-acetamide (25.0 kg) in N,N-dimethylacetamide (DMA, 140.5 kg) in a 400 L glass lined jacketed reactor with overhead stirring under nitrogen at 45 to 55° C. internal temperature N-bromosuccinimide (NBS, 19.0 kg) was charged in portions at such a rate as to maintain internal temperature to less than 55° C. The reaction mixture remained a solution at this dilution of DMA and internal temperature of 50.9° C. An “in process check” of the reaction mixture to determine reaction completion after at least 1 hr of stirring at 50° C. showed that the reaction mixture was substantially free of the starting material. Upon cooling of the reaction mixture to an internal temperature of 34° C. water (150 kg) was added in a controlled manner into the reactor to maintain an internal temperature between 40-55° C. A slight exotherm was observed during the reaction quench. The product slurry was then cooled to −5 to 5° C. and filtered through a corrosion resistant filter/dryer. The wetcake was re-slurried, washed with water (2×25 kg), and dried under full house vacuum (˜30 in Hg) with a jacket temperature of 65° C. producing N-[3-(4 bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy phenyl]-acetamide (31.6 kg, 100% purity by HPLC, 96.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[Cl:22]Cl.O>C(O)(=O)C>[Cl:22][C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: ClCl
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 3(2-chloro-4-trifluoromethylphenoxy)-benzoic acid (5 g) in glacial acetic acid (30 ml) was heated under reflux while chlorine was passed through the solution for 5 hours. The solution was left to stand for two days at room temperature and then poured into cold water (500 ml). An off-white gummy solid separated. This was extracted with ethyl acetate and the extract dried and evaporated. The brown oil remaining was dissolved in sodium bicarbonate solution and the solution extracted with ethyl acetate. The aqueous chloride was acidified with hydrochloric acid. The solution was decanted from the precipitated gum, and the gum taken up in boiling hexane. The hexane solution was filtered and allowed to cool. The required 2-chloro-5(2-chloro-4-trifluoromethylphenoxy)benzoic acid was obtained (1.0 g) as crystals of melting point 103°-104°. This acid was used as starting material for compounds 7 and 8.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>C(O)(C)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:11]=[C:12]1[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]1=[O:18]
Reactant: Nc1ccccc1Br
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2ccccc2Br)C(=O)O1
Yield: 87.9 %

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in isopropanol (240 ml) was heated to reflux for 1 hour. After cooling, the deposit was filtrated to obtain 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). A suspension of the obtained 5-((2-bromophenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.8 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution. The deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). 4-Chloro-8-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)quinoline was obtained according to Example 3(2) using the obtained 8-bromoquinolin-4(1H)-one instead of compound (3a). Compound (130) was obtained as a pale yellow solid (yield based on 6 steps: 3.4%) according to Example 3(3) using 3-(tert-butylamino)-4-cyanophenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]3[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: N#CC1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 59.2 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where azetidine-3-carbonitrile hydrochloride (0.08 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 mL, 2 eq) were added dropwise. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-5% Methanol in DCM). to obtain (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carbonitrile (0.14 g, 60% yield). 1H NMR (400 MHz, DMSO) δ=9.36 (s, 1H), 8.54 (s, 2H), 8.30 (s, 1H), 7.45-7.43 (d, J=10 Hz, 1H), 5.95-5.92 (d, J=10 Hz, 1H), 4.39-4.37 (t, 1H), 4.29-4.11 (m, 3H), 3.84-3.82 (m, 1H); LCMS calcd. for C17H12F6N5O [M+H]+ 416.29. found 416.14, at 2.64 min retention time
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(O[CH:25](N(C)C)[N:26]([CH3:28])[CH3:27])(C)C>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH:28]=[C:7]1[CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1=[O:1])[CH3:27]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC(=CN(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2b (272 mg, 1.00 mmol) in dry toluene (4.0 mL) was added Bredereck's reagent (183 mg, 1.05 mmol) dropwise over 2 minutes. The mixture stirred at rt for 1 h and heated to 60° C. for 24 h. The mixture was concentrated and the residue purified on a SiO2 column (CH2Cl2, 50% EtOAc-hexanes then EtOAc for elution) to give a viscous oil. The oil was dissolved in 50% Et2O-hexanes and concentrated to give the title compound 3b as a waxy white solid; 243 mg, 74%. This material was used immediately without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[NH2:6].C[S-].[Na+]>CN1CCCC1=O>[NH2:6][C:5]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(N)cc(OC)c1
Agent: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(N)cc(O)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
3,5-Dimethoxyaniline (9.97 g, 65.1 mmol) and sodium methyl mercaptide (9.1 g, 130 mmol) were dissolved in N-methylpyrrolidinone (60 ml). The reaction mixture was stirred at 140° C. for 1 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous Na2HPO4. The layers were separated and the organic layer was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc/hexanes to afford 3-amino-5-methoxyphenol (5.44 g). MS m/z: 140 [M+H]+
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-:23].[Na+].II.C(Cl)Cl>C1COCC1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:23][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]
Reactant: OCCOCCOCCOCCCCCCCCCCCS
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCOCCOCCOCCCCCCCCCCCSSCCCCCCCCCCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
To a solution of 2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]-ethoxy}-ethanol (145 mg, 0.43 mmol) dissolved in 5 mL of THF was added 1 mL of a NaOH solution (0.1 M), followed by iodine (5 crystals). The solution was stirred at room temperature for 24 h and added to 20 mL of CH2Cl2. After the solution was rinsed with H2O (2×5 mL), the organics were dried over MgSO4 and concentrated. The crude residue was purified by flash chromatography (CH2Cl2/MeOH, 20:1, v/v) to afford 78 mg (54%) of 2. 1H NMR 400 MHz (CDCl3) d 3.72-3.52 (br, 24 H), 3.44 (t, J=7.2 Hz, 4 H), 2.66 (t, J=7.0 Hz, 2 H), 2.41 (br s, 2H), 1.65 (m, 4H), 1.57 (m, 4H), 1.41-1.20 (br, 28H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[CH:4][N:3]=1.[C:20]([Cu])#[N:21].[C-]#N.[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C:5]2[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]#[N:21])=[N:3][CH:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1Cl
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 170 °C

Procedure:
To a solution of 2-chloro-5-[(3,4-difluorophenyl)methyl]-3-nitropyridine (10.88 g, 38.22 mmol) in NMP (50 ml), was added CuCN (10.27 g, 0.115 mmol) and NaCN (1.02 g). Heated in the microwave at 170° C. for 1 h and the resulting mixture was diluted with EtOAc and filtered through Celite. Water was added to the filtrate and the organic layer was washed with water and brine, dried and concentrated in vacuo. The resulting product was purified by chromatography on silica gel, eluting with 0-25% EtOAc/hexanes to afford an amber oil. 1H NMR (CDCl3) δ 8.82 (1H, s), 8.31 (1H, s), 7.22-7.15 (1H, m), 7.03-6.98 (1H, m), 6.94-6.90 (1H, m), 4.16 (2H, s).
Reaction SMILES: [CH2:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6](O)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].CS(Cl)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.CCN(CC)CC>[N:29]([CH:6]([Si:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[N+:30]=[N-:31]
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C(O)CC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C(CC(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 34 (1.68 g, 5.16 mmol) in CH2Cl2 (100 mL) and Et3N (3.6 mL) at 0° C. was added dropwise over 5 min methanesulfonyl chloride (2.96 g, 25.8 mmol), and the solution was allowed to warm to rt over 1 h. After stirring overnight under argon, the mixture was cooled to 0° C. and quenched with water (50 mL). The organic layer was isolated and the aqueous layer extracted twice with 20-mL portions of CH2Cl2. The combined organic extracts were concentrated in vacuo at rt. The crude mesylate was dissolved in DMF (100 mL), and to this solution was added sodium azide (1.68 g, 25.8 mmol). After stirring for 8 h at rt, the mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was isolated and aqueous layer extracted twice with 50-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 35 as a colorless oil (1.57 g, 87%): Rf=0.90 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=6.7 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 5.00 (dd, J=17.0, 1.5 Hz, 1H), 4.92 (dd, J=10.2, 1.5 Hz, 1H), 3.44 (d, J=12.4 Hz, 1H), 2.12 (m, 2H), 1.84 (m, 1H), 1.60 (t, J=12.5 Hz, 1H), 1.30 (m, 3H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 140.7, 135.3, 132.6, 129.9, 128.0, 113.3, 49.2, 38.8, 27.5, 25.9, 23.3, 20.7, 10.5; IR (neat) 3071 (w), 3051 (w), 2995 (w), 2957 (s), 2923 (m), 2866 (m), 2102 (s), 1642 (w), 1473 (w), 1432 (s), 1264 (m), 1188 (w), 1116 (s), 1004 (w), 915 (m), 743 (s), 701 (s) cm−1; MS (FAB) m/e (rel. intensity) 350 (MH+, 18), 323 (32), 322 (100), 321 (27), 320 (16), 315 (42), 306 (42), 252 (17), 251 (23), 237 (18), 236 (73), 223 (26), 208 (17); HRMS (FAB) calcd for C11H28N3Si: 350.2053, found: 350.2040. Anal. Calcd for C21H27N3Si: C, 72.16; H, 7.79; N, 12.02. Found: C, 71.99; H, 7.91; N, 11.60.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1N=C(NC2C=CC=C(O)C=2)C(F)=C[N:29]=1.N1C=CC=C(CN)C=1>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][CH2:20][C:25]2[CH:28]=[N:29][CH:22]=[CH:23][CH:24]=2)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: NCc1cccnc1
Product: Oc1cccc(Nc2nc(NCc3cccnc3)ncc2F)c1
Yield: 62 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDCl3): δ 4.40 (d, J=6.3 Hz, 2H), 5.60 (br, 1H), 6.62–6.70 (m, 3H), 7.05 (br, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (dd, J=5.1 and 7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H), 8.49 (d, J=4.5 Hz, 1H), 8.66 (s, 1H); 19F NMR (282 MHz, CDCl3): δ −169.52; LCMS: ret. time: 9.41 min.; purity: 99.25%; MS (m/e): 312.01 (ME+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)=[O:5])[CH3:3].[C:23]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])(=[O:25])[CH3:24].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:23]([NH:26][C@H:27]([C:29]([NH:1][C@H:2]([C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:5])[CH3:3])=[O:30])[CH3:28])(=[O:25])[CH3:24]
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: C[C@H](N)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 4.50 g (15 mM) of 6-[4-(L-alanylamino)-phenyl]-1,2-dihydro-2-oxonicotinic acid, Example 4, 1.97 g (15 mM) N-acetyl-L-alanine, 2.02 g (15 mM) 1-hydroxybenzotriazole, and 150 ml of DMF was stirred at room temperature and 3.09 g (15 mM) of dicyclohexylcarbodiimide was added. After 19 hours the reaction mixture was filtered and the filtrate evaporated to dryness. Water was added and the solids filtered, washed with hot ethyl acetate and ether, and dried, giving 5.01 g of 6-[4-(N-acetyl-L-alanyl-L-alanylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:6][CH2:5]2.CN(C)C=O.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([C@@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:8]2
Reactant: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1([C@H]2CCc3c(ccc(O)c3Br)C2)COC(=O)N1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
To a mixture of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0004 mol) (pure isomer 2) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) was added N-Bromosuccinimide (72.0 mg, 0.000404 mol) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) and was stirred at for 6 hrs. Water was added, and the mixture was extracted with dichloromethane. The solvent was removed and residue was purified with Isco (12 g silica gel, 0-40% MeOH:DCM) to give a white precipitate (125 mg, 95% yield). 1H NMR showed a single isomer. The solid (10.1 mg) was dissolved in MeOH (3 mL) and the solvent allowed to evaporate slowly to give white needles, which was washed with MeOH and collected (5.0 mg). LCMS 1.23 min 328.21 ([M+2], 100%). X-ray shows (S,S) configuration, see FIG. 2.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21]C=C[N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH:36]1C=CC(C=O)=N1>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][NH:36][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Reactant: O=Cc1cc[nH]n1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cc[nH]n4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 202 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 218 (step 3) and 1H-pyrazole-3-carboxaldehyde.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccc(CCBr)cc1C
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1C
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3,4-dimethylphenethyl bromide (0.4 g--see Preparation 18), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 2 hours. On cooling to room temperature, water (80 ml) was added and the mixture was extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a yellow oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.22 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 336 (M+H+, 100).