Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C[N:13](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH2:13])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (0.5 g) and DMF (0.1 ml) in DCM (10 ml) was added dropwise oxalyl chloride (0.6 ml). After stirring for 2 h, ammonia gas was purged through. After completion of reaction by tlc, the solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 0.18 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]1=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:23]3[CH2:24][CH2:25][CH2:26][CH:21]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=4)[C:22]=3[N:11]=2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(NC(N)=S)ccc1Br
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1Br
Yield: 61.9 %

Procedure:
(4-Bromo-3-methoxy-phenyl)-thiourea (1.20 g, 4.59 mmol) and 2-bromo-6-phenyl-cyclohexanone (1.29 g, 5.10 mmol) in 20 ml ethanol were stirred overnight at reflux. The brown solution was evaporated to dryness; the brown residue was dissolved in chloroform, washed three times with water and dried with magnesium sulfate. The solvent was evaporated in vacuo. Column chromatography (70 g silica, dichloromethane) afforded the title compound (1.18 g, 62%) as a light brown foam. MS ISP (m/e): 417.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): □ (ppm)=7.25 (m, 7H), 6.90 (s broad, 1H), 6.50 (dd, 1H), 4.04 (m broad, 1H), 3.58 (s, 3H), 2.75 (m broad, 2H), 2.20 (m broad, 1H), 1.77 (m broad, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])#[CH:12].N>>[NH2:16][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1cccc(N)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Nc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 3-ethynylaniline (Aldrich, 59 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 6.83 (dt, J=7.5, 1.9 Hz, 1H), 7.10-7.33 (m, 4H), 7.59 (dd, J=8.0, 4.9 Hz, 1H), 8.35 (dt, J=8.1, 1.9 Hz, 1H), 8.65 (dd, J=4.9, 1.5 Hz, 1H), 9.08 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9])(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
Preparation B5, Step 4: To a mixture of methyl 2-(methylsulfonamido)-5-(trifluoromethyl)benzoate (1.0 g, 3.367 mmol) in THF (20 ml) and water (20 ml) was added lithium hydroxide (0.4242 g, 10.10 mmol) and stirred at RT for 6 h. The reaction mixture was acidified with 1.5 N HCl and extracted with ethyl acetate (3×50 ml). The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The solid was filtered and dried under vaccum to get 2-(methylsulfonamido)-5-(trifluoromethyl)benzoic acid (0.7 g, 73%) as white solid. 1H NMR (400 MHz, CDCl3) δ 3.31 (s, 3H), 7.78 (d, 1H), 7.97 (d, 1H), 8.24 (s, 1H), 11.13 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 40.74, 116.5, 118.3, 122.8 (m), 128.8, 131.6, 144.3, 169.1. MS found: (M−H)−=282.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:14])[CH:8]=[CH:9][C:10]([O:12]C)=[O:11].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:14])[CH:8]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)C=CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C=CC(=O)c1ccccn1

Procedure:
A mixture of 15 g of 4-(2-pyridyl)-4-oxo-2-butenoic acid, methyl ester in chloroform (50 ml) is stirred with 3.14 g of sodium hydroxide in 50 ml of water for 5 hours at room temperature. The aqueous layer is separated, washed with chloroform and acidified with 4.71 g of acetic acid, yielding the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([C:34]([F:37])([F:36])[F:35])=[CH:23][N:22]=1.Cl.CO>CC(O)C>[F:1][C:2]1[C:3]([NH:4][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[C:24]([C:34]([F:35])([F:37])[F:36])=[CH:23][N:22]=2)=[CH:5][C:6]([CH3:19])=[C:7]([CH:9]2[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]2)[CH:8]=1
Reactant: Cc1cc(N)c(F)cc1C1CCC2(CC1)OCCO2
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (318.6 mg, 1.2 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (333.0 mg, 1.2 mmol) and HCl (4 N in water, 0.3 mL, 1.2 mmol) in i-PrOH (4.0 mL) was heated at 125° C. in an oil bath overnight. The reaction mixture was concentrated in vacuo. The resulting crude mixture was dissolved in THF (4 mL), MeOH (2 mL) and HCl (4N in water, 0.3 mL, 1.2 mmol), and stirred at room temperature for an additional 2 h. The reaction mixture was concentrated in vacuo, and purified by silica chromatography (0-100% EtOAC in hexanes gradient) to afford 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone; ESMS m/z 463.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:25][CH2:26][CH2:27][Cl:28])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CCCCl)c3ccccc32)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of Compound 9 (1.7 g, 5.3 mM), as prepared in Example 9, bromopropylchloride (5.3 ml, 5.3 mM) and cesium carbonate (3.5 g, 10.6 mM) in acetone (60 ml) was stirred at reflux for 24 hours then cooled to RT. The acetone was removed under reduced pressure, the residue diluted with water (60 ml) and the aqueous mixture was extracted with ethyl acetate (2×60 ml). The combined ethyl acetate layers were dried over MgSO4 and evaporated in vacuo to give the product (2.1 g, 100%) as an oil that solidified on standing. m/z (MH+) 393.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous K2CO3 (20.36 g, 146 mmol) and a catalytic amount of KI were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with EtOAc (3×100 mL). The combined extracts were washed with 5% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexane to give 14 g of an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7](O)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].[Cl:16][C:17]1[C:22]([NH2:23])=[C:21](I)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][C:21]2[C:22](=[C:17]([Cl:16])[CH:18]=[CH:19][CH:20]=2)[NH:23][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:2]
Reactant: Nc1c(Cl)cccc1I
Reactant: C=C(C(=O)OCC)C(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2cccnc2)Nc2c(Cl)cccc2C1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
A degassed mixture of 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (8.2 g, 39.6 mmol), 6-chloro-2-iodoaniline (10.0 g, 39.5 mmol), triethylamine (9 mL, 122 mmol) and palladium(II) acetate (300 mg) in acetonitrile (80 mL) was heated at 70° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was separated and the organic layer was washed with brine (50 mL), filtered, dried (phase separator) and concentrated in vacuo to give a crude solid. This was washed with a minimum of ice-cold diethyl ether to yield 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.8 g, 87%) as a white solid. δH (CDCl3) 8.73 (m, 2H), 8.04 (m, 1H), 7.66 (dd, J 7.9, 5.5 Hz, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.29 (s, 1H), 3.99 (m, 4H), 1.04 (t, J 7.1 Hz, 3H). LCMS (ES+) 315.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[NH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]=2[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.4 %

Procedure:
tert-Butyl 4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.390 g, 0.994 mmol) was placed in DCM (10 mL) at room temperature. TFA (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give 3-methyl-5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.350 g, 96.4% yield), which was used without further purification.
Reaction SMILES: CI.[CH3:3][C:4]1([CH3:28])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([OH:21])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1.[CH3:29]N(C)C=O.C[O-].[Na+]>O>[CH3:28][C:4]1([CH3:3])[C:23]2=[CH:24][CH:25]=[N:26][CH:27]=[C:22]2[C:7]2[C:8]([O:21][CH3:29])=[CH:9][C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])=[CH:11][C:6]=2[O:5]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (5.11 g., 0.036 mole) was added dropwise to a stirred solution of 10.59 g. (0.03 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano [3,4-d]pyridine in 300 ml. of N,N-dimethylformamide containing 1.78 g. (0.033 mole) of sodium methoxide. The mixture was stirred at room temperature for 18 hours and 300 ml. of water was added and extracted with petroleum ether (30°-60°). The combined petroleum ether extracts were washed with water, dried with anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on a Florisil® column with chloroform or by distillation under reduced pressure to give the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=O)[O:10]1.O.[NH2:23][NH2:24]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=[O:10])[NH:24][N:23]=1
Reactant: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A suspension of 3-(3,5-dichloro-pyridin-4-ylmethylene)-6-methoxy-3H-isobenzofuran-1-one (84.4 g, 0.126 mole), prepared as described in example 37, in CH3OH (200 ml) under N2 was added with hydrazine monohydrate (18.4 ml, 0.378 mole). The mixture was refluxed for 1 hour, then left overnight at room temperature and cooled over ice. The solid was filtered, washed with cold CH3OH and dried in oven at 50° C. under vacuum; 33.3 g of the title compound were thus obtained (yield: 80%). m.p.: 259-262° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)C.Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:12]([C:6]1[CH:7]=[C:8]([O:11][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[CH:10][C:5]=1[NH2:4])([O-:14])=[O:13]
Reactant: BrCCOc1ccccc1
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
A mixture of 2.0 g. of 4-acetamido-3-nitrophenol, 2.2 g. of β-bromophenetole, 3 g. of potassium carbonate, and 20 ml. of dimethylformanide is heated under nitrogen for 16 hours at 110° C. The mixture is cooled and poured into ice water. The precipitated solid is collected, washed with water, and dried to give 2-nitro-4-(2-phenoxyethoxy)-aniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Yield: 81.1 %

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (5 g, 24.9 mmol) in acetone (200 mL) were added benzyl bromide (5.11 mL, 29.9 mmol), potassium iodide (KI, 2.07 g, 12.45 mmol) and potassium carbonate (K2CO3, 5.17 g, 37.4 mmol), followed by mixing at 70° C. for 2 hours under a reflux condition. The product thus obtained was diluted in ethyl acetate (EtOAc), washed with brine, and dried over magnesium sulfate (MgSO4) to concentrate it. The concentrate was purified using silica column chromatography (10% ethyl acetate/hexane) to afford the title compound (5.88 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16]Br)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCCBr)c1csc(N)n1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Nc1nc(/C(=N/OCCn2ccnc2)C(=O)O)cs1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
16.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-bromoethoxy)imino]-acetate and 17 g of imidazole are boiled under reflux for 4 hours in 160 ml of acetonitrile. The mixture is evaporated to dryness under reduced pressure, the residue is taken up in 150 ml of water, 25 ml of aqueous 3N sodium hydroxide solution and 100 ml of ethyl acetate and the aqueous phase is extracted twice with 100 ml of ethyl acetate each time. The organic phase are combined, washed with a small amount of water and evaporated. The residue is saponified at 50° C. for 1.5 hours with 100 ml of aqueous 1N sodium hydroxide solution and 100 ml of methanol. After the addition of 100 ml of 1N aqueous hydrochloric acid, the mixture is evaporated. The evaporation residue is crystallized using 250 ml of methanol and the crystallizate is suction filtered. There are obtained 13.2 g of crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-imidazol-1-yl-ethoxy)imino]-acetic acid. For purification, a solution of 11 g of crude product in 100 ml of water is adsorbed on 200 ml of DOWEX 50 W (ion exchange resin; H+ form). The product is recovered by elution with 2.5% aqueous ammonia solution. After evaporation of the solvent, the product is crystallized using methanol. There are obtained 5.6 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-imidazol-1-yl-ethoxy)imino]-acetic acid of melting point 166° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:34]([NH:38][S:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][S:39]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=4)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-(4-{4-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-pyridin-2-yl)-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.16 g, 0.32 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.11 g, 0.41 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.21 g), which was subsequently deprotected.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH2:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1.C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH:24][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2ccccc2OC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-amino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (240 mg, 0.703 mmol) in pyridine/DCM (1 ml/1 ml) was added succinic anhydride (84 mg, 0.843 mmol) and stirred at room temperature for 1 hour. Then, the mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC to give (S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. HPLC Retention time 1.29 minutes (condition A): MS 442.4 (M+1)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]1([F:17])[CH2:16][NH:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C1COCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][C:13]([F:17])([F:12])[CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: FC1(F)CNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C2)nc1
Temperature: 120 °C

Procedure:
The 2-chloro-5-nitro-pyridine (317 mg, 2 mmol) and 3,3-difluoroazetidine hydrochloride (259 mg, 2 mmol) was mixed in 8 mL of THF. Diisopropylethylamine (1.4 mL) was added and the mixture was heated in a microwave at 120° C. for 20 minutes. After cooling to room temperature, the solid was filtered and the filtrate was distributed between ethyl acetate and water. The organic layers were evaporated and the solid material was triturated with methanol. The resulting solid was filtered to give 5-nitro-2-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd for C8H7F2N3O2 m/e 215.16, obsd 216.1 (ES, M+H). Hydrogenation of the nitro compound, as above, provided 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]1[C:21]([NH2:22])=[N:20][C:14]2[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=2[CH:12]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:19][C:16]1[N:17]=[CH:18][C:13]2[CH:12]=[C:11]([C:3]3[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=3[CH3:10])[C:21]([NH:22][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:20][C:14]=2[N:15]=1
Reactant: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2N)c1C
Reactant: CC(C)(C)N=C=O
Product: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.3 g of 6-(2,3,5,6-tetramethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 98 and 0.125 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1 CHCl3 :EtOAc; mp >300° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 393 (MH+, 55), 394 (MH+ +1, 13), 84 (100).
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[CH:23][CH:22]=1>C(O)C>[CH3:17][N:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[CH:25][CH:26]=1)[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1
Reactant: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amine (56.7 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-(methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amino)-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.069 mmol; yield: 54%, HPLC-MS/UV: [M+H]=482.48; rt: 11.27 min; purity: 96%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.80 (t, J=6.68 Hz, 2H), 2.94 (s, 3H), 3.52 (s, 2H), 3.69 (t, J=7.09 Hz, 2H), 7.00 (d, J=8.76 Hz, 2H), 7.19 (d, J=8.10 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8.45 Hz, 2H), 7.44 (d, J=7.75 Hz, 1H), 7.58 (t, J=8.10 Hz, 1H), 7.66 (s, 1H), 8.66 (s, 2H), 8.95 (s, 1H)