Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[C:19]2[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>CN(C=O)C.O>[Cl:28][C:26]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[C:19]=2[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g, 1.000 mmol) in DMF (5.00 ml) was added NaH (0.052 g, 55% dispersion in mineral oil, 1.20 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2 g, 1.000 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give tert-butyl 4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.236 g, 65%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.49 (9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H, m), 3.21-3.27 (2H, m), 3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[CH:3]=1.C([N:25]([CH2:29][CH3:30])[CH:26](C)C)(C)C.N1CCC1>C(O)CCC>[N:25]1([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:5]=[C:4]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[CH:3]=2)[CH2:26][CH2:30][CH2:29]1
Reactant: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3Cl)n2)n[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCC3)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 108 °C
Yield: 76.6 %

Procedure:
A mixture containing 6-chloro-2-(2-chlorophenyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (430 mg, 1.34 mmol), N,N-diisopropylethylamine (1.17 ml, 6.72 mmol), azetidine (272 mL, 4.03 mmol) and n-butanol (20 mL) was heated at 108° C. overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was treated with ethyl acetate/Petroleum ether and water and the resulting solid filtered. The solid was washed with further quantities of ethyl acetate/Petroleum ether and water and dried in vacuo to give the title compound as a white solid (350 mg, 76%). MS (ES+) m/e=341. 1H NMR: (DMSO) 2.28-2.40 (2H, m), 3.91-4.03 (4H, m), 5.90 (1H, brs), 6.30 (1H, brs), 7.31-7.60 (4H, m), 9.28 (1H, brs), 11.88 (1H, brs).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O1CCCC1>[C:10]1([CH2:9][C:8](=[O:16])[CH:1]=[CH2:2])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CON(C)C(=O)Cc1ccccc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 73 %

Procedure:
A 1M solution of vinylmagnesium bromide in THF (80 mL, 80 mmol) was added dropwise to a stirred solution of N-methoxy-N-methylphenylacetamide (12.8 g, 71.5 mmol) in distilled tetrahydrofuran (THF) (200 mL), cooled to 0°-5° C. in an ice-water bath. The solution was stirred at 0°-5° C. for 2 h and was then poured into cold 1N HCl solution (150 mL). The THF layer was separated and the aqueous (aq.) layer was extracted with EtOAc (100 mL). Organic extracts were combined, dried (MgSO4), filtered and concentrated. The crude oil was chromatographed on a silica gel column and eluted with 5-20% ethylacetate (EtOAc) in hexanes to obtain title 4-phenyl-but-1-ene-3-one (7.62 g, 73%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]([C:15]#[N:16])C([O-])=O)[CH2:6][CH2:5]2.[C-:17]#[N:18].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:11][C:15]#[N:16])([C:17]#[N:18])[CH2:6][CH2:5]2
Reactant: [C-]#N
Reactant: N#CC(C(=O)[O-])=C1CCc2cc(Br)ccc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCc2cc(Br)ccc21
Temperature: 65 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
To a solution of ethyl (2E/Z))-(5-bromo-2,3-dihydro-1H-inden-1-ylidene)(cyano)ethanoate (Prep1, 3.1 g, 10.15 mmol) in ethanol (23 mL) a solution of KCN (1.65 g, 2.5 eq) in water (6 mL) was added and the reaction mixture was warmed to 65° C. and stirred for ˜16-24 h. Then the solvent was removed under reduced pressure, the crude was treated with ether and water. Crystallization from ethanol gave the title compound (1.87 g, y=70%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:16][C:13]1[CH:14]=[CH:15][N:10]=[N:11][CH:12]=1)=[O:48]
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (1.61 ml, 9.23 mmol), 4-pyridazinamine (0.53 g, 5.54 mmol) and HATU (2.63 g, 6.92 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 1.5 g, 4.61 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours and the solid was filtered and washed with ethyl acetate to yield the title compound as a white solid. 658 mg.
Reaction SMILES: Br[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[C].[Pd].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Br
Agent: [Pd]
Solvent: CCO
Solvent: NCCN
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
An internal glass tube was introduced into an autoclave and 211 mg of ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate [obtained in accordance with the method of Bulletin of Faculty of Education, Wakayama University, 33, 33 (1984); cis:trans=0.8:1], 40 mg of 5% palladium-carbon (moisture content: 55% wet) and 8 ml of ethanol were fed thereinto. Then 90 mg of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (50 kgf/cm2) for 48 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture containing the title compound was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 95%, the yield was 81% and the cis:trans ratio was 0.8:1.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Cl-].[NH4+]>O1CCOCC1>[CH:14]1([C:3]2[C:4]3[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:5]=3[NH:6][C:2]=2[B:30]2[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc2[nH]c(B3OC(C)(C)C(C)(C)O3)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (2.00 g, 5.84 mmol) in 1,4-dioxane (20 ml) was added triethylamine (3.20 ml, 22.9 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.50 ml, 17.2 mmol) was added dropwise under an argon stream and the mixture was stirred at room temperature for 30 min. To the mixture were added 2-(dicyclohexylphosphino)biphenyl (245 mg, 0.699 mmol) and palladium acetate(II) (39.0 mg, 0.173 mmol) under an argon stream, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. A mixed solvent of hexane-ethyl acetate (10:1) was added to the obtained residue and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give methyl 6-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.66 g, yield 74%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O-])(O)=O.[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1.CO>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:4][CH2:3][CH2:1][OH:2])=[CH:13][CH:12]=1
Reactant: NCCO
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCNCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethanolamine (1.2 eq.) in either MeOH or THF were added NaHCO3 (1.5 eq.) and 4-chlorobenzaldehyde (1 eq.). The reaction was refluxed for 4 h, then cooled to 0° C. NaBH4 (1.2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C., then 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and DCM. The aqueous layer was then extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford 2-(4-chloro-benzylamino)-ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:22][CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:27]2[CH:26]=[C:25]([CH:23]([CH3:24])[CH3:22])[O:29][N:28]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: CC(C)c1cc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (CAS Registry No. 1018782-76-7) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials, 426.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:4][S:5][CH2:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH:19]1([NH:25][C:26]([NH:2][C:3]2[CH2:4][S:5][CH2:6][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)C1=C(N)CSC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(NC(=O)NC2CCCCC2)CSC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.3 parts by weight of 3-amino-4-methoxycarbonyl-1,5-dihydrothiophene hydrochloride, 6.0 parts by weight of triethylamine, 7.4 parts by weight of cyclohexyl isocyanate and 30 parts by weight of acetonitrile were combined, and the mixture was stirred for 3 hours at 25° C. and then evaporated down. The residue was washed with water and recrystallized from toluene. 4.5 parts by weight of N-cyclohexyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 153°-154° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=O)[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CCN(C(C)C)C(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[C:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])[OH:15])[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 116.7 %

Procedure:
Dichloromethane (200 mL) was added to 2-(4-chlorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.27 g, 13.7 mmol) (reference compound 51). The mixture was cooled with an ice bath. DMAP (2.008 g, 16.44 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.96 g, 20.54 mmol) and DIPEA (5.25 mL, 30.13 mmol) were added and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.25 g, 27.39 mmol) was added. The mixture was stirred at 0° C. for 15 min, then the mixture was warmed to room temperature and stirred overnight. The organic phase was washed with 1 M HCl and once with water. The organic layer was filtered through a phase separator and evaporated to yield crude methyl 2-(4-chlorobenzyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl)-piperidine-1-carboxylate (7.00 g, 117%). MS m/z 438, 440 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:30][CH2:29]1
Reactant: Br[Mg]C1CC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CC3)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (40 mg, 0.11 mmol) was dissolved in dry THF (1.1 mL) and cyclopropylmagnesium bromide (0.5 M in diethylether, 1.1 mL, 0.55 mmol) was added dropwise at rt and the reaction was allowed to stir for 10 minutes. The reaction was quenched with water, concentrated, and purified by reverse-phase HPLC to give cyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate which was taken up in 1.0 mL EtOH and 0.7 mL 4.0M HCl/dioxane and heated for 2 hours at 65° C. Reaction was then concentrated down and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH:18]([CH3:20])[CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH:18]([CH3:19])[CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2OC(C)C)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-isopropoxy-phenyl)-methanone (Example 200) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C20H27N5O4SF [(M+H)+] 452.1766, observed 452.1766.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].[F:25][C:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([NH:21][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:26]([F:25])([CH3:27])[CH3:28])[CH:33]=2)=[O:36])[CH:22]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)F)no4)c(F)cc3F)c2cc1OC
Yield: 31 %

Procedure:
To a stirred solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmoles) from the previous step and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 42A (96 mg, 0.32 mmoles) in anhydrous DMF (10 mL), was added 4-(dimethylamino)pyridine (20 mg, 0.16 mmoles) and diisopropylethylamine (80 μL, 0.45 mmoles) and the reaction heated to 70 C overnight. The reaction was then concentrated to an oil and purified by silica gel chromatography eluting with a gradient of ethyl acetate/dichloromethane, 3-80%, to afford 1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (46.33 mg, 31% yield) as a white solid. 1H (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 8.13 (m, 1H), 7.67 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 6.12 (s, 1H), 3.98 (s, 6H), 1.65 (d, J=21 Hz, 6H); LCMS (ESI) m/z (M+H)+ 504.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.O(CC)CC.C([Li])CCC.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:16]=[CH:17][CH:18]=[CH:19]2)[OH:27]
Reactant: c1ccsc1
Reactant: O=Cc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc2ncccc2c1)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a stirred and cooled (-5°/0° C.) solution of 5.4 parts of thiophene in 21.3 parts of 1,1'-oxybisethane were added portionwise 43.5 parts of a solution of n. butyllithium in hexanes 1.6M. After stirring for 20 min. at 0° C., there was added a solution of 5 parts of intermediate 16, namely 6-quinolinecarboxaldehyde, in 71.2 parts of tetrahydrofuran. Stirring at 0° C. was continued for 1 hour and then the reaction mixture was poured into 200 parts of ice-water. The product was extracted with 1, 1'-oxybisethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C12 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 2.4 parts (31.1%) of α-(2-thienyl)-6-quinolinemethanol (interm. 17).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[OH:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:28]([CH3:30])[CH3:29])=[O:15]
Reactant: CN(C)C(=O)CCCO
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in tetrahydrofuran (70 ml.) is added, dropwise at 0° C., to a stirred solution of 4-hydroxy-N,N-dimethylbutyramide (1.20 g.) and triethylamine (2.1 g.) in tetrahydrofuran (35 ml.). The mixture is stored for two days. The solid is filtered off and washed with ether, and the filtrate and washings are evaporated. The residue is dissolved in ether and the solution is washed with water, 0.4 N aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated. The residue is crystallised from a mixture of light petroleum (b.p. 40°-60° C.) and ether to give (±)-3-dimethylcarbamoylpropyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.3 g.) m.p. 42°-43° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1Cl
Product: CC(C)N1CCC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Cl)CC1

Procedure:
The titled compound was prepared analogously as describe in Example 82, using 2-(2-chlorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 1-isopropyl-4-aminopiperidine. MS 463.1, 464.1, 465.1 and 466.1 (M+H, 2Cl pattern).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Yield: 63.2 %

Procedure:
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10% HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6%) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.