Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])=[CH:35][C:36]=1[C:41]([F:42])([F:43])[F:44]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 33 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a beige solid. LC/MS [439 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.27 (s, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.54 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.76 (dd, J=8.3, 1.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 5.51 (s, 1H), 3.17 (dd, J=12.4, 8.0 Hz, 1H), 3.00 (dd, J=12.4, 5.6 Hz, 1H), 2.60-2.55 (m, 2H), 2.54 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[OH:23][C:19]([C:15]1[CH:14]=[C:13]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=2)[CH:18]=[CH:17][CH:16]=1)([C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(-c2cccc(C=O)c2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 72.8 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 3-formylphenylboronic acid (0.45 g) and 1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.05 g), the amorphous title compound (0.80 g) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][N:9]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl)-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:22][CH3:23].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>O>[CH3:23][O:22][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Reactant: C1CSCCN1
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCSCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
1,2-Dibromoethane (19.2 ml, 286 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (6.0 g, 22 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (14.4 g, 107 mmol) in DMF. The mixture was stirred at 85° C. for 2.5 hours, allowed to cool and insoluble material was removed by filtration. The solvent was removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (93/7). The product was trituated with ethyl acetate to give 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (5.3 g, 63%). A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (2.0 g, 5.3 mmol) in thiomorpholine (15 ml) was stirred at ambient temperature for 5 hours. The mixture was diluted with water and the resulting precipitate collected by filtration. The solid product was dissolved in methylene chloride, washed with brine and passed through phase separating paper. The solvent was removed by evaporation to give 6-methoxy-4-phenoxy-7-(2-thiomorpholinoethoxy)quinazoline (2.0 g, 94%) as a pale yellow solid.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 3-(4-trifluoromethoxyphenoxy)propylamine (1.18 g) and triethylamine (0.50 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[OH:15].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: COc1ccc(CCO[C@H]2CCCC[C@H]2O)cc1OC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCO[C@H]2CCCC[C@H]2OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A 10-mL round bottom flask under nitrogen atmosphere was charged with cis-2-(3,4-dimethoxyphenethoxy)cyclohexan-1-ol (13) (80 mg, 0.28 mmol), anhydrous dichloromethane (3 mL), and anhydrous pyridine (70 μL, 0.86 mmol). After the reaction mixture was cooled to 0° C., a solution of 4-nitro-benzenesulfonyl chloride (95 mg, 0.43 mmol) in anhydrous dichloromethane (1.5 mL) was added dropwise. The reaction was stirred at 0° C. for 30 minutes, and then at room temperature until total consumption of all starting material 13 (20 h), as revealed by TLC (1:1, v/v EtOAc:hexane). The reaction mixture was diluted with dichloromethane (10 mL) and aqueous H2SO4 (5%, 10 mL). After the aqueous layer was extracted with CH2Cl2 (2×10 mL), the organic layers were combined, washed successively with diluted aqueous H2SO4 (5%, 10 mL) and brine (10 mL), dried (anhydrous MgSO4), and concentrated in vacuo to give a yellow oil. Purification of this crude material by elution through a silica gel plug using a mixture of ethyl acetate-hexanes (1:2, v/v) afforded 14 (95 mg, 72%). Rf 0.71 (EtOAc-hexanes, 1:1, v/v); 1H-NMR (400 MHz, CDCl3) δ 1.21-1.69 (m, 8H), 2.01-2.11 (m, 1H), 2.63 (t, 2H, J 6.9 Hz), 3.36-3.38 (m, 1H), 3.43-3.57 (m, 2H), 3.83 (s, 6H, OCH3), 4.84-4.86 (m, 1H), 6.63-6.69 (m, 2H), 6.75 (d, 1H, J 8.1 Hz), 8.01-8.05 (m, 2H), 8.24-8.28 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 21.19, 21.57, 27.20, 29.00, 35.90, 55.76, 55.87, 69.93, 82.65, 111.07, 112.19, 120.63, 124.06, 128.92, 131.39, 143.45, 147.45, 148.68, 150.33.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CS(C)=O>[O:11]=[C:9]([CH3:10])[CH:8]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:12])[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)CC(=O)c1ccccn1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of 3.38 g (20.7 mmol) of 1-(pyridin-2-yl)butane-1,3-dione dissolved in dimethyl sulfoxide was slowly added dropwise to 0.911 g (22.78 mmol) of sodium hydride in 25 ml of dimethyl sulfoxide such that the temperature did not exceed 30° C. The mixture was stirred at 20° C. for another 30 minutes. 3.486 g (22.78 mmol) of methyl bromoacetate in a little dimethyl sulfoxide were then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for a further 4 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was repeatedly washed with water. Drying of the combined organic phases, removal of the solvent under reduced pressure and chromatography of the residue gave 3.48 g of product (71.4% of theory); NMR (CDCl3, 400 MHz): 2.4 (s, 3H); 2.9 (d, 1H); 3.05 (d, 1H); 3.69 (s, 3H); 5.49 (dd, 1H); 7.50 (m, 1H); 7.86 (m, 1H); 8.07 (m, 1H); 8.7 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Br)c2cnc(S(C)(=O)=O)nc21
Reactant: NCCN1CCOCC1
Product: Cn1nc(Br)c2cnc(NCCN3CCOCC3)nc21

Procedure:
Prepared as described above in Example 8 starting from 3-bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and N-aminoethylmorpholine to give the title compound (3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine; 1H-NMR (DMSO): δ 2.43 (m, 4H), 2.50 (m, 2H), 3.47 (m, 2H), 3.55 (m, 2H), 3.77 (s, 3H), 7.61 (br s, 1H), 8.63 (s, 1H); LC/MS (m/e)=340.21 (MH+), Rt=1.13 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=1)(=O)=O.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]1([C:29]#[C:30][C:7]2[CH:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=[O:20])[CH:8]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1=O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(C#Cc2ccccc2)cc1=O

Procedure:
A solution of 4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.0 g, 5.4 mmol), phenylacetylene (1.1 g, 11 mmol), triethylamine (3.6 mL, 25 mmol), and PdCl2(PPh3)2 (0.42 g, 0.6 mmol) in DMF (20 mL) was heated to 90° C. under inert atmosphere for 1 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as an amorphous solid (1.5 g; TLC Rf=0.35, 1:1 EtOAc:hexanes; HPLC RT=8.64 min, method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g of 4-(tert-butoxycarbonyl)aminopiperidine was dissolved in 50 ml of dichloromethane. After adding 1.6 ml of triethylamine and 1.2 ml of ethyl bromoacetate, the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 3.0 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH:8]3[O:15][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][C@@H:7]([OH:15])[C@H:8]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[CH2:9]2
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2c(cc1OC)CC1OC1C2
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)C[C@@H](N1CCN(c3ccccc3OC)CC1)[C@H](O)C2
Yield: 22.9 %

Procedure:
A solution of 2.94 g of 2,3-dimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.9 g of 1-(o-methoxyphenyl)piperazine, and 1 ml of isopropanol in 30 ml of xylene is refluxed for 5 days. The reaction mixture is concentrated in vacuo, the residue taken up in ethyl acetate, and this is thoroughly extracted with dilute hydrochloric acid. The combined acid extracts are made basic with dilute sodium hydroxide solution, and this is thoroughly extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated in vacuo to an oil, which gives 1.3 g of solid on trituration with ethyl acetate. Recrystallization from ethyl acetate gives 600 mg of the title compound, melting point 172°-174° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]O>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)CCCO
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Product: CN(C)CCCN1C(=O)C(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=570.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3 -dione and 3-dimethylamino-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])O[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:25]([OH:26])[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)n1O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of 3-(4-(4-chlorophenoxy)phenyl)-2,6-dimethylpyran-4-one (1.0 g), hydroxylamine hydrochloride (1.06 g), sodium acetate (1.25 g) and water (5 ml) in ethanol (10 ml) was heated at reflux for 3 days. After cooling to rt the mixture was diluted with water (20 ml) and the precipitate filtered off and washed with ethyl acetate. Recrystallisation from DMF afforded the title compound (0.2 g), m.p. 232°-236°, NMR δH (d6-DMSO)7.5-7.4 (2H, d, a 8 Hz), 7.3-7.2 (2H, d, J 8 Hz), 7.15-7.0 (4H, m), 6.75 (1H, s), 2.35 (3H, s), 2.15 (3H, s).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:12][C:11]=1[S:25]([NH2:28])(=[O:27])=[O:26]>C(#N)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:12][C:11]=1[S:25]([N:28]=[CH:3][N:4]([CH3:5])[CH3:6])(=[O:27])=[O:26]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A solution of N,N,-dimethylformamide dimethyl acetal (1.2 g, 10.1 mmol) in acetonitrile (10 mL) is slowly added to a solution of 2-chloro-5-(4-hydroxy-benzoyl)-benzenesulfonamide (2.61 g, 8.4 mmol) in acetonitrile (10 mL). The reaction is allowed to stir for 5 hours at ambient temperature. Volatiles were removed in vacuo. The residue is partitioned between ethyl acetate and water, the organic layer is separated and the solvent is removed in vacuo, affording 2.5 g (81% yield) of the title compound which is carried on directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S-:14][C:15]#[N:16].[NH4+].C(OCC)(=O)C>CC(C)=O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:16]=[C:15]=[S:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)N=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-tert-butylbenzoyl chloride (6 g, 198 mmol) in acetone (250 mL) was added ammonium thiocynate (28 g, 237 mmol). The resulting yellow suspension was stirred at room temperature for 2 hours, condensed to dryness and then reconstituted through the addition of ethyl acetate (200 mL). The organic portion was washed with a saturated sodium bicarbonate solution (2×200 ml) and brine (200 mL). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated to a sticky liquid. The residue was chilled in a −10° C. freezer to give 37 grams of Intermediate A as a yellow solid (88%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C1COCC1>[CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1cnc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A mixture of 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)benzeneamine (0.1 g, 0.33 mmole), co-solvent (5 ml, DMF/THF=6/40) and phenyl isocyanate (0.2 ml, 0.92 mmole) was heated to 80° C. After 12 hrs, the reaction mixture was cooled, and the THF removed in vacuo. Then the mixture was diluted with EA, washed with brine, and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue on silica gel (EA/Hex=1/2) yielded the desired compound (42.2 mg, 30.4%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH2:22][CH2:21][NH:20]C1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:20][CH2:21][CH2:22][OH:18])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: O=C1NCCO1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCCNc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copper iodide (7 mg), 4 μL, of N,N-dimeyhylethylenediamine in 2 mL of 1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture was evaporated and the residue was diluted with ethyl acetate (50 mL), washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified on reverse phase HPLC to give 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol as a by-product.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[O:19])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH3:33][C:34]([CH3:41])([CH2:38][CH2:39][CH3:40])[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][C:34]([CH3:41])([CH2:38][CH2:39][CH3:40])[C:35]([N:30]1[CH2:31][CH2:32][N:27]([CH:24]2[NH:23][CH2:22][CH:21]([NH:20][C:18]([NH:17][C:7]3[N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)[N:9]=[C:5]([C:2]4([CH3:1])[CH2:3][CH2:4]4)[CH:6]=3)=[O:19])[CH2:26][CH2:25]2)[CH2:28][CH2:29]1)=[O:36]
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Reactant: CCCC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(C)C(=O)N1CCN(C2CCC(NC(=O)Nc3cc(C4(C)CC4)nn3-c3ccc(C)cc3)CN2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Treat a solution or slurry of the 1-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (Preparation 5, 1 equiv., 0.1510 g), 2,2-dimethyl pentanoic acid (1.15 equiv., 0.0521 g) and catalytic DMAP (ca. 0.1 equiv., 0.049 g) in dichloromethane (ca. 0.1 M, 5 mL) with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC1.15 equiv., 0.0767 g). Agitate the resulting mixture at ambient temperature for 48 hours then wash with saturated aq. sodium bicarbonate solution. Dry the organic layer over sodium sulfate and concentrate under reduced pressure. Purification A: Purify on silica gel using a gradient 2 M ammonia-methanol in dichloromethane, a gradient of ethyl acetate in dichloromethane or hexanes. Purification B: Purify by reverse phase on an Xterra 30×75 mm 5 micron MS C18 column using a gradient of aqueous 10 mM ammonium bicarbonate in acetonitrile affords the title compound. LCMS(ES+): m/z=544. [M+H].