Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH2:15][CH2:16]NC[C:19]=3[CH:20]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Br[C:22]1[C:23](=O)[N:24](C)[CH:25]=C(Br)C=1.CN1CCCC1C1C=CC(N)=NC=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([CH:15]3[CH2:16][CH2:22][CH2:23][N:24]3[CH3:25])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cc(Br)cc(Nc2cc3c(cn2)CCNC3)c1=O
Agent: CN1CCCC1c1ccc(N)nc1
Product: CN1CCCC1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 81 %

Procedure:
Using the same general procedure as described for the preparation of 226b, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (1.51 g, 5.65 mmol) with 5-(1-methylpyrrolidin-2-yl)-2-amino pyridine (1.00 g, 5.65 mmol) gave an 81% yield (1.65 g) of 229a as a yellow solid: mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) d 8.73 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.15 (d, 1H, J=2.1 Hz), 7.55 (dd, 1H, J=8.9, 2.1 Hz), 7.52 (s, 1H), 7.30 (d, 1H, J=8.9 Hz), 3.52 (s, 3H), 3.13 (t, 1H, J=7.5 Hz), 2.99 (t, 1H, J=7.5 Hz), 2.19 (m, 1H), 2.10 (m, 1H), 2.05 (s, 3H), 1.79 (m, 2H), 1.71 (m, 1H); MS (ESI+) m/z 363.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1[CH:33]=[CH:32]N=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:38][C:39]([OH:41])=[O:40].C([K])C>C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:13])[CH2:38][C:39]([O:41][CH2:32][CH3:33])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(=O)O
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a 250-mL round-bottomed flask was added (R)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (5.68 g, 19.2 mmol) (Sigma-Aldrich), 1,1′-carbonyldiimidazole (4.68 g, 28.8 mmol), and THF (100 mL). The reaction mixture was stirred at RT for 4 h. The reaction mixture was treated with magnesium chloride (3.66 g, 38.4 mmol) (Strem Chem.) followed by ethyl potassium malonate (6.54 g, 38.4 mmol) (Sigma-Aldrich) and heated at 50° C. for 18 h. The solvents were removed under vacuum and the residue was dissolved EtOAc (200 mL), washed sequentially with 10% sodium bisulfate (10 mL), sat NaHCO3 (2×10 mL), brine, dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluted with a gradient of 0-30% EtOAc in hexanes, to provide the title compound (5.73 g, 82% yield) as a white solid. ee % was not determined m/z (ESI, +ve) 388.2 (M+Na)+.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:5]2[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:16]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A modification of the method described in Part F of Example 6 was used to treat 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid (5.14 g, 16.5 mmol) with oxalyl chloride (2.59 mL, 29.7 mmol) and morpholine (4.33 mL, 49.5 mmol). The oxalyl chloride addition was carried out at ambient temperature, and the reaction with morpholine was complete in three hours. Following the work-up procedure, 6.2 g of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[S:18](Cl)(=[O:20])=[O:19])([O:11][CH3:12])=[O:10]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:19])=[O:20]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 73 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2-(carbomethoxy)thiophene-3-sulphonyl chloride in 73% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 198°-200° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].S(Cl)(Cl)=O.O[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: OCc1cccnc1
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 0.5 ml (0.006 mol) of thionyl chloride in 20 ml of methylene chloride are stirred at room temperature for 5 minutes and, then a solution of 2.2 ml (0 023 mol) of 3-hydroxymethylpyridine in 20 ml of methylene chloride is added thereto at 0°. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate gives 3-pyridylmethyl 2-(4-acetamidobutyryl)-5chlorohydrocinnamate as a beige oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][O:21][C:15]=3[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][NH:23][CH3:24].[CH2:25]=O>C(O)(=O)C>[CH3:22][N:23]([CH2:25][C:20]1[O:21][C:15]2[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:18][CH2:17][C:16]=2[CH:19]=1)[CH3:24]
Reactant: c1ccc(CCCCCCN2CCc3ccoc3C2)cc1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(CCCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.120 g (0.423 mmol) of 6-(6-phenylhexyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.046 g (0.51 mmol) of 50% aqueous dimethylamine and 0.041 g (0.51 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[CH3:16][O:17][C:18]([C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19].C(N(CC)CC)C>O1CCOCC1>[CH3:16][O:17][C:18]([C@H:20]1[N:25]([C:8]2[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)nc1C(F)(F)F
Yield: 61 %

Procedure:
Combine 2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (240 mg, 1.70 mmol), (S)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.04 mmol) and triethylamine (5.11 mmol) in a 0.85 M solution of dioxane. Microwave reaction mixture for 30 min at 150° C. Filter reaction mixture and rinse with acetonitrile. Purify filtrate by column chromatography in a 0-70% ethyl acetate/heptane gradient to give (S)-4-(5-Methoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl-ester contaminated with approximately 15% of the mono hydrolysis product. The mixture is carried on to next step without further purification. (61% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(C(C)(C)C#N)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of methyl 4-chloro-3-(1-cyano-1-methylethyl)benzoate (8.0 g, 34 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide•monohydrate (2.13 g, 51 mmol), methanol (100 mL) and water (5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid. The resulting white precipitate was collected by filtration, washed with water, and dried to give the title compound (7.40 g, 99%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][C@H:41]([CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH:41]([CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34].[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:42]5[CH2:43][CH2:44][NH:39][CH2:40][C@H:41]5[CH3:45])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: C[C@@H]1CNCCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-methyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(R)-methyl-piperazin-1-yl)thiazol-4-one.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1)=[O:11]
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[C:3]([CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:2][OH:1]
Reactant: CON
Reactant: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one (30 g; 118 mmol) in methanol (240 ml) was added pyridine (15 ml; 189 mmol) followed by a portionwise addition of methoxyamine hydrochloride (15 g; 178 mmol). The reaction mixture was stirred at 24° C. for 18 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 33 g (99% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z 1:1) as a brown oil.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH2:7])C=C.[CH:8]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[C:10](O)[CH:9]=1.[CH2:22](OCCCCCCCCCCCC)[CH2:23][CH2:24]CCCCCCCCC>>[CH2:24]([C:18]1[CH:19]=[C:14]([C:13]2[CH:7]=[CH:6][C:5]([OH:4])=[C:11]([CH2:10][CH:9]=[CH2:8])[CH:12]=2)[CH:15]=[CH:16][C:17]=1[OH:20])[CH:23]=[CH2:22]
Reactant: CCCCCCCCCCCCOCCCCCCCCCCCC
Reactant: C=CCOCC=C
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Product: C=CCc1cc(-c2ccc(O)c(CC=C)c2)ccc1O

Procedure:
3,3′-Diallyl 4,4′-dihydroxybiphenyl was prepared by the Claisen rearrangement of the diallyl ether of 4,4′-bisphenol and was converted into its didodecyl ether in the same manner as for Compound 9 of Example 1 (66% yield). The dodecyl ether was a white crystalline solid, melting point 116-118° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24]([OH:28])[CH2:25][CH2:26][CH3:27])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:28][CH:24]([CH2:25][CH2:26][CH3:27])[CH:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[F:36])(=[O:11])=[O:10]
Reactant: CCCC(O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(OS(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., triethylamine (0.300 ml, 2.16 mmol) and methanesulfonyl chloride (0.150 ml, 1.93 mmol) were added to a methylene chloride (10 ml) solution of the 1-[(4-chlorophenyl)sulfonyl]-1-(2,5-difluorophenyl)-2-pentanol (449 mg, 1.20 mmol) obtained in Example 11. The resulting mixture was then stirred at 0° C. for 2 hours. The reaction mixture was diluted with methylene chloride, washed successively with a saturated aqueous solution of ammonium chloride, water and brine, dried over MgSO4, then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (15% ethyl acetate-hexane), whereby the title compound (503 mg, 93%) was obtained as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[C:6](\[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:11][CH:10]=1)/[CH3:7])C>C(O)C.[OH-].[Na+]>[C:15]12([C:12]3[CH:11]=[CH:10][C:9]([O:8]/[C:6](/[CH3:7])=[CH:5]\[C:4]([OH:25])=[O:3])=[CH:14][CH:13]=3)[CH2:22][CH:21]3[CH2:23][CH:17]([CH2:18][CH:19]([CH2:20]3)[CH2:24]1)[CH2:16]2
Reactant: CCOC(=O)/C=C(/C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C/C(=O)O)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A solution of 12.2 g of 3-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester in 120 ml of ethanol and 24 ml of 2 N sodium hydroxide solution is then stirred for 5 days at about 25° C. It is then evaporated in vacuo to a volume of approx. 20 ml and the residue is partitioned between twice 200 ml of methylene chloride and 200 ml of 2 N hydrochloric acid. The organic phase are wahsed until neutral, treated with active charcoal, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 3-[4-(1-adamantyl)-phenoxy]-crotonic acid of melting point 215°-218° C (decomposition).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:23]Cl>CO>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:23])=[O:4]
Reactant: COc1cccc(CCNC(=O)C(F)(F)F)c1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64 mmol) in methanol (325 mL) was cooled to −78 C., and treated with CaCO3 (14.7 g, 145 mmol), followed by a solution of ICl (29 g, 181 mmol) in methanol (40 mL). The reaction was allowed to warm to 20 C. while stirring overnight and then filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 23.8 g of a white solid powder. 1H NMR (400 MHz, CDCl3) d 7.68 (d, J=9 Hz, 1 H), 6.76 (s, 1 H), 6.57 (d, J=9 Hz, 1 H), 6.42 (bs, 1 H), 3.77 (s, 3 H), 3.61 (dd, J=7, 7 Hz, 2 H), 2.99 (dd, J=7, 7 Hz, 2 H). MS calculated for C11H11F3INO2+H: 374, observed: 374.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](N)=[S:13].O>C(O)C>[CH2:1]([NH:4][C:12](=[S:13])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: NC(=S)Cc1ccccn1
Solvent: O
Solvent: CCO
Product: C=CCNC(=S)Cc1ccccn1
Reaction time: 8 h

Procedure:
Allylamine (3.1 g.) is added with stirring to 4.0 g. of 2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. The resulting mixture is allowed to stand overnight at 5°C., then 5 ml. of ethanol is added. The mixture is stirred for 5 hours and then extracted with dichloromethane. The extracts are dried and concentrated and the residue is chromatographed on a silica gel "dry-column" to give N-allyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:10][C:11]1[N:16]=[C:15]([NH:8][C:5]2[CH:4]=[C:3]([CH:2]([F:9])[F:1])[NH:7][N:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(C(F)F)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)c1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 70 °C
Reaction time: 30 h
Yield: 6.8 %

Procedure:
To a solution of 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 60.1 mmol) in EtOH (350 mL) was added 2,4-dichloropyrimidine (10.7 g, 72.1 mmol) and DIPEA (10.9 g, 84.1 mmol). The reaction was stirred at 70° C. for 30 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography to afford 2-chloro-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (1.00 g, 7%). 1H NMR (400 MHz, DMSO) δ 13.23 (d, J. 68.6 Hz, 1H), 10.57 (s, 1H), 8.22 (d, J=4.9 Hz, 1H), 7.08 (m, 3H). MS (ESI) m/z: 246.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][C:27]([S@@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16]/[C:17](=[N:32]/[S@:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])/[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(CC/C(=N/[S@@](=O)C(C)(C)C)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Temperature: 70 °C
Yield: 77.6 %

Procedure:
To a solution of (S)-methyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (982 mg, 2 mmol) and (S)-2-methylpropane-2-sulfinamide (265 mg, 2 mmol) in anhydrous THF (20 mL) at rt was added Ti(OEt)4 (1 g, 4 mmol). The reaction mixture was heated at 70° C. for 24 h. After cooling to rt, the reaction mixture was poured into brine with vigorous stirring. The resulting suspension was filtered through a pad of celite and the solid was washed with brine. The combined organic phases were dried, filtered and concentrated to give methyl (1S)-1-(4-bromophenyl)ethyl((Z)-3-((S)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl)carbamate (794 mg, 65%). 1H NMR (CD3OD): 1.24 (m, 9H), 1.58 (d, 4H), 1.61 (m, 1H), 2.95 (m, 1H), 3.48 (m, 2H), 3.66 (m, 1H), 3.80 (m, 3H), 4.58 (m, 1H), 3.78 (m, 3H), 5.36 (m, 1H), 7.18 (m, 3H), 7.30 (m, 2H), 7.50 (m, 2H), 7.96 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[C:19]([C:23]([NH:25][C:26]4[C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:34][CH3:35])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=3[C:11]=2[N:10]=1.[Na+].[I-:37].II>O1CCOCC1.ClCCl.CO.[Cu]I>[CH2:34]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH3:33])[C:26]=1[NH:25][C:23]([C:19]1[C:13]2[CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[I:37])=[N:10][C:11]=3[C:12]=2[N:21]([CH3:22])[N:20]=1)=[O:24])[CH3:35]
Reactant: [I-]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3Br)nc1-2
Agent: [Cu]I
Agent: II
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3I)nc1-2
Temperature: 150 °C
Yield: 46.9 %

Procedure:
To a solution 8-[(2-bromophenyl)amino]-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (68 mg, 0.129 mmol) in dioxane (0.5 mL) in a sealed tube, NaI (38 mg, 0.257 mmol), CuI (1.2 mg, 0.006 mmol), iodine (74 mg, 0.129 mmol) and trans-N,N′-dimethylcycloesane-1,2-diammine were added. The mixture was then heated at 150° C. for 12 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 8/2/) to 35 mg of the title compound (50% yield).