Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[ClH:27].[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:17]1[C:18]([CH3:20])=[N:19][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:16]1
Reactant: Cc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nn1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(NC2CCNCC2)nn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
4-[1-(2,4-Dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.28 mmol) was dissolved in dioxane (2 ml) saturated with HCl gas. The mixture was stirred overnight at room temperature, concentrated and the residue triturated with diethyl ether to yield the title compound as a brownish solid (57 mg, 56%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][S:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH2:8][S:9](=[O:33])[C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1SC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)C2

Procedure:
4 g of methyl 7-oxo-8-phenyl-pyrido[1,2-c]thieno[2,3-e][1,3]thiazine-10-carboxylate were dissolved in 100 ml of methylene chloride, whereupon the solution was cooled to 0° and a solution of 2.43 g of m-chloroperbenzoic acid in 40 ml of methylene chloride was added dropwise. After the reaction was completed, the precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate, filtered and evaporated. After chromatography on silica gel, the product was recrystallized from acetonitrile. There was obtained methyl 7-oxo-8-phenyl-pyrido[1,2-c]thieno[2,3-e]-[1,3]thiazine-10-carboxylate 4-oxide as yellow crystals of m.p. 183°-186°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(Cl)c4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,3-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][CH:5]([CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:4][O:3]1.I[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[O:6][CH:5]([CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([O:21][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH2:22][O:23][CH2:24][CH3:25])[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)NCCI
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Using a modification on the procedure described in Part L of Example 2, 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol (8.50 g, 23.8 mmol) was treated with tert-butyl 2-iodoethylcarbamate (7.10 g, 26.2 mmol) and cesium carbonate (11.62 g, 35.67 mmol) in DMF (120 mL). During the workup, after the reaction mixture was concentrated under reduced pressure, the residue was treated with water (75 mL) and stirred for 30 minutes. A precipitate was isolated by filtration and washed with diethyl ether to yield 8.7 g of tert-butyl 2-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as an off-white solid, mp 152-153° C.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47](=O)[CH3:48])[CH:42]=[C:43]([O:45][CH3:46])[CH:44]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:47]([C:41]2[CH:40]=[C:39]([O:38][CH3:37])[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=2)[CH:48]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 35 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(3,5-dimethoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (44 mg, 35% yield).
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1.B.Cl>O1CCCC1>[O:1]1[C:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[CH:21]=[CH:20][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(CO)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 19.040 g (61.953 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)benzoic acid in 100 ml of tetrahydrofuran, 74.3 ml (74.3 mmol) of 1.0 M borane in tetrahydrofuran was added dropwise under ice-cooling, followed by overnight stirring at room temperature. Dilute hydrochloric acid was added, followed by stirring at room temperature for 0.5 hours and 3 extractions with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of methanol; 15 ml of concentrated hydrochloric acid was added, followed by stirring at 70° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate 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 (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8].B(F)(F)F.O(CC)CC>C1COCC1>[OH:8][CH2:7][C:6]1[C:5]([CH3:13])=[C:4]([OH:3])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(O)cccc1CO
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
To a 5 L 3 neck RB equipped with overhead stirrer was charged NaBH4 (87.0 g, 2.30 mol) and THF (3.0 L) and the resulting slurry was cooled to 10° C. To the slurry was then added 3-hydroxy-2-methyl benzoic acid (175 g, 1.15 mol) portionwise over 20 min (Tmax 17° C.). A stirrable slurry formed, and was aged for an additional 45 min at 10-15° C. after which BF3-OEt2 (321 mL, 2.53 mol) was added slowly over 1.5 hours. The slurry was aged at 10° C.-15° C. for 2 h then assayed for reaction completion (98.5% conversion). The slurry was cooled to <10° C. and quenched with 931 mL MeOH slowly over 1.5 h (gas evolution). The resulting slurry was aged overnight at RT. The batch was cooled to <10° C. then quenched with 1 N HCl (1.5 L) to get a homogeneous solution (pH solution˜1), which was aged for 30 min and then the organic solvents were removed by rotary evaporation to approximately 1.8 L of total reaction volume (bath temperature was set to 50° C.; internal temp of concentrate after rotary evaporation was ˜40° C.). The slurry was held at 45° C. for 30 min then cooled slowly to 15° C. The solids were filtered and washed with cold (15° C.) water (2×300 mL), providing 3-hydroxymethyl-2-methyl phenol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:18]=[C:17]([NH:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:16]2[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=2[CH2:10]1.[CH3:29][O:30][C:31]1[N:36]=[C:35](B2OCCN(C3C=CC=CC=3)CCO2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]2[N:18]=[C:17]([NH:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:16]3[C:15]([CH3:27])=[N:14][C:13]([NH2:28])=[N:12][C:11]=3[CH2:10]2)=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[N:36]=2)[CH:7]=1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1nc(N)nc2c1C(NOC1CCCCO1)=N[C@@H](c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3C(NOC3CCCCO3)=N2)n1
Temperature: 85 °C
Yield: 124.7 %

Procedure:
(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine (0.838 g, 1.86 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.33 g, 4.47 mmol), sodium carbonate 2M solution (3.72 mL, 7.44 mmol) were combined in N,N-Dimethylacetamide (12 mL) and then the mixture was purged with nitrogen for 5 minutes. 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.136 g, 0.186 mmol) was then added and the reaction was heated in 85° C. oil bath overnight. Next day, the reaction was diluted with ethyl acetate 80 mL, washed with brine (80 mL), dried over sodium sulfate, and concentrated to a crude product which was then purified by flash column chromatography, SiO2, gradient 20-100% ethyl acetate/hexane to give a white solid, 1.11 g of product, contaminated with the impurity of mass 182 (byproduct from the boronic ester, compound 6). MS (ES) [M+H] calc'd for C25H27FN6O3, 479. found, 479.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Temperature: 130 °C
Yield: 56.3 %

Procedure:
To a solution of 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 4 mL of dioxane are added 53 mg of 3-aminopyridine. The reaction mixture is heated by microwave at 130° C. for 20 minutes and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 129 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-pyridin-3-ylurea, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CC2
Yield: 91.2 %

Procedure:
6-Nitroindan-1-one (18.1 g, 102 mmol) was dissolved in ethanol (400 ml) and reduced using Pd (5%) on carbon (2.0 g) and 35 psi hydrogen pressure on a Parr apparatus. Filtration on celite followed by evaporation gave 6-aminoindan-1-one (13.7 g, 93 mmol). NMR (DMSO) 7.2 (d, J=7.7Hz, 1H), 6.9 (dd, Jab=7.7Hz, J ax=2.3 Hz, 1H), 6.75 (d, J=2.3Hz, 1H), 5.3 (brs, 2H), 2.9 (t, J=5.6 Hz, 2H), 2.55 (t, J=5.6 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:22])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:21])=[CH:5][CH:4]=1)#[N:2].[ClH:23].[CH2:24]([OH:26])[CH3:25]>>[ClH:23].[CH2:24]([O:26][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([CH3:22])[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11](=[O:20])[N:10]2[CH3:21])=[CH:7][CH:8]=1)[CH3:25]
Reactant: CCO
Reactant: COC(=O)CN1C(=O)N(C)[C@@](C)(c2ccc(C#N)cc2)C1=O
Agent: Cl
Product: CCOC(=N)c1ccc([C@@]2(C)C(=O)N(CC(=O)OC)C(=O)N2C)cc1

Procedure:
A solution of 2.56 g of methyl (S)-(4-(4-cyanophenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate (8.5 mmol) in 40 ml of absolute ethanol was cooled to 0° C. Dry hydrogen chloride gas was passed into the solution, the temperature always being kept below 10° C., until the nitrile band was no longer present in the IR spectrum. The ethanolic solution was concentrated to 20 ml and treated with 200 ml of diethyl ether. The suspension was concentrated and dried in a high vacuum.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1c(-c2ccncc2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 7.64-7.70 (2H, m), 7.95-8.01 (2H, m), 8.37 (1H, s), 8.39 (2H, s), 9.05-9.07 (2H, m), 9.40 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1cc(F)c(F)c(C)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
To 2,4,5-trifluoro-3-methyl-N-acetylaniline (1.94 g) is added conc. sulfuric acid (19 ml) and the mixture is cooled to 0° C. Thereto potassium nitrate (2 g) is added below 20° C. and the mixture is stirred for 15 minutes. The reaction mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure to give 2,4,5-trifluoro-3-methyl-6-nitro-N-acetylaniline (2.08 g), as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:29][CH2:30][CH2:31]Br>CO>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([CH2:31][CH2:30][Br:29])[CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)CCCNCCC1COc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CCCN(CCBr)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
29.1 g (0.1 mol) of N-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine are dissolved in 200 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 18.8 g (0.1 mol) of 1,2-dibromoethane are added to the solution. The reaction mixture is stirred for 16 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]amine is thus obtained in the form of an oil which can be used further in the crude state.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[N:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=3)=[CH:14][CH:15]=2)=[C:7]([CH3:32])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:17]1[C:16]([C:13]2[S:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=3[CH3:32])=[CH:15][CH:14]=2)=[CH:20][C:19]([C:21]([F:24])([F:22])[F:23])=[N:18]1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
(4-{5-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-3-methylphenyl)-acetic acid methyl ester (122 mg, 025 mmol) was dissolved in 6 mL mixture of THF and water (3:1, V/V). Lithium hydroxide monohydrate (23 mg, 0.55 mmol) was then added. After stirring at room temperature for 2 hrs, the mixture was neutralized to pH 7 by 1N HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by reverse HPLC to give a white solid (66 mg, 55% yield). 1H-NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.65 (s, 2H), 6.88-6.84 (m, 3H), 7.17-7.11 (m, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.56-7.42 (m, 4H). MS (ES) 477.2, [M+H]+.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4][CH2:3][CH:2]1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].N>C1COCC1>[CH3:27][C:2]1([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:3][CH2:4][N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(OCc1ccccc1)C1CCN1C(=O)OCc1ccccc1
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of Example 22A (325 mg, 1 mmol) and iodomethane (0.12 ml, 2.0 mmol) in THF (5 mL) was treated with NaN(TMS)2 in THF (1.0 M, 2 mL, 2.0 mmol) at −70° C. under nitrogen. The temperature of the cooling bath was slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for additional 2 h. After quenching with water, the mixture was partitioned between water and EtOAc. The organic phase was washed with water and concentrated. The residue was purified on flash column chromatograph to give Example 22B. (250 mg, 77% yield). MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH:25]([CH3:27])[CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Yield: 89.3 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.2 ml (0.026 mol) of isopropylamine in 30 ml of DMF were reacted at room temperature affording a residue which was kugelrohr distilled at 80 Pa, pot temperature 112° C., to give 4.86 g (89.3%) of product as a yellow solid; mp 43.5°-45° C.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:29])([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CS(C)=O>[CH3:28][C:18]([N:29]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)(C)Cc1ccc(OC)cc1)C(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
632 mg of 2-n-butoxyphenylglyoxal hydrate are dissolved in 0.5 ml of dimethylsulfoxide, and a solution of 440 mg of α,α-dimethyl-4-methoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 20° C. for one hour, whereby a solution of α-(α,α-dimethyl-4-methoxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:4])[CH3:3].Br[C:28]1[CH:29]=[CH:30][C:31]([F:40])=[C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:33]=1>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:28]3[CH:29]=[CH:30][C:31]([F:40])=[C:32]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)[CH:33]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:1])[CH3:3]
Reactant: Fc1ccc(Br)cc1-c1ccncc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(F)F)ccn12
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1

Procedure:
7-(1,1-Difluoroethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was reacted with 4-(5-bromo-2-fluorophenyl)pyridine following the procedure described in Example 32 to give 7-(1,1-difluoroethyl)-3-[4-fluoro-3-(pyridin-4-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 2.16 (1H, t, J 19), 7.31 (1H, d, J 7), 7.43 (1H, dd, J 10 and 8), 7.54 (2H, dd, J 6 and 1), 7.57-7.66 (2H, m), 8.00 (1H, s), 8.67 (1H, d, J 7), 8.74 (2H, d, J 6); m/z (ES+) 355 (M++H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]([CH3:17])([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:7]>CO>[CH3:16][C:5]1([CH3:17])[O:7][C:6]1([O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1
Reactant: C[O-]
Reactant: CSc1ccc(C(=O)C(C)(C)Br)cc1
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(SC)cc2)OC1(C)C

Procedure:
95.1 g (1.76 mols) of sodium methylate are dissolved in 600 ml of methanol, and 437.1 g (1.60 mols) of 2-bromo-2-methyl-1-[4-(methylthio)-phenyl]-propan-1-one, dissolved in 300 ml of methanol, are added dropwise to this solution at reflux temperature. The methanol is then removed by distillation. The residue is poured into ice water, and the mixture is extracted with diethyl ether. The ether solution is washed with water, dried over Na2SO4 and concentrated. The crystals obtained are purified by vacuum distillation.