Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(NC(C)C)n1
Product: CSc1nc(NC(C)C)c(C=O)c(-c2ccccc2F)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluorophenylboronic acid to give the title compound 4-(2-fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.31 (d, 6H, J=5.7 Hz), 2.56 (s, 3H), 4.51 (m, 1H), 7.05-7.31 (m, 2H), 7.41-7.55 (m, 2H), 9.02 (br s, 1H), 9.64 (s, 1H). LC MS (m/e)=306 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][C:8](=[O:9])[N:7]([CH3:13])[C:5]1=[O:6].Br[CH2:15][C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(#N)C>[CH2:20]([O:19][C:17]([C:16](=[CH2:22])[CH2:15][C:10]1([CH2:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH2:15])[C:11](=[O:12])[N:4]([CH3:3])[C:5](=[O:6])[N:7]([CH3:13])[C:8]1=[O:9])=[O:18])[CH3:21]
Reactant: C=C(CBr)C(=O)OCC
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(CC1(CC(=C)C(=O)OCC)C(=O)N(C)C(=O)N(C)C1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of sodium hydride (0.75 g, 80% dispersion in oil) and 1,3-dimethylbarbituric acid (1.56 g, 0.01 mol) in acetonitrile (10 mL) was added a solution of ethyl 2-(bromomethyl)propenoate (3.86 g, 0.02 mol) in acetonitrile (5 mL). The resulting mixture was allowed to stir at room temperature under nitrogen overnight. Thin layer chromatography (ethyl acetate/petroleum spirit: 1/4) indicated all the starting materials had been consumed. Water (30 mL) was added and the slightly pink solution was extracted three times with ethyl acetate (3×30 mL). The combined organic layer was washed with water, brine and then dried over anhydrous magnesium sulfate. After removal of solvent, purification by column chromatography (silica-gel 100 g, ethyl acetate:pet. spirit 40°-60° C. 1:4) gave pure product (11) (3.20 g, 84%) as a colourless liquid which solidified when stored in the freezer. 1 H-NMR (CDCl3) δ(ppm): 1.22 (t, 6H); 3.00 (s, 4H); 3.20 (s, 6H); 4.08 (q, 4H); 5.50 (s, 2H) and 6.15 (s, 2H). 13C-NMR (CDCl3) δ(ppm): 13.9, 28.2, 39.9, 55.4, 61.0, 128.2, 135.2, 151.0, 166.2 and 169.9.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:6][C:5]([C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:22])=[CH:4][C:3]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]2=[N:30]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[OH:1][C:2]1[C:7]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])(=[O:19])=[O:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:6][C:5]([C:21]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:22])=[CH:4][C:3]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]2=[N:30]1
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)c2ccc(S(=O)(=O)Cl)cc2)c1
Reactant: CN(C)CCN
Product: CN(C)CCNS(=O)(=O)c1ccc(C(C)(C)c2cc(C(C)(C)CC(C)(C)C)cc(-n3nc4ccccc4n3)c2O)cc1

Procedure:
The title compound is prepared according to the procedure given in instant Example 35 using 8.0 g of the intermediate compound prepared in Example 34a and 1.4 g of 2-dimethylaminoethylamine. After several recrystallizations from ethyl acetate and ethyl acetate/heptane mixtures, 5.6 g of the title compound is prepared as a near white solid melting at 118-120° C. The structure of the compound is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22](O)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27][C:26]1=[O:35]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([N:31]3[CH2:32][CH2:33][C:34]4[NH:25][C:26](=[O:35])[CH:27]=[CH:28][C:29]=4[CH2:30]3)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=c1ccc2c([nH]1)CCNC2
Reactant: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(C2=NC(C(=O)N3CCc4[nH]c(=O)ccc4C3)CS2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid and 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:26][CH:27]=[CH2:28])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].C(O)C>[Pd].CO>[CH3:1][C:2]([CH3:29])([CH2:26][CH2:27][CH3:28])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reaction time: 72 h
Yield: 52.5 %

Procedure:
A mixture of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one (0.036 g, 0.091 mmol), 3 mL of ethanol (a small amount of methanol was also added to help solubility) and 10% Pd/C (10 mg) was stirred under a hydrogen atmosphere (balloon) for 3 d, then filtered through Celite and concentrated to afford 0.019 g (53%) of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pentan-1-one as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([Br:24])[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Yield: 56 %

Procedure:
Following the procedure as described in Example 4, making variations as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with N-bromosuccinimide, the title compound was obtained as a yellow oil in 56% yield: MS (ES+) m/z 408.2 (M+1), 410.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:20]2[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2C(F)(F)F)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 2-chloro-3-trifluoromethylpyridine (0.25 g) was heated to 100° C. for 12 h. The reaction mixture was cooled and partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (5–50% EtOAc hexane) afforded the title compound. M.S (M+1): 394.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([O:22]C(=O)C)[CH2:17][O:18]C(=O)C)=[O:13])[C:8]([I:26])=[C:7]([CH2:27][O:28]C(=O)C)[C:6]=1[I:32])(=[O:3])[CH3:2].[OH-].[Na+].Br[CH2:36][CH:37]([OH:40])[CH2:38][OH:39].Cl>CO.O>[C:1]([N:4]([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([OH:22])[CH2:17][OH:18])=[O:13])[C:8]([I:26])=[C:7]([CH2:27][OH:28])[C:6]=1[I:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: OCC(O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CO)c1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 1 h

Procedure:
N-acetyl-3-acetoxymethyl-5-(2,3-diacetoxypropylaminocarbonyl)-2,4,6-triiodoaniline (1.0 g, 1.27 mmol) was suspended in a mixture of methanol (6 ml) and water (30 ml) and pH was adjusted to 12.0 using a 2 M aqueous solution of NaOH. After stirring for 1 h, 1-bromo-2,3-propanediol (0.99 g, 6.4 mmol) was added and the pH was adjusted to 11.6 using a 2 M aqueous solution of HCl. 1-Bromo-2,3-propanediol (0.99 g, 6.4 mmol) was again added after 16 and 18 h and after 24 h, pH was adjusted to 6.5 using a 2 M aqueous solution of HCl. After evaporation, the residue was purified by preparative HPLC. Yield: 0.373 g (40%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[F:18][C:19]([F:29])([F:28])C[I+]C1C=CC=CC=1>>[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:1][N+:2]([CH3:11])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:19]([F:29])([F:28])[F:18]
Reactant: FC(F)(F)C[I+]c1ccccc1
Reactant: CN(C)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: C[N+](C)(CC(F)(F)F)c1ccccc1
Reaction time: 0.5 h
Yield: 177.8 %

Procedure:
61 mg (0.50 mmol) of N,N-dimethylaniline was added to a solution of 218 mg (0.50 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate in an argon atmosphere at room temperature, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel thin-layer chromatography to obtain 157 mg (89%) of N,N-dimethyl-N-phenyl-N-2,2,2-trifluoroethylammonium trifluoromethanesulfonate.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[C:29]([F:30])=[CH:28][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:30][C:29]1[CH:28]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[C:26]([F:35])=[CH:25][C:24]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NS(=O)(=O)c1cc(F)c(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cc(F)c(S(N)(=O)=O)cc2F)cc1)[C@H](O)CCc1cccnc1
Temperature: 80 °C
Yield: 36.9 %

Procedure:
Prepared according to the method described in Example 12) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.2 g, Example 33), 4-bromo-2,5-difluorobenzenesulfonamide (0.19 g, Example 37a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 80° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.11 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH3:1][N:2]1[C:6]([CH:7]([OH:8])[C:17]([F:19])([F:18])[F:16])=[CH:5][N:4]=[C:3]1[CH3:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ncc(C=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C(O)C(F)(F)F)n1C
Yield: 58.6 %

Procedure:
According to Reference Example 8-2, by use of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (125 mg, 1.01 mmol) dissolved in N,N-dimethylformamide (2.5 mL), potassium carbonate (28 mg, 0.20 mmol) and (trifluoromethyl)trimethylsilane (0.358 mL, 2.42 mmol), the mixture was stirred and reacted at a temperature of room temperature to 50° C. for 2.8 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(1,2-dimethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethanol (Compound DZ) (115 mg, yield: 59%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl>[CH2:1]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:17](=[O:18])[CH2:16][Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)N(Cc1ccccc1)C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred and cooled mixture of 33 parts of N-benzylN-tert.-butylamine in 60 parts of sodium hydroxide solution 20% and 160 parts of 1,2-dichloroethane are added dropwise 34 parts of 2-chloroacetyl chloride at a temperature between -5° and -10° C. Upon completion, stirring is continued at the same temperature for one hour. The reaction mixture is allowed to reach room temperature and the organic layer is separated, washed with water, dried and evaporated, yielding 43 parts of N-benzylN-tert.-butyl-2-chloroacetamide as a residue.
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[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-c2ccnn2C)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 418 [M+1]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:17]#[N:18])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:17][NH2:18])=[CH:10][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A slurry of 18 g (0.45 mole) of lithium aluminum hydride in 1000 mL of dry tetrahydrofuran was cooled to 5° C. while stirring under nitrogen. To the slurry was added alpha-(2-(4-chlorophenyl)ethyl)-alpha-phenyl-1H-1,2,4-triazole-1-propanenitrile in 2000 mL of dry., tetrahydrofuran over 3 hours. The reaction was kept at 5°-10° C. during the addition then allowed to warm to room temperature and stirred overnight. The reaction was cooled in an ice bath and quenched with the slow addition of sodium sulfate. The solvent was removed and the residue was extracted with ethyl acetate and washed with 1000 mL water and 1000 mL brine. After drying, and removal of the solvent, 137 g (89.5% yield) of a very viscous oil resulted.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:15][C:16]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=2[I:1])=[O:6])[CH2:28][CH2:27]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3I)CC2)c(F)c1

Procedure:
Example CM was prepared in analogy to Example 123 from 2-Iodo-5-methanesulfonyl-benzoic acid (example BQ) and 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial). MS (m/e): 567.0 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14]>N([O-])=O.[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)ccc1O
Temperature: 15 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In a 500-ml flask, place 44.8 g (0.4 m) of 4-fluorophenol (1a; X=F) and 132 ml of acetic acid and stir to a solution. Add 0.6 g of sodium nitrite and cool the solution to 15° C. Add 36.0 g (0.4 m) of 70% nitric acid in drop wise keeping the temperature at 22-27° C. over 10-15 min. Stir the resulting yellow slurry at room temperature for 3 hrs. Warm the mixture to 65° C. to make a clear solution and add 132 ml of warm (65° C.) water slowly. Stir the resulting slurry and cool to 15° C. Collect solid, wash with water thoroughly, and dry in air to give 53.4 g (85%) of 4-fluoro-2-nitrophenol (2a; X=F) as yellow granular solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18].O>CC(C)=O>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: Oc1ccc(F)cc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1Br
Yield: 100 %

Procedure:
To a mixture of 2-bromo-4-fluorophenol (9.75 g, 0.051 mol) and potassium carbonate (7.76 g, 0.056 mol) in acetone (125 mL) was added allyl bromide (4.64 mL, 0.054 mol) and the reaction mixture heated to reflux for 3.5 hours. The cooled reaction mixture was then poured into water and the resulting oily suspension extracted with dichloromethane (2×500 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 11.79 g (100%) of 1-(allyloxy)-2-bromo-4-fluorobenzene as a yellow oil. MS (ESI) m/z 229.9 (M+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:26]2[CH:27]=[CH:22][CH:23]=[CH:24][C:25]=2[F:37])=[CH:33][C:32]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3cc(-c4ccccc4F)c(C#N)cc3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile as described in Example 65 to give 4,2′-difluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a white solid: δH (400 MHz, CDCl3) 1.62 (6H, s), 4.47 (1H, s), 7.08 (1H, d, J 7), 7.39-7.46 (2H, m), 7.55 (1H, dd, J 8 and 3), 7.60-7.64 (3H, m), 7.85 (1H, s), 8.81 (1H, d, J 7); m/z (ES+) 391 (M++H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: Cc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methylbenzyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) and piperazine.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCNN
Reactant: Cc1cccc(C)c1NC(=O)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 1.3 g (14.9 mmol) of 3-butenylhydrazine in 60 mL of THF was cooled to 0° C. and treated sequentially with 4.0 g (13.5 mmol) of 2,4-dichloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide 30 (Example 1, Step B) and 2.1 mL (14.9 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 23 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (75 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 17:3) to give the title compound. 1H-NMR (DMSO-d6) δ 2.24 (s, 6H), 2.40-2.48 (m, 2H), 3.32 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.03 (dd, J=10.3 Hz, 1.1 Hz, 1H), 5.13 (dd, J=17.2 Hz, 1.5 Hz, 1H), 5.75-5.86 (m, 1H), 7.07 (s, 3H), 8.15 (s, 1H), 9.61 (s, 1H). Mass Spectrum (ESI) m/e=346.1 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:21])[N:5]=1)[CH3:3].[H-].[Na+].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[CH3:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:20])[N:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([CH:2]([O:1][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][N:29]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH3:3])=[N:5]2
Reactant: Cc1cccc2nc(C(C)O)n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)Oc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reaction time: 0.17 h

Procedure:
A solution of compound 181 (0.069 g, 0.25 mmol) in THF (5 mL) was treated with sodium hydride (0.007 g, 0.27 mmol) and stirred for 10 min. A solution of intermediate compound 13 (0.077 g, 0.27 mmol) in THF (1 mL) was added to the reaction mixture. The flask originally containing the intermediate compound 13 was washed with additional THF (1 mL) and the washings were also added to the reaction mixture. The reaction was allowed to proceed, and additional sodium hydride (0.005 g, 0.21 mmol) was added at 21.5 h and 23 h. The reaction was quenched after a total of 24 h by addition of saturated ammonium chloride solution (5 mL). The mixture was extracted with dichloromethane (3×5 mL), and the combined organic extracts were dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (1:1 EtOAc: hexanes→3:2 EtOAC:hexanes) to give compound 182. ESI-MS m/z=529 (MH+). The reaction described above and compound 182 are shown below.