Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7]>O.CC#N>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 118.6 %

Procedure:
To a solution of 105 mg (1.6 mmol) of KCN in 1 mL of water, 220 mg (0.8 mmol) of 2-bromo-4′-phenylacetophenone in 3 mL of MeCN was added. The mixture was warmed in a 50° C. bath to dissolve some of the halide. After ˜20 min the solids dissolved. The reaction was stirred for 30 min, then partitioned between 1.2 N HCl and EtOAc. The organic layer was washed with brine, dried and concentrated leaving 210 mg of the title compound which was used in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][NH2:10])[CH2:3][CH2:2]1.[NH2:11][C:12]1[N:13]=[C:14]([CH3:31])[C:15]2[C:21](=S)[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]=2[N:17]=1>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9]/[N:10]=[C:21]2\[NH:20][C@@H:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Br:30])[CH2:18][C:16]3[N:17]=[C:12]([NH2:11])[N:13]=[C:14]([CH3:31])[C:15]\2=3)[CH2:3][CH2:2]1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: NOCCN1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OCCN1CCOCC1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of O-(2-morpholinoethyl)hydroxylamine (600 mg, 4.1 mmol) in anhydrous toluene (6 mL) was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (0.150 g, 0.41 mmol) and mercuric acetate (II) (262 mg, 0.82 mmol). The resultant mixture was heated to 100° C. for 1 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a yellow-green oil, which was purified by preparative HPLC eluting with TFA/ACN/H2O. The fractions were concentrated to provide (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-morpholinoethyl oxime (196 mg, 0.41 mmol). [M+H] calc'd for C20H24BrFN6O2, 480; found, 480.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[C:17][Si](C)(C)C)=[CH:14][N:13]=[C:12]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([C:16]#[CH:17])=[CH:14][N:13]=[C:12]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1cnc(N2CCCCC2)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cnc(N2CCCCC2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(piperidin-1-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (101 mg, 0.27 mmol), K2CO3 (74.5 mg, 0.54 mmol, 2.0 eq) in EtOH (4 ml) was stirred at room temperature for 1 h. The mixture was filtered, the filtration was washed with water, extracted with EtOAc, dried (Na2SO4). EtOAc was removed by evaporation, the residue was recrystalized from ether to afford compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynyl-2-(piperidin-1-yl)pyrimidin-4-amine (Compound 172) (68 mg, 81.9%). MS (m/z): 309.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.66-0.68 (m, 2H), 0.95 (d, J=6.8 Hz, 2H), 1.53 (d, J=3.6 Hz, 4H), 1.63-1.66 (m, 2H), 1.89-1.93 (m, 1H), 3.75 (t, J=5.4 Hz, 4H), 4.54 (s, 1H), 6.25 (bs, 1H), 7.94 (bs, 1H), 8.14 (s, 1H), 12.17 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([CH2:12][CH3:13])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([C:10]1[S:11][C:4]2=[N:3][C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)=[CH:7][C:6](=[O:8])[N:5]2[N:9]=1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn2c(=O)cc(Cl)nc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nn2c(=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2s1
Temperature: 150 °C

Procedure:
To a solution of 7-chloro-2-ethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (2.0 g, 9.27 mmol, 1.0 equiv) in 50 mL of anhydrous acetonitrile in a microwave vial is added tert-butyl 1-piperazinecarboxylate (2.073 g, 11.13 mmol, 1.2 equiv) followed by N,N-diisopropylethylamine (4.86 mL, 27.8 mmol, 3.0 equiv). The mixture is heated in a microwave reactor for 25 min at 150° C. Upon completion, the mixture is concentrated in vacuo to give crude tert-butyl 4-(2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow oil. This material is advanced directly to the next step.
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)(O)[O-].[Na+].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH3:13]>O>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)[CH3:13].[Na+:5]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(S(=O)[O-])cc1
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 147.9 %

Procedure:
In a 125 mL, three-necked flask fiited with thermometer, addition funnel, and glass stopper was placed 11.5 grams (91.2 mmol) of sodium sulfite, 8.32 grams (97.7 mmol) of sodium bicarbonate, and 50 mL of water. After heating the mixture to 75-80° C., 10.0 grams (48.9 mmol) of 4-ethylbenzenesulfonyl chloride was added dropwise over 0.5 hours. When the addition was complete, heating was continued for 3 hours at which time a white precipitate formed. The suspension was cooled to room temperature and allowed to stir for 16 hours. The precipitate was collected by filtration, washed with cold water, combined with a second crop from the filtrate, and dried under high vaccum to give 13.9 grams (>100% yield) of crude sodium 4-ethylbenzenesulfinate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(F)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 56 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.681 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 152 mg of a white solid (56%), mp 222.7-223.8° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.89 (dt, J=5.6, 8.1 Hz, 1H); 7.76 (dd, J=1.6, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.56 (d, J=8.1 Hz, 1H); 7.47 (t, J=7.1 Hz, 1H), 7.41-7.53 (m, 2H); 7.37 (dd, J=8.7, 11 Hz, 1H); 4.38-4.52 (m, 2H). 13C NMR (DMSO-d6) ppm: 160.9 (d, J=264 Hz), 157.6, 156.8, 154.1, 151.5, 149.6, 149.0, 143.6, 136.4 (d, J=11 Hz), 133.9, 132.2, 131.7, 131.6, 130.5, 130.2, 128.8, 123.6, 114.4 (d, J=20 Hz), 110.2, 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.5C2H6O: C, 54.61; H, 3.27; Cl, 7.68; N, 18.19; S, 6.94. Found: C, 54.37; H, 3.26; Cl, 7.89; N, 18.26; S, 6.55.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH:28]2[CH2:29][CH2:30][CH:24]1[CH2:25][C:26](=[O:31])[CH2:27]2)=[O:22])([CH3:19])([CH3:18])[CH3:17].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.[Cl-].[NH4+]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH:28]2[CH2:29][CH2:30][CH:24]1[CH2:25][C:26]([OH:31])([C:37]1[N:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH2:27]2)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: c1ccnnc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cccnn1)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.8 mL, 4.5 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine (0.76 mL, 4.5 mmol) in THF (25 mL) at −30° C., warmed to 0° C. and stirred for 30 minutes. After cooling to −78° C., a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) and pyridazine (0.29 mL, 4. mmol) in THF (5 mL) was added dropwise and stirred for 1 hour. A solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 60-100% ethyl acetate/cyclohexane. The fractions containing the two desired products were concentrated under vacuum to give the title compounds.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:11]2[C:15]([CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:14][C:13]([C:25]([F:28])([F:27])[F:26])=[N:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH3:2].[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:11]2[C:15]([CH2:16][NH2:17])=[CH:14][C:13]([C:25]([F:26])([F:27])[F:28])=[N:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CN)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
In 6 mL of dioxane, tert-butyl (1-(3-ethoxy-5-methylphenyl)-3-(trifluormethyl)-1H-pyrazol-5-yl)methylcarbamate (354 mg, 0.886 mmol) was dissolved and hydrogen chloride in dioxane (1.44 mL, c=4 mol/L, 5.76 mml, 6.5 equiv.) was added. The reaction mixture was stirred overnight and filtered, the filtercake was washed with dioxane (2×15 mL) and dried to give (1-(3-ethoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (211 mg, 71%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1.[BrH:19]>C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CO
Reactant: Br
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CBr

Procedure:
To 26 parts 4-hydroxymethyl-2,5-diisopropylbenzenesulfonamide dissolved in 100 parts chloroform heated just below reflux is added hydrogen bromide in a slow stream for an hour. The organic phase is washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give 4-bromomethyl-2,5-diisopropylbenzenesulfonamide.
Reaction SMILES: NC1C=CC(CN2CCN(C(OC(C)(C)C)=O)[C@H](C)C2)=CC=1.[CH3:23][C@H:24]1[CH2:29][N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[BH4-].[Na+]>>[CH3:23][C@@H:24]1[CH2:29][N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][CH3:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]1[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: C[C@@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D5) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. for 48 h prior to addition of sodium borohydride. δH (CDCl3, 400 MHz) 7.13 (2H, d), 6.57 (2H, d), 4.16 (1H, m), 3.78 (1H, d), 3.42 (1H, d), 3.29 (1H, d), 3.08 (1H, td), 2.83 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.07 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d). MS (ES+): 342.3 (MNa+), 220.2, no molecular ion (MH+) observed.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=O)[CH3:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=1)=[CH2:34])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(c1ccc(F)cc1)[Sn](CCCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (1.39 mL, 10.1 mmol) in 20 mL THF at 0° C. was added butyllithium (4.02 mL, 10.0 mmol). After 10 min, tributylstannane (2.45 mL, 9.23 mmol) was added. After 10 min, the reaction mixture was cooled to −78° C. and a solution of 1-(4-fluorophenyl)ethanone (1.09 mL, 9.05 mmol) in 10 mL THF was added slowly by syringe in portions over 10 min. After 10 min, triethylamine (9.43 mL, 67.9 mmol) and methanesulfonyl chloride (2.80 mL, 36.2 mmol) was added and the bath allowed to expire overnight. The reaction mixture was treated with 50 mL hexanes and filtered, rinsing with hexanes. The filtrate was extracted with ACN, and the hexanes layer was dried over sodium sulfate, filtered, and concentrated. Purification with C-18 silica gel, eluting with DCM/ACN, gave tributyl(1-(4-fluorophenyl)vinyl)stannane as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCCOc1ccc2ccccc2c1

Procedure:
A mixture of β-naphthol (1gm, 0.006 mole), anhydrous K2CO3 (10 gm, in excess) and 1-bromo 4-chlorobutane (0.8 ml, 0.006 mole) was refluxed in dry acetone (50 ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound, which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound, m.p. 112° C., (yield 1.6 gm, 98%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[C:22]([NH:32][CH:33]([C:36](O)=[O:37])[CH2:34][OH:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[C:26]1([CH2:25][O:24][C:22](=[O:23])[NH:32][CH:33]([CH2:36][OH:37])[C:34](=[O:35])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nn1cccc1
Reactant: O=C(NC(CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC(CO)C(=O)Nn1cccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 1-aminopyrrole (4.92 g) and DCC (6.18 g) in dry DCM (100 ml) was added carbobenzyloxy-D,L-serine (7.18 g) in small portions over a period of about 1 hour. After stirring overnight at room temperature, the precipitate was removed by filtration, and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) and the appropriate fractions were concentrated. Recrystallization of the residue from ethyl acetate afforded 4.68 g of the product as a powder, m.p. 153°-154° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH:18]1([C:21]2[C:22]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:20][CH2:19]1>>[ClH:17].[CH:18]1([C:21]2[C:22]([N:30]3[CH2:31][CH2:32][N:33]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:34][CH2:35]3)=[N:23][CH:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=2)[CH2:19][CH2:20]1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 152.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (487 mg) described in Preparation Example 50, the title compound (736 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=5[F:19])[C:4]=4[CH:3]=3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1
Reactant: Fc1cc(F)c(CN2CCNc3ncc(I)cc32)cc1F
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)c(F)cc3F)CCN4)cc2)CC1
Yield: 30 %

Procedure:
7-Iodo-1-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (30% yield). M.p. (foam), LCMS: m/z=482.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.35-2.52 (m, 4H), 3.39-3.42 (m, 2H), 3.42-3.56 (m, 2H), 3.58-3.66 (m, 2H), 3.68-3.88 (m, 2H), 4.45 (s, 2H), 4.98 (s, 1H), 6.72 (s, 1H), 6.89-7.02 (m, 1H), 7.08-7.15 (m, 1H), 7.35-7.44 (m, 4H), 7.70 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][C:16](=O)[CH2:17][CH:18]([CH3:20])[CH3:19])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:15]2
Reactant: CC(C)CC(=O)Cc1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 7 h
Yield: 93 %

Procedure:
To a solution of tert-butyl[4-chloro-2-(4-methyl-2-oxopentyl)phenyl]carbamate (280 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (0.7 mL) at room temperature, and the mixture was stirred for 7 hours. The reaction mixture was diluted with ethyl acetate and stopped the reaction by addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (166 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([OH:22])=O>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1cc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-methyl-5-(trifluoromethyl)benzoic acid (CAS RN 117186-02-4) after a reaction time of 67 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Light brown oil (9%). MS (ESI): m/z=385.15[M+H]+.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=CC=1>>[S:20]1[CH:14]=[C:19]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:18]=[CH:17]1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: Sc1ccccc1
Product: O=C(c1ccsc1)c1cccc2ccccc12

Procedure:
A mixture of 1-naphthoic acid (8 g, 46.46 mmol), thiophenol (8 ml, 78.05 mmol) and polyphosphoric acid (80 g) was heated for 12 hours on water bath at 80 EC. Reaction mixture was poured onto ice water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give oil, which was crystallized from methanol to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH3:17][Si:16]([CH2:15][CH2:14][O:13][CH2:12][C:5]1[C:6]([C:7]#[N:8])=[C:2]([NH2:1])[NH:3][N:4]=1)([CH3:19])[CH3:18]
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1c[nH]nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCc1n[nH]c(N)c1C#N
Temperature: 0 °C
Yield: 17 %

Procedure:
3-Amino-1H-pyrazole-4-carbonitrile (10 g, 92.5 mmol) was dissolved in 100 mL of DMF and the solution was stirred at 0° C. Sodium hydride (60% in mineral oil, 7.4 g, 185 mmol) was added in small portions. The mixture was stirred for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (90% purity, 17.1 g, 92.5 mmol) was added. The mixture was stirred at room temperature for 1 hr and then extracted with chloroform and aqueous ammonium chloride solution. The organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified through ISCO flash column chromatography (220 g silica gel, ethyl acetate in hexanes 5% to 40% in 25 minutes). The fractions with a slightly larger Rf as the major component were evaporated and then crystallized from 7% ethyl acetate in hexanes to give a white crystalline pure compound as 1N-trimethylsilylethoxymethyl-5-amino-4-cyanopyrazole (3.75 g). The fractions with a slightly lower Rf as the major component were evaporated and then crystallized from 4% ethyl acetate in hexanes to give a pure crystalline compound as 1N-trimethylsilylethoxymethyl-3-amino-4-cyanopyrazole (3.50 g). The mother liquor and fractions containing both components were combined and evaporated to give a mixture (7.4 g, total yield for this step 67%). For 1N-trimethylsilylethoxymethyl-5-amino-4-cyanopyrazole: LC/MS calcd for C10H18N4OSi (m/e) 238.12, obsd 237.2 (M−H, ES−); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (s, 9H), 0.82 (t, J=8.0 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H), 5.24 (s, 2H) 6.80 (s, 2H) 7.58 (s, 1H); For 1N-trimethylsilylethoxymethyl-3-amino-4-cyanopyrazole: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (s, 9H), 0.83 (t, J=8.0 Hz, 2H), 3.51 (t, J=8.0 Hz, 2H), 5.15 (s, 2H), 5.65 (s, 2H), 8.28 (s, 1H).