Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[O:4]=[C:5]([N:25]1[CH2:29][C:28]2=[CH:30][O:31][CH:32]=[C:27]2[CH2:26]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9].[OH-].[Na+]>O1CCCC1.O>[O:4]=[C:5]([N:25]1[CH2:26][C:27]2=[CH:32][O:31][CH:30]=[C:28]2[CH2:29]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OCc1ccccc1)C(CC(=O)N1Cc2cocc2C1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC(=O)N1Cc2cocc2C1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
10 ml of ethanol are added to a solution of 1 g (2.56 mmol) of phenylmethyl γ-oxo-α(R,S)-(phenylmethyl)-5,6-dihydro-4H-furo[3,4-c]pyrrole-5-butanoate in 10 ml of tetrahydrofuran followed, at 0° C., by a solution of 0.308 g (7.7 mmol) of sodium hydroxide in 10 ml of water. The mixture is stirred for 2 h at 0° C., and then for 2 h at room temperature. The solution obtained is concentrated, 30 ml of water are added and the solution is washed with twice 35 ml of diethyl ether. The aqueous phase is cooled, and then a 2M solution of hydrochloric acid is added to pH 2. The precipitate formed is filtered, it is washed with twice 20 ml of water and it is dried under vacuum. 0.47 g of a white solid is obtained. Yield 61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2([OH:27])[CH2:18][CH2:17][CH:16]([O:19][Si](C(C)(C)C)(C)C)[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2([OH:27])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)C1(O)CCC(O[Si](C)(C)C(C)(C)C)CC1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)C1(O)CCC(O)CC1)c1ccc(F)cc1
Yield: 26.5 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-1-hydroxy-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Intermediate 80, 700 mg) was treated with 1.0M TBAF in THF (3.0 ml) for 16 hours. The reaction was concentrated to reduce the volume of THF, then diluted with ethyl acetate. The organic layer was washed once with water followed by brine, then filtered and dried over sodium sulfate. The resulting residue was suspended in a minimum of dichloromethane and the resulting precipitate was isolated by filtration to yield a single diastereomer of 1,4-dihydroxy-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (132 mg). MS MH+ 282.4
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]3[N:30]=[C:29]([C:31]4[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][N:26]=3)[CH:18]=2)=[O:15])=[CH:12][CH:11]=1.C(OCC)(=O)C>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:18]=3)=[O:15])=[CH:38][CH:39]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Temperature: 10 °C
Reaction time: 15 h

Procedure:
N-Methylpiperazine (99 mg, 1.0 mmol) is added to a stirred suspension of 4-chloromethyl-N-[4-methyl-3-[[4-(1-oxido-3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]-benzamide (220 mg, 0.49 mmol) In ethanol (5 mL). The mixture is then stirred at 10° C. for 15 h to give a solution, which is then cooled to RT and treated with ethyl acetate (200 mL). The resulting solution is washed with aqueous sodium hydroxide (100 mL of 2M) and saturated aqueous sodium chloride solution (100 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 25% aqueous ammonia-methanol-dichloromethane (0.5:10:90) to give the title compound as a yellow crystalline solid, m.p. 232-235° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12](O)(=[O:15])[CH:13]=[CH2:14]>CS(O)(=O)=O>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:12](=[O:15])[CH2:13][CH2:14]2
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(=O)O
Agent: CS(=O)(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(=O)O2
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of trimethyl-hydroquinone (3.04 g) and acrylic acid (1.44 g) was added methyl-sulfonic acid (30 mL). The mixture was heated slowly up to 100° C. under nitrogen. The reaction mixture was stirred at 100° C. for 1 hour. The solution was poured into ice, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water solution, water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 10% to 25%) gave 1.77 g of 6-hydroxy-5,7,8-trimethyl-chroman-2-one.
Reaction SMILES: Cl.[CH3:2][C@:3]1([N:8]2[C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4]1.[C:30]([O:34][C:35]([NH:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:30]([O:34][C:35](=[O:36])[NH:37][C:38]([CH3:43])([CH3:42])[C:39]([N:5]1[CH2:6][CH2:7][C@@:3]([N:8]2[C:12]3[N:13]=[C:14]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)([CH3:2])[CH2:4]1)=[O:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: C[C@]1(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC[C@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
To a mixture of the product of Example 4, Step 2, 5-{7-[(3S)-3-methylpyrrolidin-3-yl]-2-(morpholin-4-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (˜1.0 g, ˜1.77 mmol), 2-tert-butoxycarbonylamino-2-methyl-propionic acid (504 mg, 2.48 mmol) and DIEA (2.16 mL, 12.4 mmol) in 10 mL NMP, was added HATU (1.0 g, 2.67 mmol). The reaction was covered with foil and stirred at room temperature for 18 h. The reaction mixture was dropped into aqueous NaHCO3 and the resulting precipitate was collected by filtration. The filtrate was extracted with DCM (3 times). The filtrate and solids were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by Biotage (40-FM cartridge) using a gradient of 0-10% MeOH/EtOAc as eluent to give the title compound (771 mg, 76%) as a foamy solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 8.73 (s, 2 H), 6.71-6.54 (m, 3 H), 4.06-3.83 (m, 2 H), 3.70-3.41 (m, 12 H), 3.08 (t, J=8.1 Hz, 2 H), 2.47-2.35 (m, 1H, partially overlapped with DMSO), 2.10-2.01 (m, 1 H), 1.39-1.28 (m, 18 H). m/z (APCI+) for C28H41CN9O4568.3 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(Cl)(Cl)Cl>[C:4]([O:22][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
N,N'-bis-BOC-Ornithine tert-Butyl Ester (22) was synthesized from N,N'-bis-BOC-ornithine (12) according to the general procedure : yield, 86%; mp 80°-82° C.; [α]25D+11.3° (c 1.3, CHCl3); 1H NMR δ 5.07 (br d, 1H, J=7.8), 4.63 (m, 1H), 4.16 (t, 1H, J=6.9), 3.14 (t, 2H, J=6.0), 1.82-150 (m, 4H), 1 .45 (s, 9H), 1.43 (s, 18H). Anal. Calcd for C19H36N2O6 : C, 58.7; H, 9.3,; N, 7.2. Found: C, 58.7; H, 9.7; N, 7.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[CH3:12][C:13](=O)CC(=O)C>C(O)C.Cl>[CH3:12][C:13]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[N:11]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
3-Nitrobenzene-1,2-diamine (1.0 g) was dissolved in ethanol (90 mL) and 5N hydrochloric acid (24 mL), and to this solution was added 2,4-pentanedione (1.3 g). The mixture was heated for 3 hours under reflux, cooled down to room temperature and concentrated. To this concentrate was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium bicarbonate and water, and dried over sodium sulfate to give the title compound (1.1 g).
Reaction SMILES: O.[NH2:2][NH2:3].C(O)CCC.Cl[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1>CCO>[F:16][C:13]1[CH:14]=[CH:15][C:10]([NH:2][NH2:3])=[N:11][CH:12]=1
Reactant: NN
Reactant: Fc1ccc(Cl)nc1
Solvent: CCCCO
Solvent: O
Solvent: CCO
Product: NNc1ccc(F)cn1

Procedure:
To a mixture of hydrazine monohydrate (14.75 mL, 304 mmol) and 1-butanol (10 mL) was added 2-chloro-5-fluoropyridine (5.00 g, 38.0 mmol). The solution was microwaved in a sealed, thick-walled glass tube at 180° C. for 1 h. The resulting white suspension was transferred with EtOH to a round bottom flask then concentrated. The resulting white solid was taken up in ethyl acetate (250 mL) and the insoluble material removed by filtration. The filtrate was concentrated to give the title compound a pale orange solid. This solid was used in the following step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12](C#N)=[CH:13][CH:14]=3)C=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN(C1C=CC=CC=1)C1C=CC(C#N)=CC=1.CCC=S>>[CH2:2]1[C:1]2[NH:7][C:15]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(ccn2-c2ccccc2)c1
Agent: CCC=S
Agent: N#Cc1ccc(N(Cl)c2ccccc2)cc1
Product: c1ccc2c3c([nH]c2c1)CCCC3

Procedure:
N-phenyl-5-cyanoindole from N-chloro-N-phenyl-4-cyanoaniline and methylthioacetaldehyde;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][O:44][NH:45][CH3:46]>CN(C=O)C>[CH3:43][O:44][N:45]([CH3:46])[C:8]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: CNOC
Reactant: Nc1nccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-aminopyrazine-2-carboxylic acid (1 g, 7.2 mmol) in DMF (15 ml) is added EDC hydrochloride (1.7 g, 8.6 mmol), HOBt (1.16 g, 8.6 mmol), diisopropylethylamine (3.08 ml, 18 mmol) and N-methoxy-N-methylamine hydrochloride (0.84 g, 8.6 mmol), and the resulting solution is stirred at room temperature for 15 hours. The reaction is concentrated in vacuo, and sat. aq. NaHCO3 (50 ml) is added to the residue. The product is extracted into EtOAc (3×60 ml), washed with sat. aq. NaCl (2×50 ml), dried (MgSO4) and concentrated in vacuo to afford a yellow residue. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]1[O:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:14][CH:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[OH:15])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(OCc2ccccc2)cc1
Yield: 59.1 %

Procedure:
By the same procedure as in Example 26-B), while using (2S)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (1.50 g) and 4-(benzyloxy)phenol (2.96 g), there was obtained 1.72 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[CH2:1]([C:3]1([C:20]2[C:19]3[C:23](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=3)[NH:22][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Fc1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(F)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-fluoroindole, the title compound is prepared as in example 1. 217 mg (92%). NMR (400 MHz, CDCl3): δ 0.85 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.31 (m, 1H), 2.58 (m, 1H), 2.97 (m, 2H), 6.83 (m, 4H), 6.98 (m, 3H), 8.06 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN(C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 14 h
Yield: 72.5 %

Procedure:
A solution of compound 112 (0.43 g, 1.506 mmol) in dry ethanol (5 mL) was treated with 10% Pd—C (0.04 g) and purged with hydrogen gas at room temperature. The reaction was stirred at the same temperature under a hydrogen atmosphere (balloon pressure) overnight (14 h). The reaction was filtered through a celite bed and washed with dry ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.85 g, 3.013 mmol) at room temperature and stirred for 24 h. The solvent was evaporated and crude material was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 116 (0.4 g, 72%, over two steps) as a yellow solid. mp 104-106° C.; 1H NMR (DMSO-d6) δ: 1.39-1.60 (m, 3H), 1.66-1.72 (m, 1H), 1.82-1.94 (m, 3H), 2.05-2.08 (m, 1H), 2.23 (s, 3H), 2.34 (s, 3H), 2.64-2.71 (m, 1H), 2.91-2.96 (m, 1H), 6.48 (brs, 1H), 6.64 (dd, 1H, J=1.5, 8.4 Hz), 6.99-7.05 (m, 2H), 7.10 (t, 1H, J=4.2 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.60 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.57 (s, 1H); ESI-MS m/z (%): 367 (MH+, 31), 322 (18), 184 (100); ESI-HRMS calculated for C21H27N4S (MH+), Calculated: 367.1965; Observed: 367.1950.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[CH:14]=[O:15])[CH3:2].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[CH:14]([OH:15])[CH3:16])[CH3:2]
Reactant: CCc1c(C=O)cnn1-c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1c(C(C)O)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. solution of 7.55 (37.7 mmol) of 5-ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (Example 86) in anhydrous THF (100 mL) under N2 was added over 5 minutes 15.7 (47.1 mmol) of 3.0 M MeMgBr in Et2O. The mixture was warmed to room temperature and stirred for 16 h, then 25 mL of 5% NH4Cl was added and the mixture was extracted with CH2Cl2 (70 mL), and the extract was washed with saturated NaCl (15 mL). The organic layer separated, dried over MgSO4, and concentrated to give 1-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-ethanol (7.91 g). ESI MS m/z 217 [C13H16N2O+H]+.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[K+].[CH2:10](Br)[C:11]#[CH:12]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:12]([N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[O:3])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=C1CNC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCN1C(=O)CNC1=O
Temperature: 75 °C
Yield: 60.1 %

Procedure:
To a solution of hydantoin (10 g, 100 mmol) in THF (150 mL) add tetrabutylammonium bromide (4 g, 12.3 mmol), potassium hydroxide (5.6 g, 100 mmol) and then propargyl bromide (11.9 g, 100 mmol). Heat the mixture to 75° C. for 18 h. Dilute the mixture with EtOAc (200 mL), wash with water (2×100 mL) and 1N aqueous HCl (100 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow powder (8.3 g, 60%). Triturate the solid with diethyl ether (100 mL) to obtain the title compound as a white crystalline solid (7.8 g, 56%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[CH3:15][C:13]1[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=[C:9]([NH2:8])[N:14]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cncc(C)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(Nc2ncccc2-c2nc(C)nc(N)n2)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-methyl-6-(2-(5-methylpyridin-3-ylamino)pyridin-3-yl)-1,3,5-triazin-2-amine (0.063 g, 0.118 mmol) in TFA (3.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and was concentrated to about 50% of the original volume. The remaining mixture was pipetted carefully into a saturated solution of NaHCO3, which had been cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The material was suspended in DMSO (5 mL) and water (10 drops) was added. The solid was collected by filtration to give 4-methyl-6-(2-(5-methylpyridin-3-ylamino)pyridin-3-yl)-1,3,5-triazin-2-amine (0.0137 g, 0.047 mmol, 39.6% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 11.96-12.04 (m, 1H); 8.81 (br. s., 2H); 8.39 (br. s., 1H); 8.23 (br. s., 1H); 8.05 (s, 1H); 7.89 (br. s., 1H); 7.77 (br. s., 1H); 6.96 (br. s., 1H); 2.45 (br. s., 3H); 2.32 (s, 3H). m/z (ESI, +ve ion) 294.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:27][C:28]1([CH3:38])[O:33][CH2:32][C:31]([CH3:37])([C:34](O)=[O:35])[CH2:30][O:29]1>>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH2:12][C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([C:34]([C:31]3([CH3:37])[CH2:30][O:29][C:28]([CH3:38])([CH3:27])[O:33][CH2:32]3)=[O:35])[CH2:10][CH2:11]2)(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Yield: 79.1 %

Procedure:
Ethyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylicacid ethyl ester (0.333 g, 0.8 mmol) and 2,2,5-trimethyl-(1,3)dioxane-5-carboxylic acid (0.168 g, 0.96 mmol), 0.339 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 536.1 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH:18]1[CH2:20][CH2:19]1)C.[OH-].[K+]>C(O)CO.O>[CH:18]1([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:10]([CH3:11])[C:5]=2[C:4]([OH:21])=[O:3])[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)O
Temperature: 155 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (0.54 g, 1.86 mmol) in ethylene glycol (10 ml) is added solid potassium hydroxide (0.42 g, 7.47 mmol) and the mixture is stirred at 150-160° C. for 16 h. After completion of the reaction, the mixture is diluted with water (30 ml) and extracted with ethyl acetate (2×10 ml). The aqueous layer is acidified with 2M HCl to pH 3 and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (3×40 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid (0.34 g, 1.3 mmol, 70%).
Reaction SMILES: [C:1]([O:4][C:5]1([C:18]([OH:20])=O)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CCN(CC)CC.CCN(C(C)C)C(C)C.[CH3:37][NH:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C=O)C>[CH2:11]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:1](=[O:3])[CH3:2])([C:18](=[O:20])[N:38]([CH3:37])[C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:47])([F:48])[F:49])=[CH:41][CH:40]=2)[CH2:10][CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1(C(=O)O)CCN(Cc2ccccc2)CC1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC1(C(=O)N(C)c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of 1.4 g (5 mmol) 4-acetoxy-1-benzyl-piperidine-4-carboxylic acid 0.49 mL (5.8 mmol) oxalylchloride, cat. amount DMF and 2.1 mL (15 mmol) NEt3 in DCM at 0° C. was stirred for 1 h. The mixture was concentrated and to 0.79 g (2.42 mmol) of the acid chloride and 2.1 mL (12.1 mmol) DIPEA in 25 mL DCM was added 0.554 g (2.9 mmol) methyl-(4-trifluoromethoxy-phenyl)-amine. The mixture was stirred for 15 h at room temperature. KHSO4 (1N) was added and the mixture was extracted with DCM. The combined organic extracts were dried with MgSO4 and evaporated. 0.782 g (72%) of the title compounds as obtained. MS (m/e): 451.3 [(M+H)+].